IMULDOSA 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.

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

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

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

Subcutaneous Adult Dosage Regimen

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

The recommended dose of IMULDOSA for pediatric patients (6-17 years old) with plaque psoriasis based on body weight is shown below (Table 1).

Table 1: Recommended Dose of IMULDOSA for Subcutaneous Injection in Pediatric Patients (6-17 years old) with Plaque Psoriasis

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="0"> <col width=""/> <col width=""/> <tfoot> <tr class="First Last"> <td colspan="2">There is no dosage form for IMULDOSA that allows weight-based dosing for pediatric patients below 60 kg.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"> <br/> <span class="Bold">Body Weight of Patient at the Time of Dosing</span></td><td align="center" class="Rrule" valign="middle"> <br/> <span class="Bold">Recommended Dose</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"> <br/>  60 kg to 100 kg </td><td align="center" class="Rrule" valign="middle"> <br/>  45 mg </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle"> <br/>  more than 100 kg </td><td align="center" class="Rrule" valign="middle"> <br/>  90 mg </td> </tr> </tbody> </table></div>

Subcutaneous Adult Dosage Regimen

Subcutaneous Pediatric Dosage Regimen

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

The recommended dose of IMULDOSA for pediatric patients (6 to 17 years old) with psoriatic arthritis, based on body weight, is shown below (Table 2).

Table 2: Recommended Dose of IMULDOSA for Subcutaneous Injection in Pediatric Patients (6 to 17 years old) with Psoriatic Arthritis

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="0"> <col width=""/> <col width=""/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"> <br/> <span class="Bold">Body Weight of Patient at the Time of Dosing </span></td><td align="center" class="Rrule" valign="middle"> <br/> <span class="Bold">Recommended Dose</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"> <br/>  60 kg or more </td><td align="center" class="Rrule" valign="middle"> <br/>  45 mg </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle"> <br/>  greater than 100 kg with co-existent moderate- to-severe plaque psoriasis </td><td align="center" class="Rrule" valign="middle"> <br/>  90 mg </td> </tr> </tbody> </table></div>

Intravenous Induction Adult Dosage Regimen

A single intravenous infusion dose of IMULDOSA using the weight-based dosage regimen specified in Table 3 [ see Instructions for dilution of IMULDOSA 130 mg vial for intravenous infusion ( 2.6)].

Table 3: Initial Intravenous Dosage of IMULDOSA

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="0"> <col width=""/> <col width=""/> <col width=""/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"> <br/> <span class="Bold">Body Weight of Patient at the time of dosing</span></td><td align="center" class="Rrule" valign="middle"> <br/> <span class="Bold">Dose </span></td><td align="center" class="Rrule" valign="middle"> <br/> <span class="Bold">Number of 130 mg/26 mL (5 mg/mL) IMULDOSA vials</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"> <br/>  55 kg or less </td><td align="center" class="Rrule" valign="middle"> <br/>  260 mg </td><td align="center" class="Rrule" valign="middle"> <br/> 2 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"> <br/>  more than 55 kg to 85 kg </td><td align="center" class="Rrule" valign="middle"> <br/>  390 mg </td><td align="center" class="Rrule" valign="middle"> <br/> 3 </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle"> <br/>  more than 85 kg </td><td align="center" class="Rrule" valign="middle"> <br/>  520 mg </td><td align="center" class="Rrule" valign="middle"> <br/> 4 </td> </tr> </tbody> </table></div>

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.

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.

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

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.

IMULDOSA (ustekinumab-srlf) is a clear to slightly opalescent and colorless to slightly yellow solution.

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Subcutaneous Injection

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{ "type": "ul", "children": [ "Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe" ], "text": "" }

Intravenous Infusion

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{ "type": "ul", "children": [ "Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial" ], "text": "" }

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

{ "type": "p", "children": [], "text": "IMULDOSA is contraindicated in patients with clinically significant hypersensitivity to ustekinumab products or to any of the excipients in IMULDOSA[\n \n see Warnings and Precautions (\n \n 5.5)\n \n ].\n\n " }

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

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

Avoid initiating treatment with IMULDOSA 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 IMULDOSA 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 IMULDOSA and discontinue IMULDOSA for serious or clinically significant infections until the infection resolves or is adequately treated.

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

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

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

Ustekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies were reported among subjects who received ustekinumab in clinical studys   [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 products 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 products who had pre-existing risk factors for developing non-melanoma skin cancer. Monitor all patients receiving IMULDOSA 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)] .

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

Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical studys. 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 product initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab products.

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

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

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

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

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

Adult Subjects with Plaque Psoriasis

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

Table 4 summarizes the adverse reactions that occurred at a rate of at least 1% with higher rates in the ustekinumab groups during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 ( 14) .

Table 4: Adverse Reactions, Reported by ≥1% of Subjects with Plaque Psoriasis and at Higher Rates in the Ustekinumab groups through Week 12 in Ps STUDY 1 and Ps STUDY 2

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="681"> <col width="32.8305582761998%"/> <col width="29.2752203721841%"/> <col width="19.5200783545544%"/> <col width="18.3741429970617%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="2" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Ustekinumab</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Placebo</span></td><td align="center" class="Rrule" valign="top"> <br/> 45 mg </td><td align="center" class="Rrule" valign="top"> <br/> 90 mg </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Subjects treated</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">665</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">664</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">666</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Nasopharyngitis </td><td align="center" class="Rrule" valign="top"> <br/> 51 (8%) </td><td align="center" class="Rrule" valign="top"> <br/> 56 (8%) </td><td align="center" class="Rrule" valign="top"> <br/> 49 (7%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Upper respiratory tract infection </td><td align="center" class="Rrule" valign="top"> <br/> 30 (5%) </td><td align="center" class="Rrule" valign="top"> <br/> 36 (5%) </td><td align="center" class="Rrule" valign="top"> <br/> 28 (4%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Headache </td><td align="center" class="Rrule" valign="top"> <br/> 23 (3%) </td><td align="center" class="Rrule" valign="top"> <br/> 33 (5%) </td><td align="center" class="Rrule" valign="top"> <br/> 32 (5%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Fatigue </td><td align="center" class="Rrule" valign="top"> <br/> 14 (2%) </td><td align="center" class="Rrule" valign="top"> <br/> 18 (3%) </td><td align="center" class="Rrule" valign="top"> <br/> 17 (3%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Diarrhea </td><td align="center" class="Rrule" valign="top"> <br/> 12 (2%) </td><td align="center" class="Rrule" valign="top"> <br/> 13 (2%) </td><td align="center" class="Rrule" valign="top"> <br/> 13 (2%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Back pain </td><td align="center" class="Rrule" valign="top"> <br/> 8 (1%) </td><td align="center" class="Rrule" valign="top"> <br/> 9 (1%) </td><td align="center" class="Rrule" valign="top"> <br/> 14 (2%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Dizziness </td><td align="center" class="Rrule" valign="top"> <br/> 8 (1%) </td><td align="center" class="Rrule" valign="top"> <br/> 8 (1%) </td><td align="center" class="Rrule" valign="top"> <br/> 14 (2%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Pharyngolaryngeal pain </td><td align="center" class="Rrule" valign="top"> <br/> 7 (1%) </td><td align="center" class="Rrule" valign="top"> <br/> 9 (1%) </td><td align="center" class="Rrule" valign="top"> <br/> 12 (2%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Pruritus </td><td align="center" class="Rrule" valign="top"> <br/> 9 (1%) </td><td align="center" class="Rrule" valign="top"> <br/> 10 (2%) </td><td align="center" class="Rrule" valign="top"> <br/> 9 (1%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Injection site erythema </td><td align="center" class="Rrule" valign="top"> <br/> 3 (&lt;1%) </td><td align="center" class="Rrule" valign="top"> <br/> 6 (1%) </td><td align="center" class="Rrule" valign="top"> <br/> 13 (2%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Myalgia </td><td align="center" class="Rrule" valign="top"> <br/> 4 (1%) </td><td align="center" class="Rrule" valign="top"> <br/> 7 (1%) </td><td align="center" class="Rrule" valign="top"> <br/> 8 (1%) </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Depression </td><td align="center" class="Rrule" valign="top"> <br/> 3 (&lt;1%) </td><td align="center" class="Rrule" valign="top"> <br/> 8 (1%) </td><td align="center" class="Rrule" valign="top"> <br/> 4 (1%) </td> </tr> </tbody> </table></div>

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 adult plaque psoriasis clinical trials [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 placebo-treated subjects and 13.4 weeks for ustekinumab-treated subjects), 27% of ustekinumab-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in 0.3% of ustekinumab-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) [see Warnings and Precautions ( 5.1)] .

In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of ustekinumab-treated subjects reported infections (0.87 per subject-years of follow- up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up).

Malignancies

In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years, representing 8998 subject-years of exposure), 1.7% of ustekinumab-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of ustekinumab-treated subjects (0.52 per hundred subject- 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 ustekinumab-treated patients 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 ustekinumab was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects (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 ustekinumab was assessed in 927 subjects in two randomized, double- blind, placebo-controlled trials in adults with active psoriatic arthritis (PsA). The overall safety profile of ustekinumab in subjects with PsA was consistent with the safety profile seen in adult psoriasis clinical trials. A higher incidence of arthralgia, nausea, and dental infections was observed in ustekinumab-treated subjects when compared with placebo-treated subjects (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo- controlled portions of the PsA clinical trials.

Crohn’s Disease

The safety of ustekinumab was assessed in 1407 subjects with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] greater than or equal to 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 ustekinumab 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 ustekinumab every 8 weeks, or placebo for 44 weeks in trial CD-3. Subjects in these 3 trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX)], oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn’s disease [see Clinical Studies ( 14.4)] .

The overall safety profile of ustekinumab was consistent with the safety profile seen in the adult psoriasis and psoriatic arthritis clinical trials. Common adverse reactions in trials CD-1 and CD-2 and in trial CD-3 are listed in Tables 5 and 6, respectively.

Table 5: Common adverse reactions through Week 8 in trials CD-1 and CD-2 occurring in ≥3% of ustekinumab-treated subjects and higher than placebo

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="698.383"> <col width="31.1274043039421%"/> <col width="34.3553608836412%"/> <col width="34.5172348124167%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Placebo</span> <br/> <span class="Bold">N=466</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Ustekinumab</span> <br/> <span class="Bold">6 mg/kg single intravenous induction dose</span> <br/> <span class="Bold">N=470</span></td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Vomiting </td><td align="center" class="Rrule" valign="top"> <br/> 3% </td><td align="center" class="Rrule" valign="top"> <br/> 4% </td> </tr> </tbody> </table></div>

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 6: Common adverse reactions through Week 44 in trial CD-3 occurring in ≥3% of ustekinumab-treated subjects and higher than placebo

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="738.549"> <col width="33.3333333333333%"/> <col width="33.3333333333333%"/> <col width="33.3333333333333%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Placebo</span> <br/> <span class="Bold">N=133</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Ustekinumab</span><span class="Bold">90 mg subcutaneous maintenance dose every 8 weeks</span> <br/> <span class="Bold">N=131</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Nasopharyngitis </td><td align="center" class="Rrule" valign="top"> <br/> 8% </td><td align="center" class="Rrule" valign="top"> <br/> 11% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Injection site erythema </td><td align="center" class="Rrule" valign="top"> <br/> 0 </td><td align="center" class="Rrule" valign="top"> <br/> 5% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Vulvovaginal candidiasis/mycotic infection </td><td align="center" class="Rrule" valign="top"> <br/> 1% </td><td align="center" class="Rrule" valign="top"> <br/> 5% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Bronchitis </td><td align="center" class="Rrule" valign="top"> <br/> 3% </td><td align="center" class="Rrule" valign="top"> <br/> 5% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Pruritus </td><td align="center" class="Rrule" valign="top"> <br/> 2% </td><td align="center" class="Rrule" valign="top"> <br/> 4% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Urinary tract infection </td><td align="center" class="Rrule" valign="top"> <br/> 2% </td><td align="center" class="Rrule" valign="top"> <br/> 4% </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Sinusitis </td><td align="center" class="Rrule" valign="top"> <br/> 2% </td><td align="center" class="Rrule" valign="top"> <br/> 3% </td> </tr> </tbody> </table></div>

Infections

In patients 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 patient 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 ustekinumab-treated subjects (0.36 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per hundred patient-years) developed non- melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.2% of ustekinumab-treated subjects (0.27 events per hundred patient- years) and in none of the placebo-treated subjects.

Hypersensitivity Reactions Including Anaphylaxis

In CD trials, two patients reported hypersensitivity reactions following ustekinumab administration. One patient experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness of breath, and flushing) after a single subcutaneous administration (0.1% of patients receiving subcutaneous ustekinumab). In addition, one patient experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body temperature) after the initial intravenous ustekinumab dose (0.08% of patients receiving intravenous ustekinumab). These patients were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour.

Ulcerative Colitis 

The safety of ustekinumab was evaluated in two randomized, double-blind, placebo- controlled clinical trials (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to severely active ulcerative colitis [ see Clinical Studies ( 14.5) ]. The overall safety profile of ustekinumab in patients with ulcerative colitis was consistent with the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of ustekinumab-treated subjects and at a higher rate than placebo were:

Infections

In patients with ulcerative colitis, serious or other clinically significant infections included gastroenteritis and pneumonia. In addition, listeriosis and ophthalmic herpes zoster were reported in one patient each   [see Warnings and Precautions (5.1)].

Malignancies

With up to one year of treatment in the ulcerative colitis clinical trials, 0.4% of ustekinumab-treated subjects (0.48 events per hundred patient-years) and 0.0% of placebo-treated subjects (0.00 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.5% of ustekinumab-treated subjects (0.64 events per hundred patient- years) and 0.2% of placebo-treated subjects (0.40 events per hundred patient-years).

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ustekinumab or of other ustekinumab products.

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.

The following adverse reactions have been reported during post-approval use of ustekinumab products. 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 product exposure.

Immunesystemdisorders: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.

Skinreactions:Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis.

In plaque psoriasis trials the safety of ustekinumab products 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.

The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, ustekinumab products, antagonists of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation of IMULDOSA in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and adjust the individual dose of the drug as needed.  [see Clinical Pharmacology ( 12.3)].

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

Risk Summary

Limited data from observational studies, published case reports, and postmarketing surveillance on the use of ustekinumab products during pregnancy are insufficient to inform a drug associated risk of major birth defects, miscarriage, and other adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore, ustekinumab products may be transferred to the developing fetus (see Clinical Considerations).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).

The background risk of major birth defects and miscarriage for the indicated population(s) are unknown. 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

Fetal/Neonatal Adverse Reactions

Because ustekinumab products may theoretically interfere with immune response to infections, consider risks and benefits prior to administering live vaccines to infants exposed to IMULDOSA in utero. There are insufficient data regarding exposed infant serum levels of ustekinumab products at birth and the duration of persistence of ustekinumab products in infant serum after birth. Although a specific timeframe to delay administration of live attenuated vaccines in infants exposed in utero is unknown, consider the risks and benefits of delaying a minimum of 6 months after birth because of the clearance of the product.

Data

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.

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 products on milk production. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ustekinumab products are unknown. No adverse effects on the breastfed infant causally related to ustekinumab products 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 IMULDOSA and any potential adverse effects on the breastfed child from IMULDOSA or from the underlying maternal condition.

Plaque Psoriasis

The safety and effectiveness of IMULDOSA have been established for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 to 17 years of age who are candidates for phototherapy or systemic therapy.

Use of IMULDOSA 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) of ustekinumab 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 IMULDOSA 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) of ustekinumab in 44 subjects [see Adverse Reactions (6.1), Pharmacokinetics (12.3)].

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

Psoriatic Arthritis

The safety and effectiveness of IMULDOSA have been established for treatment of psoriatic arthritis in pediatric patients 6 to 17 years old.

Use of IMULDOSA in these age groups is supported by evidence from adequate and well controlled trials of ustekinumab in adults with psoriasis and PsA, pharmacokinetic data from adult patients with psoriasis, adult patients with PsA and pediatric patients with psoriasis, and safety data of ustekinumab from two clinical trials in 44 pediatric patients 6 to 11 years old with psoriasis and 110 pediatric patients 12 to 17 years old with psoriasis. The observed pre-dose (trough) concentrations are generally comparable between adult patients with psoriasis, adult patients with PsA and pediatric patients with psoriasis, and the PK exposure is expected to be comparable between adult and pediatric patients with PsA   [see Adverse Reactions (6.1),ClinicalPharmacology(12.3),and ClinicalStudies(14.1,14.2,14.3)].

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

Of the 6709 patients exposed to ustekinumab, a total of 340 were 65 years of age or older (183 patients with plaque psoriasis, 65 patients with psoriatic arthritis, 58 patients with Crohn’s disease and 34 patients with ulcerative colitis), and 40 patients were 75 years of age or older. Clinical trials of ustekinumab did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity. In case of overdosage, monitor the patient for any signs or symptoms of adverse reactions or effects and institute appropriate symptomatic treatment immediately. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

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

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

IMULDOSA (ustekinumab-srlf) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution with pH of 5.7- 6.3.

{ "type": "p", "children": [], "text": "IMULDOSA (ustekinumab-srlf) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution with pH of 5.7- 6.3." }

IMULDOSA for Subcutaneous Use

{ "type": "p", "children": [], "text": "\nIMULDOSA for Subcutaneous Use\n" }

Available as 45 mg of ustekinumab-srlf in 0.5 mL and 90 mg of ustekinumab-srlf in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 29-gauge fixed ½ inch needle. The syringe is fitted with a passive needle guard and a needle cover that does not contains latex.

{ "type": "p", "children": [], "text": "Available as 45 mg of ustekinumab-srlf in 0.5 mL and 90 mg of ustekinumab-srlf in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 29-gauge fixed ½ inch needle. The syringe is fitted with a passive needle guard and a needle cover that does not contains latex." }

Each 0.5 mL prefilled syringe delivers 45 mg ustekinumab-srlf, histidine (2.23 mg) and L-histidine hydrochloride monohydrate (4.14 mg), polysorbate 80 (0.02 mg), and sucrose (25.9 mg).

{ "type": "p", "children": [], "text": "Each 0.5 mL prefilled syringe delivers 45 mg ustekinumab-srlf, histidine (2.23 mg) and L-histidine hydrochloride monohydrate (4.14 mg), polysorbate 80 (0.02 mg), and sucrose (25.9 mg)." }

Each 1 mL prefilled syringe delivers 90 mg ustekinumab-srlf, histidine (4.46 mg) and L-histidine hydrochloride monohydrate (8.28 mg), polysorbate 80 (0.04 mg), and sucrose (51.8 mg).

{ "type": "p", "children": [], "text": "Each 1 mL prefilled syringe delivers 90 mg ustekinumab-srlf, histidine (4.46 mg) and L-histidine hydrochloride monohydrate (8.28 mg), polysorbate 80 (0.04 mg), and sucrose (51.8 mg)." }

IMULDOSA for Intravenous Infusion

{ "type": "p", "children": [], "text": "\nIMULDOSA for Intravenous Infusion\n" }

Available as 130 mg of ustekinumab-srlf in 26 mL, supplied as a single-dose 30 mL Type I glass vial with a coated stopper.

{ "type": "p", "children": [], "text": "Available as 130 mg of ustekinumab-srlf 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-srlf, edetate disodium (0.52 mg), histidine (20 mg), L-histidine hydrochloride monohydrate (27 mg), methionine (10.4 mg), Polysorbate 80 (10.4 mg) and sucrose (2,210 mg).

{ "type": "p", "children": [], "text": "Each 26 mL vial delivers 130 mg ustekinumab-srlf, edetate disodium (0.52 mg), histidine (20 mg), L-histidine hydrochloride monohydrate (27 mg), methionine (10.4 mg), Polysorbate 80 (10.4 mg) and sucrose (2,210 mg)." }

Ustekinumab products are human IgG1κ monoclonal antibodies that bind with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab products were shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn’s disease and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab products, was shown to be protective.

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)].

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 maxvalue (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in subjects with plaque psoriasis.

Following multiple subcutaneous doses of ustekinumab in adult subjects with plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state trough serum ustekinumab concentrations were 0.69 ± 0.69 mcg/mL for patients less than or equal to 100 kg receiving a 45 mg dose and 0.74 ± 0.78 mcg/mL for patients 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 patients with Crohn’s disease, and 129.1 ± 27.6 mcg/mL in patients 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 patients with Crohn’s disease, and 3.3 ± 2.3 mcg/mL in patients 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 patients with Crohn’s disease and 3.0 L (95% CI: 2.96, 3.07) in patients with ulcerative colitis. The total volume of distribution at steady-state was 4.6 L in patients with Crohn’s disease and 4.4 L in patients with ulcerative colitis.

Elimination

The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all plaque psoriasis trials following subcutaneous administration. Population pharmacokinetic analyses showed that the clearance of ustekinumab was 0.19 L/day (95% CI: 0.185, 0.197) in patients with Crohn’s disease and 0.19 L/day (95% CI: 0.179, 0.192) in patients 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 patients with Crohn’s disease and ulcerative colitis.

Metabolism

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

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 patients 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 ustekinumab in pediatric subjects 6 to 17 years of age 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 to 17 years of age.

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

Drug Interaction Studies

The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4). However, the clinical relevance of in vitro data has not been established [see Drug Interactions ( 7.3)].

No in vivo drug interaction studies have been conducted with ustekinumab products.

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

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

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

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.

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.

Clinica Response

The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 7 below.

Table 7: Clinical Outcomes at week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="726.579"> <col width="14.3510891451583%"/> <col width="14.2870217829032%"/> <col width="14.2595643419367%"/> <col width="14.2687168222588%"/> <col width="14.2961742632253%"/> <col width="14.2687168222588%"/> <col width="14.2687168222588%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Week 12</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Ps STUDY 1</span> <br/> <span class="Bold">Ustekinumab</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Ps STUDY 2</span> <br/> <span class="Bold">Ustekinumab</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Placebo</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">45 mg</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">90 mg</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Placebo</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">45 mg</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">90 mg</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Subjects randomized</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">255</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">255</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">256</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">410</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">409</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">411</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> PASI 75 response </td><td align="center" class="Rrule" valign="top"> <br/> 8 (3%) </td><td align="center" class="Rrule" valign="top"> <br/> 171 (67%) </td><td align="center" class="Rrule" valign="top"> <br/> 170 (66%) </td><td align="center" class="Rrule" valign="top"> <br/> 15 (4%) </td><td align="center" class="Rrule" valign="top"> <br/> 273 (67%) </td><td align="center" class="Rrule" valign="top"> <br/> 311 (76%) </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top"> <br/>  PG <br/> A of Cleared or Minimal </td><td align="center" class="Rrule" valign="top"> <br/>  10 (4%) </td><td align="center" class="Rrule" valign="top"> <br/> 151 (59%)  </td><td align="center" class="Rrule" valign="top"> <br/> 156 (61%)  </td><td align="center" class="Rrule" valign="top"> <br/> 18 (4%)  </td><td align="center" class="Rrule" valign="top"> <br/> 277 (68%)  </td><td align="center" class="Rrule" valign="top"> <br/> 300 (73%)  </td> </tr> </tbody> </table></div>

Examination of age, gender, and race subgroups did not identify differences in response to ustekinumab 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 8 below).

Table 8: Clinical Outcomes by Weight Ps STUDY 1 and Ps STUDY 2

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="642"> <col width="30.3426791277259%"/> <col width="9.84423676012461%"/> <col width="12.1495327102804%"/> <col width="12.1495327102804%"/> <col width="11.214953271028%"/> <col width="12.1495327102804%"/> <col width="12.1495327102804%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Ps STUDY 1</span> <br/> <span class="Bold">Ustekinumab</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Ps STUDY 2</span> <br/> <span class="Bold">Ustekinumab</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Placebo</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">45 mg</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">90 mg</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Placebo</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">45 mg</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">90 mg</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Subjects randomized</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">255</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">255</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">256</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">410</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">409</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">411</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7" valign="top"> <br/> <span class="Bold"> PASI 75 response at Week 12* <br/> </span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> ≤100 kg </td><td align="center" class="Rrule" valign="top"> <br/> 4% </td><td align="center" class="Rrule" valign="top"> <br/> 74% </td><td align="center" class="Rrule" valign="top"> <br/> 65% </td><td align="center" class="Rrule" valign="top"> <br/> 4% </td><td align="center" class="Rrule" valign="top"> <br/> 73% </td><td align="center" class="Rrule" valign="top"> <br/> 78% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> 6/166 </td><td align="center" class="Rrule" valign="top"> <br/> 124/168 </td><td align="center" class="Rrule" valign="middle"> <br/> 107/164 </td><td align="center" class="Rrule" valign="top"> <br/> 12/290 </td><td align="center" class="Rrule" valign="top"> <br/> 218/297 </td><td align="center" class="Rrule" valign="top"> <br/> 225/289 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> &gt;100 kg </td><td align="center" class="Rrule" valign="top"> <br/> 2% </td><td align="center" class="Rrule" valign="top"> <br/> 54% </td><td align="center" class="Rrule" valign="top"> <br/> 68% </td><td align="center" class="Rrule" valign="top"> <br/> 3% </td><td align="center" class="Rrule" valign="top"> <br/> 49% </td><td align="center" class="Rrule" valign="top"> <br/> 71% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> 2/89 </td><td align="center" class="Rrule" valign="top"> <br/> 47/87 </td><td align="center" class="Rrule" valign="top"> <br/> 63/92 </td><td align="center" class="Rrule" valign="top"> <br/> 3/120 </td><td align="center" class="Rrule" valign="top"> <br/> 55/112 </td><td align="center" class="Rrule" valign="top"> <br/> 86/121 </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7" valign="top"> <br/> <span class="Bold"> PGA of Cleared or Minimal at Week 12*</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> ≤100 kg </td><td align="center" class="Rrule" valign="top"> <br/> 4% </td><td align="center" class="Rrule" valign="top"> <br/> 64% </td><td align="center" class="Rrule" valign="top"> <br/> 63% </td><td align="center" class="Rrule" valign="top"> <br/> 5% </td><td align="center" class="Rrule" valign="top"> <br/> 74% </td><td align="center" class="Rrule" valign="top"> <br/> 75% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> 7/166 </td><td align="center" class="Rrule" valign="top"> <br/> 108/168 </td><td align="center" class="Rrule" valign="top"> <br/> 103/164 </td><td align="center" class="Rrule" valign="top"> <br/> 14/290 </td><td align="center" class="Rrule" valign="top"> <br/> 220/297 </td><td align="center" class="Rrule" valign="top"> <br/> 216/289 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> &gt;100 kg </td><td align="center" class="Rrule" valign="top"> <br/> 3% </td><td align="center" class="Rrule" valign="top"> <br/> 49% </td><td align="center" class="Rrule" valign="top"> <br/> 58% </td><td align="center" class="Rrule" valign="top"> <br/> 3% </td><td align="center" class="Rrule" valign="top"> <br/> 51% </td><td align="center" class="Rrule" valign="top"> <br/> 69% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> 3/89 </td><td align="center" class="Rrule" valign="top"> <br/> 43/87 </td><td align="center" class="Rrule" valign="top"> <br/> 53/92 </td><td align="center" class="Rrule" valign="top"> <br/> 4/120 </td><td align="center" class="Rrule" valign="top"> <br/> 57/112 </td><td align="center" class="Rrule" valign="top"> <br/> 84/121 </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="7" valign="top">* Patients were dosed with study medication at Weeks 0 and 4. <br/> </td> </tr> </tbody> </table></div>

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 ustekinumab (ustekinumab at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomized to ustekinumab 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.

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.

Clinical Response

The efficacy results at Week 12 for Ps STUDY 3 are presented in Table 9.

Table 9: Summary of Efficacy Endpoints in the Adolescent Psoriasis Study at Week 12

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="673"> <col width="33.4456112542104%"/> <col width="33.2970081236378%"/> <col width="33.2573806221518%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="2" valign="top"> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Ps STUDY 3</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Placebo</span> <br/> <span class="Bold">n (%)</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Ustekinumab</span><span class="Bold">*</span> <br/> <span class="Bold">n (%)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">N</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">37</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">36</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">PGA</span></td><td class="Rrule" colspan="2" valign="top"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> PGA of cleared (0) or minimal (1) </td><td align="center" class="Rrule" valign="top"> <br/> 2 (5.4%) </td><td align="center" class="Rrule" valign="top"> <br/> 25 (69.4%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">PASI</span></td><td align="center" class="Rrule" colspan="2" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> PASI 75 responders </td><td align="center" class="Rrule" valign="top"> <br/> 4 (10.8%) </td><td align="center" class="Rrule" valign="top"> <br/> 29 (80.6%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> PASI 90 responders </td><td align="center" class="Rrule" valign="top"> <br/> 2 (5.4%) </td><td align="center" class="Rrule" valign="top"> <br/> 22 (61.1%) </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="3" valign="top">* Using the weight-based dosage regimen specified in Table 1. <br/> </td> </tr> </tbody> </table></div>

The safety and efficacy of ustekinumab was assessed in 927 patients (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled trials in adult patients 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. Patients in these trials had a diagnosis of PsA for at least 6 months. Patients 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.

Patients 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 patients continued on stable doses of MTX (≤25 mg/week). The primary endpoint was the percentage of patients achieving ACR 20 response at Week 24.

In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the patients, 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 patients 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 patients 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 10). 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 patients treated with ustekinumab alone or in combination with methotrexate. Responses were similar in patients regardless of prior TNFα exposure.

Table 10: ACR 20, ACR 50, ACR 70 and PASI 75 responses in PsA STUDY 1 and PsA STUDY 2 at Week 24

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="680"> <col width="30.1255640572886%"/> <col width="11.9972532862468%"/> <col width="11.5754365312929%"/> <col width="12.0659211300765%"/> <col width="11.0751422405336%"/> <col width="11.5950559152443%"/> <col width="11.5656268393172%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Ps STUDY 1</span> <br/> <span class="Bold">Ustekinumab</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Ps STUDY 2</span> <br/> <span class="Bold">Ustekinumab</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Placebo</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">45 mg</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">90 mg</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Placebo</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">45 mg</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">90 mg</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Number of patients</span> <br/> <span class="Bold">randomized</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">206</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">205</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">204</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">104</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">103</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">105</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> ACR 20 response, N (%) </td><td align="center" class="Rrule" valign="top"> <br/> 47 (23%) </td><td align="center" class="Rrule" valign="top"> <br/> 87 (42%) </td><td align="center" class="Rrule" valign="top"> <br/> 101 (50%) </td><td align="center" class="Rrule" valign="top"> <br/> 21 (20%) </td><td align="center" class="Rrule" valign="top"> <br/> 45 (44%) </td><td align="center" class="Rrule" valign="top"> <br/> 46 (44%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> ACR 50 response, N (%) </td><td align="center" class="Rrule" valign="top"> <br/> 18 (9%) </td><td align="center" class="Rrule" valign="top"> <br/> 51 (25%) </td><td align="center" class="Rrule" valign="top"> <br/> 57 (28%) </td><td align="center" class="Rrule" valign="top"> <br/> 7 (7%) </td><td align="center" class="Rrule" valign="top"> <br/> 18 (17%) </td><td align="center" class="Rrule" valign="top"> <br/> 24 (23%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> ACR 70 response, N (%) </td><td align="center" class="Rrule" valign="top"> <br/> 5 (2%) </td><td align="center" class="Rrule" valign="top"> <br/> 25 (12%) </td><td align="center" class="Rrule" valign="top"> <br/> 29 (14%) </td><td align="center" class="Rrule" valign="top"> <br/> 3 (3%) </td><td align="center" class="Rrule" valign="top"> <br/> 7 (7%) </td><td align="center" class="Rrule" valign="top"> <br/> 9 (9%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Number</span><span class="Bold"></span><span class="Bold">of</span><span class="Bold"></span><span class="Bold">patients</span><span class="Bold"></span><span class="Bold">with</span> <br/> <span class="Bold">≥ 3% BSA <span class="Sup">a</span></span></td><td align="center" class="Rrule" valign="top"> <br/> <br/> <span class="Bold">146</span></td><td align="center" class="Rrule" valign="top"> <br/> <br/> <span class="Bold">145</span></td><td align="center" class="Rrule" valign="top"> <br/> <br/> <span class="Bold">149</span></td><td align="center" class="Rrule" valign="top"> <br/> <br/> <span class="Bold">80</span></td><td align="center" class="Rrule" valign="top"> <br/> <br/> <span class="Bold">80</span></td><td align="center" class="Rrule" valign="top"> <br/> <br/> <span class="Bold">81</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">PASI 75 response, N (%)</span></td><td align="center" class="Rrule" valign="top"> <br/> 16 (11%) </td><td align="center" class="Rrule" valign="top"> <br/> 83 (57%) </td><td align="center" class="Rrule" valign="top"> <br/> 93 (62%) </td><td align="center" class="Rrule" valign="top"> <br/> 4 (5%) </td><td align="center" class="Rrule" valign="top"> <br/> 41 (51%) </td><td align="center" class="Rrule" valign="top"> <br/> 45 (56%) </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="7" valign="top"><span class="Sup">a</span>Number of patients with ≥ 3% BSA psoriasis skin involvement at baseline <br/> <br/> </td> </tr> </tbody> </table></div>

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

Figure 1: Percent of patients achieving ACR 20 response through Week 24

The results of the components of the ACR response criteria are shown in Table 11.

Table 11: Mean change from baseline in ACR components at Week 24

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="682"> <col width="30.791788856305%"/> <col width="19.5307917888563%"/> <col width="24.8093841642229%"/> <col width="24.8680351906158%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> <span class="Bold">PsA STUDY 1</span> <br/> <span class="Bold">Ustekinumab</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Placebo</span> <br/> <span class="Bold">(N = 206)</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">45 mg</span> <br/> <span class="Bold">(N = 205)</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">90 mg</span> <br/> <span class="Bold">(N = 204)</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Number of swollen joints <span class="Sup">a</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Baseline </td><td align="center" class="Rrule" valign="top"> <br/> 15 </td><td align="center" class="Rrule" valign="top"> <br/> 12 </td><td align="center" class="Rrule" valign="top"> <br/> 13 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Mean Change at Week 24 </td><td align="center" class="Rrule" valign="top"> <br/> -3 </td><td align="center" class="Rrule" valign="top"> <br/> -5 </td><td align="center" class="Rrule" valign="top"> <br/> -6 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Number of tender joints <span class="Sup">b</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Baseline </td><td align="center" class="Rrule" valign="top"> <br/> 25 </td><td align="center" class="Rrule" valign="top"> <br/> 22 </td><td align="center" class="Rrule" valign="top"> <br/> 23 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Mean Change at Week 24 </td><td align="center" class="Rrule" valign="top"> <br/> -4 </td><td align="center" class="Rrule" valign="top"> <br/> -8 </td><td align="center" class="Rrule" valign="top"> <br/> -9 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Patient’s assessment of pain <span class="Sup">c</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Baseline </td><td align="center" class="Rrule" valign="top"> <br/> 6.1 </td><td align="center" class="Rrule" valign="top"> <br/> 6.2 </td><td align="center" class="Rrule" valign="top"> <br/> 6.6 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Mean Change at Week 24 </td><td align="center" class="Rrule" valign="top"> <br/> -0.5 </td><td align="center" class="Rrule" valign="top"> <br/> -2.0 </td><td align="center" class="Rrule" valign="top"> <br/> -2.6 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Patient global assessment <span class="Sup">c</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Baseline </td><td align="center" class="Rrule" valign="top"> <br/> 6.1 </td><td align="center" class="Rrule" valign="top"> <br/> 6.3 </td><td align="center" class="Rrule" valign="top"> <br/> 6.4 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Mean Change at Week 24 </td><td align="center" class="Rrule" valign="top"> <br/> -0.5 </td><td align="center" class="Rrule" valign="top"> <br/> -2.0 </td><td align="center" class="Rrule" valign="top"> <br/> -2.5 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Physician global assessment <span class="Sup">c</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Baseline </td><td align="center" class="Rrule" valign="top"> <br/> 5.8 </td><td align="center" class="Rrule" valign="top"> <br/> 5.7 </td><td align="center" class="Rrule" valign="top"> <br/> 6.1 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Mean Change at Week 24 </td><td align="center" class="Rrule" valign="top"> <br/> -1.4 </td><td align="center" class="Rrule" valign="top"> <br/> -2.6 </td><td align="center" class="Rrule" valign="top"> <br/> -3.1 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Disability index (HAQ) <span class="Sup">d</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Baseline </td><td align="center" class="Rrule" valign="top"> <br/> 1.2 </td><td align="center" class="Rrule" valign="top"> <br/> 1.2 </td><td align="center" class="Rrule" valign="top"> <br/> 1.2 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Mean Change at Week 24 </td><td align="center" class="Rrule" valign="top"> <br/> -0.1 </td><td align="center" class="Rrule" valign="top"> <br/> -0.3 </td><td align="center" class="Rrule" valign="top"> <br/> -0.4 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> CRP (mg/dL) <span class="Sup">e</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Baseline </td><td align="center" class="Rrule" valign="top"> <br/> 1.6 </td><td align="center" class="Rrule" valign="top"> <br/> 1.7 </td><td align="center" class="Rrule" valign="top"> <br/> 1.8 </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Mean Change at Week 24 </td><td align="center" class="Rrule" valign="top"> <br/> 0.01 </td><td align="center" class="Rrule" valign="top"> <br/> -0.5 </td><td align="center" class="Rrule" valign="top"> <br/> -0.8 </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="4" valign="top"> <br/> <span class="Sup">a</span>Number of swollen joints counted (0-66) <br/> <span class="Sup">b</span>Number of tender joints counted (0-68) <br/> <span class="Sup">c</span>Visual analogue scale; 0= best, 10=worst. <br/> <span class="Sup">d</span>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. <br/> <span class="Sup">e</span>CRP: (Normal Range 0.0-1.0 mg/dL) </td> </tr> </tbody> </table></div>

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

Physical Function

Ustekinumab-treated patients showed improvement in physical function compared to patients treated with 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 ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24.

Ustekinumab was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult patients 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. Patients in CD-1 had failed or were intolerant to treatment with one or more TNF blockers, while patients in CD-2 had failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with a TNF blocker.

Trials CD-1 and CD-2

In trials CD-1 and CD-2, 1409 patients were randomized, of whom 1368 (CD-1, n=741; CD-2, n=627) were included in the final efficacy analysis. Induction of clinical response (defined as a reduction in CDAI score of greater than or equal to 100 points or CDAI score of less than 150) at Week 6 and clinical remission (defined as a CDAI score of less than 150) at Week 8 were evaluated. In both trials, patients were randomized to receive a single intravenous administration of ustekinumab at either approximately 6 mg/kg, placebo (see Table 3), or 130 mg (a lower dose than recommended).

In trial CD-1, patients had failed or were intolerant to prior treatment with a TNF blocker: 29% patients had an inadequate initial response (primary non- responders), 69% responded but subsequently lost response (secondary non-responders) and 36% were intolerant to a TNF blocker. Of these patients, 48% failed or were intolerant to one TNF blocker and 52% had failed 2 or 3 prior TNF blockers. At baseline and throughout the trial, approximately 46% of the patients were receiving corticosteroids and 31% of the patients were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score was 319 in the ustekinumab approximately 6 mg/kg group and 313 in the placebo group.

In trial CD-2, patients had failed or were intolerant to prior treatment with corticosteroids (81% of patients), at least one immunomodulator (6-MP, AZA, MTX; 68% of patients), or both (49% of patients). Additionally, 69% never received a TNF blocker and 31% previously received but had not failed a TNF blocker. At baseline, and throughout the trial, approximately 39% of the patients were receiving corticosteroids and 35% of the patients were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score was 286 in the ustekinumab and 290 in the placebo group.

In these induction trials, a greater proportion of patients treated with ustekinumab (at the recommended dose of approximately 6 mg/kg dose) achieved clinical response at Week 6 and clinical remission at Week 8 compared to placebo (see Table 12 for clinical response and remission rates). Clinical response and remission were significant as early as Week 3 in ustekinumab -treated patients and continued to improve through Week 8.

Table 12: Induction of Clinical Response and Remission in CD-1* and CD-2**

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="688"> <col width="12.2010264355573%"/> <col width="13.9440302120655%"/> <col width="16.5585358768277%"/> <col width="12.8691778832187%"/> <col width="14.1473806526581%"/> <col width="16.5585358768277%"/> <col width="13.721313062845%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="2" valign="top"> <br/> </td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> <span class="Bold">CD-1</span> <br/> <span class="Bold">n = 741</span></td><td align="center" class="Rrule" colspan="3" valign="top"> <br/> <span class="Bold">CD-2</span> <br/> <span class="Bold">n = 627</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Placebo</span> <br/> <span class="Bold">N = 247</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Ustekinumab</span><span class="Bold">†</span> <br/> <span class="Bold">N = 249</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Treatment</span> <br/> <span class="Bold">Difference and 95% CI</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Placebo</span> <br/> <span class="Bold">N = 209</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Ustekinumab</span><span class="Bold">†</span> <br/> <span class="Bold">N = 209</span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Treatment</span> <br/> <span class="Bold">difference</span> <br/> <span class="Bold">and 95% CI</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Clinical <br/> Response <br/> (100 point), <br/> Week 6 </td><td align="center" class="Rrule" valign="top"> <br/> 53 <br/> (21%) </td><td align="center" class="Rrule" valign="top"> <br/> 84 <br/> (34%) <span class="Sup">a</span></td><td align="center" class="Rrule" valign="top"> <br/> 12% <br/> (4%, 20%) </td><td align="center" class="Rrule" valign="top"> <br/> 60 <br/> (29%) </td><td align="center" class="Rrule" valign="top"> <br/> 116 <br/> (56%) <span class="Sup">b</span></td><td align="center" class="Rrule" valign="top"> <br/> 27% <br/> (18%, 36%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Clinical <br/> Remission, <br/> Week 8 </td><td align="center" class="Rrule" valign="top"> <br/> 18 <br/> (7%) </td><td align="center" class="Rrule" valign="top"> <br/> 52 <br/> (21%) <span class="Sup">b</span></td><td align="center" class="Rrule" valign="top"> <br/> 14% <br/> (8%, 20%) </td><td align="center" class="Rrule" valign="top"> <br/> 41 <br/> (20%) </td><td align="center" class="Rrule" valign="top"> <br/> 84 <br/> (40%) <span class="Sup">b</span></td><td align="center" class="Rrule" valign="top"> <br/> 26% <br/> (17%, 35%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Clinical <br/> Response <br/> (100 point), <br/> Week 8 </td><td align="center" class="Rrule" valign="top"> <br/> 50 <br/> (20%) </td><td align="center" class="Rrule" valign="top"> <br/> 94 <br/> (38%) <span class="Sup">b</span></td><td align="center" class="Rrule" valign="top"> <br/> 18% <br/> (10%, 25%) </td><td align="center" class="Rrule" valign="top"> <br/> 67 <br/> (32%) </td><td align="center" class="Rrule" valign="top"> <br/> 121 <br/> (58%) <span class="Sup">b</span></td><td align="center" class="Rrule" valign="top"> <br/> 21% <br/> (12%, 29%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> 70 Point <br/> Response, <br/> Week 6 </td><td align="center" class="Rrule" valign="top"> <br/> 75 <br/> (30%) </td><td align="center" class="Rrule" valign="top"> <br/> 109 <br/> (44%) <span class="Sup">a</span></td><td align="center" class="Rrule" valign="top"> <br/> 13% <br/> (5%, 22%) </td><td align="center" class="Rrule" valign="top"> <br/> 81 <br/> (39%) </td><td align="center" class="Rrule" valign="top"> <br/> 135 <br/> (65%) <span class="Sup">b</span></td><td align="center" class="Rrule" valign="top"> <br/> 26% <br/> (17%, 35%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> 70 Point <br/> Response, <br/> Week 3 </td><td align="center" class="Rrule" valign="top"> <br/> 67 <br/> (27%) <br/> </td><td align="center" class="Rrule" valign="top"> <br/> 101 <br/> (41%) <span class="Sup">a</span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> 13% <br/> (5%, 22%) </td><td align="center" class="Rrule" valign="top"> <br/> 66 <br/> (32%) </td><td align="center" class="Rrule" valign="top"> <br/> 106 <br/> (51%) <span class="Sup">b</span></td><td align="center" class="Rrule" valign="top"> <br/> 19% <br/> (10%, 28%)  <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="7" valign="top">Clinical remission is defined as CDAI score &lt; 150; Clinical response is defined as reduction in CDAI score by at least 100 points or being in clinical remission: 70 point response is defined as reduction in CDAI score by at least 70 points <br/> <br/> * Patient population consisted of patients who failed or were intolerant to TNF blocker therapy <br/> ** Patient population consisted of patients who failed or were intolerant to corticosteroids or immunomodulators (e.g., 6-MP, AZA, MTX) and previously received but not failed a TNF blocker or were never treated with a TNF blocker. <br/> † Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 3. <br/> <span class="Sup">a</span>0.001≤ p &lt; 0.01 <br/> <span class="Sup">b</span>p &lt; 0.001 </td> </tr> </tbody> </table></div>

Trial CD-3

The maintenance trial (CD-3), evaluated 388 patients who achieved clinical response (≥100 point reduction in CDAI score) at Week 8 with either induction dose of ustekinumab in trials CD-1 or CD-2. Patients were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks or placebo for 44 weeks (see Table 13).

Table 13: Clinical Response and Remission in CD-3 (Week 44; 52 weeks from initiation of the induction dose)

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="691"> <col width="38.5075779515397%"/> <col width="17.0093638382083%"/> <col width="24.0081088908196%"/> <col width="20.4749493194324%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> <br/> <span class="Bold">Placebo*</span> <br/> <span class="Bold">N = 131†</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">90 mg</span> <br/> <span class="Bold">Ustekinumab</span><span class="Bold"></span> <br/> <span class="Bold">every 8 weeks</span> <br/> <span class="Bold">N = 128†</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Treatment</span><span class="Bold"></span><span class="Bold">difference</span> <br/> <span class="Bold">and</span><span class="Bold"></span><span class="Bold">95%</span><span class="Bold"></span><span class="Bold">CI</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Clinical Remission </td><td align="center" class="Rrule" valign="top"> <br/> 47 (36%) </td><td align="center" class="Rrule" valign="top"> <br/> 68 (53%) <span class="Sup">a</span></td><td align="center" class="Rrule" valign="top"> <br/> 17% (5%, 29%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Clinical Response </td><td align="center" class="Rrule" valign="top"> <br/> 58 (44%) </td><td align="center" class="Rrule" valign="top"> <br/> 76 (59%) <span class="Sup">b</span></td><td align="center" class="Rrule" valign="top"> <br/> 15% (3%, 27%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Clinical Remission in patients in remission at the start of maintenance therapy** </td><td align="center" class="Rrule" valign="top"> <br/> 36/79 (46%) </td><td align="center" class="Rrule" valign="top"> <br/> 52/78 (67%) <span class="Sup">a</span></td><td align="center" class="Rrule" valign="top"> <br/> 21% (6%, 36%) </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="4" valign="top">Clinical remission is defined as CDAI score &lt; 150; Clinical response is defined as reduction in CDAI of at least 100 points or being in clinical remission <br/> *The placebo group consisted of patients who were in response to ustekinumab and were randomized to receive placebo at the start of maintenance therapy. <br/> ** Patients 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. <br/> <span class="Sup">†</span>Patients who achieved clinical response to ustekinumab at the end of the induction study. <br/> <span class="Sup">a</span>p &lt; 0.01 <br/> <span class="Sup">b</span>0.01≤ p &lt; 0.05 <br/> </td> </tr> </tbody> </table></div>

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

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

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

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

Ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1 and UC-2 (NCT02407236)] in adult patients 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, patients had a median Mayo score of 9, with 84% of patients having moderate disease (Mayo score 6-10) and 15% having severe disease (Mayo score 11-12).

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

Study UC-1

In UC-1, 961 patients were randomized at Week 0 to a single intravenous administration of ustekinumab of approximately 6 mg/kg, 130 mg (a lower dose than recommended), or placebo. Patients 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% patients were receiving oral corticosteroids, 28% patients were receiving immunomodulators (AZA, 6-MP, or MTX) and 69% patients 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 14.

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 14.

In UC-1, a significantly greater proportion of patients treated with ustekinumab (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 14).

Table 14: Proportion of Patients Meeting Efficacy Endpoints at Week 8 in UC-1

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="681.359"> <colgroup> <col width="23.1700175678314%"/> <col width="11.1458130001952%"/> <col width="10.5211789966816%"/> <col width="11.2824516884638%"/> <col width="11.6728479406598%"/> <col width="32.2076908061683%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Endpoint</span></td><td align="center" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Placebo</span> <br/> <span class="Bold">N = 319</span></td><td align="center" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Ustekinumab</span><span class="Bold">†</span> <br/> <span class="Bold">N = 322</span></td><td align="center" class="Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Treatment</span><span class="Bold">difference</span><span class="Bold">and 97.5% CI</span><span class="Sup">a</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">N</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">%</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">N</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">%</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Clinical </span><span class="Bold">Remission*</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">22</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">7%</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">62</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">19%</span></td><td align="center" class="Rrule" valign="top"> <br/> 12% <br/> (7%, 18%) <span class="Sup">b</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Bio-naïve <span class="Sup">⸸</span></td><td align="center" class="Rrule" valign="top"> <br/> 14/151 </td><td align="center" class="Rrule" valign="top"> <br/> 9% </td><td align="center" class="Rrule" valign="top"> <br/> 36/147 </td><td align="center" class="Rrule" valign="top"> <br/> 24% </td><td align="center" class="Rrule" rowspan="2" valign="top"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Prior biologic failure </td><td align="center" class="Rrule" valign="top"> <br/> 7/161 </td><td align="center" class="Rrule" valign="top"> <br/> 4% </td><td align="center" class="Rrule" valign="top"> <br/> 24/166 </td><td align="center" class="Rrule" valign="top"> <br/> 14% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Endoscopic </span><span class="Bold">Improvement <span class="Sup">§</span></span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">40</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">13%</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">80</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">25%</span></td><td align="center" class="Rrule" valign="top"> <br/> 12% <br/> (6%, 19%) <span class="Sup">b</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Bio-naïve <span class="Sup">⸸</span></td><td align="center" class="Rrule" valign="top"> <br/> 28/151 </td><td align="center" class="Rrule" valign="top"> <br/> 19% </td><td align="center" class="Rrule" valign="top"> <br/> 43/147 </td><td align="center" class="Rrule" valign="top"> <br/> 29% </td><td align="center" class="Rrule" rowspan="2" valign="top"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Prior biologic failure </td><td align="center" class="Rrule" valign="top"> <br/> 11/161 </td><td align="center" class="Rrule" valign="top"> <br/> 7% </td><td align="center" class="Rrule" valign="top"> <br/> 34/166 </td><td align="center" class="Rrule" valign="top"> <br/> 20% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Clinical </span><span class="Bold">Response <span class="Sup">†</span></span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">99</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">31%</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">186</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">58%</span></td><td align="center" class="Rrule" valign="top"> <br/> 27% <br/> (18%, 35%) <span class="Sup">b</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Bio-naïve <span class="Sup">⸸</span></td><td align="center" class="Rrule" valign="top"> <br/> 55/151 </td><td align="center" class="Rrule" valign="top"> <br/> 36% </td><td align="center" class="Rrule" valign="top"> <br/> 94/147 </td><td align="center" class="Rrule" valign="top"> <br/> 64% </td><td align="center" class="Rrule" rowspan="2" valign="top"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Prior biologic failure </td><td align="center" class="Rrule" valign="top"> <br/> 42/161 </td><td align="center" class="Rrule" valign="top"> <br/> 26% </td><td align="center" class="Rrule" valign="top"> <br/> 86/166 </td><td align="center" class="Rrule" valign="top"> <br/> 52% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Histologic-</span><span class="Bold">Endoscopic </span><span class="Bold">Mucosal </span><span class="Bold">Improvement <span class="Sup">‡</span></span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">26</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">8%</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">54</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">17%</span></td><td align="center" class="Rrule" valign="top"> <br/> 9% <br/> (3%, 14%) <span class="Sup">b</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Bio-naïve <span class="Sup">⸸</span></td><td align="center" class="Rrule" valign="top"> <br/> 19/151 </td><td align="center" class="Rrule" valign="top"> <br/> 13% </td><td align="center" class="Rrule" valign="top"> <br/> 30/147 </td><td align="center" class="Rrule" valign="top"> <br/> 20% </td><td align="left" class="Rrule" rowspan="2" valign="top"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Prior biologic failure </td><td align="center" class="Rrule" valign="top"> <br/> 6/161 </td><td align="center" class="Rrule" valign="top"> <br/> 4% </td><td align="center" class="Rrule" valign="top"> <br/> 21/166 </td><td align="center" class="Rrule" valign="top"> <br/> 13% </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="6" valign="top"><span class="Sup">†</span>Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 3. <br/> <span class="Sup">⸸</span> An additional 7 patients on placebo and 9 patients on ustekinumab (6 mg/kg) had been exposed to, but had not failed, biologics. <br/> * 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). <br/> <span class="Sup">§</span>Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). <br/> <span class="Sup">†</span>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. <br/> <span class="Sup">‡</span>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 &lt;5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue). <br/> <span class="Sup">a</span>Adjusted treatment difference (97.5% CI) <br/> <span class="Sup">b</span>p &lt; 0.001 </td> </tr> </tbody> </table></div>

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 ustekinumab-treated patients.

Study UC-2

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

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

Results of the primary and secondary endpoints at Week 44 in patients treated with ustekinumab at the recommended dosage (90 mg every 8 weeks) compared to the placebo are shown in Table 15.

Table 15: Efficacy Endpoints of Maintenance at Week 44 in UC-2 (52 Weeks from Initiation of the Induction Dose)

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="666.596"> <colgroup> <col width="26.2569832402235%"/> <col width="11.1233040702314%"/> <col width="10.4948124501197%"/> <col width="11.2529928172386%"/> <col width="11.6620111731844%"/> <col width="29.2098962490024%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">End</span> <br/> <span class="Bold">point</span></td><td align="center" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Placebo</span>* <br/> N = 175† </td><td align="center" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">90</span><span class="Bold">mg</span><span class="Bold">Ustekinumab</span> <br/> <span class="Bold">every</span><span class="Bold">8</span><span class="Bold">weeks</span> <br/> N = 176 </td><td align="center" class="Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Treatment</span><span class="Bold">difference</span><span class="Bold">and 95% CI</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">N</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">%</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">N</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">%</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Clinical </span><span class="Bold">Remission**</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">46</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">26%</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">79</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">45%</span></td><td align="center" class="Rrule" valign="top"> <br/> 19% <br/> (9%, 28%) <span class="Sup">a</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Bio-naïve <span class="Sup">⸸</span></td><td align="center" class="Rrule" valign="top"> <br/> 30/84 </td><td align="center" class="Rrule" valign="top"> <br/> 36% </td><td align="center" class="Rrule" valign="top"> <br/> 39/79 </td><td align="center" class="Rrule" valign="top"> <br/> 49% </td><td align="center" class="Rrule" rowspan="2" valign="top"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Prior biologic failure </td><td align="center" class="Rrule" valign="top"> <br/> 16/88 </td><td align="center" class="Rrule" valign="top"> <br/> 18% </td><td align="center" class="Rrule" valign="top"> <br/> 37/91 </td><td align="center" class="Rrule" valign="top"> <br/> 41% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Maintenance </span><span class="Bold">of </span><span class="Bold">Clinical Response at Week 44 <span class="Sup">†</span></span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">84</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">48%</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">130</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">74%</span></td><td align="center" class="Rrule" valign="top"> <br/> 26% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"> <br/> (16%, 36%) <span class="Sup">a</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Bio-naïve <span class="Sup">⸸</span></td><td align="center" class="Rrule" valign="top"> <br/> 49/84 </td><td align="center" class="Rrule" valign="top"> <br/> 58% </td><td align="center" class="Rrule" valign="top"> <br/> 62/79 </td><td align="center" class="Rrule" valign="top"> <br/> 78% </td><td align="center" class="Rrule" rowspan="2" valign="top"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Prior biologic failure </td><td align="center" class="Rrule" valign="top"> <br/> 35/88 </td><td align="center" class="Rrule" valign="top"> <br/> 40% </td><td align="center" class="Rrule" valign="top"> <br/> 64/91 </td><td align="center" class="Rrule" valign="top"> <br/> 70% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Endoscopic </span><span class="Bold">Improvement <span class="Sup">§</span></span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">47</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">27%</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">83</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">47%</span></td><td align="center" class="Rrule" valign="top"> <br/> 20% <br/> (11%, 30%) <span class="Sup">a</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Bio-naïve <span class="Sup">⸸</span></td><td align="center" class="Rrule" valign="top"> <br/> 29/84 </td><td align="center" class="Rrule" valign="top"> <br/> 35% </td><td align="center" class="Rrule" valign="top"> <br/> 42/79 </td><td align="center" class="Rrule" valign="top"> <br/> 53% </td><td align="center" class="Rrule" rowspan="2" valign="top"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Prior biologic failure </td><td align="center" class="Rrule" valign="top"> <br/> 18/88 </td><td align="center" class="Rrule" valign="top"> <br/> 20% </td><td align="center" class="Rrule" valign="top"> <br/> 38/91 </td><td align="center" class="Rrule" valign="top"> <br/> 42% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Corticosteroid-free </span><span class="Bold">Clinical Remission <span class="Sup">‡</span></span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">45</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">26%</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">76</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">43%</span></td><td align="center" class="Rrule" valign="top"> <br/> 17% <br/> (8%, 27%) <span class="Sup">a</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Bio-naïve <span class="Sup">⸸</span></td><td align="center" class="Rrule" valign="top"> <br/> 30/84 </td><td align="center" class="Rrule" valign="top"> <br/> 36% </td><td align="center" class="Rrule" valign="top"> <br/> 38/79 </td><td align="center" class="Rrule" valign="top"> <br/> 48% </td><td align="center" class="Rrule" rowspan="2" valign="top"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Prior biologic failure </td><td align="center" class="Rrule" valign="top"> <br/> 15/88 </td><td align="center" class="Rrule" valign="top"> <br/> 17% </td><td align="center" class="Rrule" valign="top"> <br/> 35/91 </td><td align="center" class="Rrule" valign="top"> <br/> 38% </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Maintenance of Clinical Remission at Week 44 in patients who achieved clinical remission 8 weeks after induction</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">18/50</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">36%</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">27/41</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">66%</span></td><td align="center" class="Rrule" valign="top"> <br/> 31% <br/> (12%, 50%) <span class="Sup">b</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Bio-naïve <span class="Sup">⸸</span></td><td align="center" class="Rrule" valign="top"> <br/> 12/27 </td><td align="center" class="Rrule" valign="top"> <br/> 44% </td><td align="center" class="Rrule" valign="top"> <br/> 14/20 </td><td align="center" class="Rrule" valign="top"> <br/> 70% </td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/> Prior biologic failure </td><td align="center" class="Rrule" valign="top"> <br/> 6/23 </td><td align="center" class="Rrule" valign="top"> <br/> 26% </td><td align="center" class="Rrule" valign="top"> <br/> 12/18 </td><td align="center" class="Rrule" valign="top"> <br/> 67% </td><td align="left" class="Rrule" valign="top"></td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="6" valign="top"> <br/> <br/> <span class="Sup">⸸ </span>An additional 3 patients on placebo and 6 patients on ustekinumab had been exposed to, but had not failed, biologics. <br/> * The placebo group consisted of patients who were in response to ustekinumab and were randomized to receive placebo at the start of maintenance therapy. <br/> ** 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). <br/> <span class="Sup">†</span> 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. <br/> <span class="Sup">§</span> Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). <br/> <span class="Sup">‡</span> Corticosteroid-free clinical remission was defined as patients in clinical remission and not receiving corticosteroids at Week 44. <br/> <span class="Sup">a</span> p =&lt;0.001 <br/> <span class="Sup">b</span> p=0.004 </td> </tr> </tbody> </table></div>

Other Endpoints

Week 16 Responders to Ustekinumab Induction

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

Histologic-Endoscopic Mucosal Improvement at Week 44

The proportion of patients achieving histologic-endoscopic mucosal improvement during maintenance treatment in UC-2 was 75/172 (44%) among patients on ustekinumab and 40/172 (23%) in patients 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 patients treated with ustekinumab and 12/319 (4%) of patients in the placebo group. At Week 44 of UC-2, endoscopic normalization was achieved in 51/176 (29%) of patients treated with ustekinumab and in 32/175 (18%) of patients in placebo group.

1 Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973-2007) - Linked To County Attributes - Total U.S., 1969-2007 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2010, based on the November 2009 submission.

{ "type": "p", "children": [], "text": "\n1 Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973-2007) - Linked To County Attributes - Total U.S., 1969-2007 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2010, based on the November 2009 submission.\n\n " }

IMULDOSA (ustekinumab-srlf) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution. It is supplied as individually packaged, single-dose prefilled syringes or single-dose vials.

{ "type": "p", "children": [], "text": "IMULDOSA (ustekinumab-srlf) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution. It is supplied as individually packaged, single-dose prefilled syringes or single-dose vials." }

For Subcutaneous Use

{ "type": "p", "children": [], "text": "\nFor Subcutaneous Use\n" }

Prefilled Syringes

{ "type": "p", "children": [], "text": "\nPrefilled Syringes\n" }

{ "type": "ul", "children": [ "45 mg/0.5 mL (NDC 51407-929-11)", "90 mg/mL (NDC 51407-930-11)" ], "text": "" }

Each prefilled syringe is equipped with a 29-gauge fixed ½ inch needle, a needle safety guard, and a needle cover that does not contain latex.

{ "type": "p", "children": [], "text": "Each prefilled syringe is equipped with a 29-gauge fixed ½ inch needle, a needle safety guard, and a needle cover that does not contain latex." }

For Intravenous Infusion

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion\n" }

Single-dose Vial

{ "type": "p", "children": [], "text": "\nSingle-dose Vial\n" }

{ "type": "ul", "children": [ "130 mg/26 mL (5 mg/mL) (NDC 51407-931-11)" ], "text": "" }

Storage and Stability

{ "type": "p", "children": [], "text": "\nStorage and Stability\n" }

Store IMULDOSA vials and prefilled syringes refrigerated between 2ºC to 8ºC (36ºF to 46ºF). Store IMULDOSA vials upright. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake.

{ "type": "p", "children": [], "text": "Store IMULDOSA vials and prefilled syringes refrigerated between 2ºC to 8ºC (36ºF to 46ºF).\n \nStore IMULDOSA vials upright.\n \nKeep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake.\n " }

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 IMULDOSA after the expiration date on the carton or on the prefilled syringe.

{ "type": "p", "children": [], "text": "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 IMULDOSA after the expiration date on the carton or on the prefilled syringe." }

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

{ "type": "p", "children": [], "text": "Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)." }

Infections

{ "type": "p", "children": [], "text": "\nInfections\n" }

Inform patients that IMULDOSA 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)].

{ "type": "p", "children": [], "text": "Inform patients that IMULDOSA 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 \n [see Warnings and Precautions (5.1)].\n" }

Malignancies

{ "type": "p", "children": [], "text": "\nMalignancies\n" }

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

{ "type": "p", "children": [], "text": "Inform patients of the risk of developing malignancies while receiving IMULDOSA \n [see Warnings and Precautions (5.4)].\n" }

HypersensitivityReactions

{ "type": "p", "children": [], "text": "\nHypersensitivityReactions\n" }

{ "type": "ul", "children": [ "Advise patients to seek immediate medical attention if they experience any signs or symptoms of serious hypersensitivity reactions and discontinue IMULDOSA \n [see Warnings and Precautions (5.5)].\n" ], "text": "" }

PosteriorReversibleEncephalopathySyndrome(PRES)

{ "type": "p", "children": [], "text": "\nPosteriorReversibleEncephalopathySyndrome(PRES)\n" }

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)].

{ "type": "p", "children": [], "text": "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) \n [see Warnings and Precautions (5.6)].\n" }

Immunizations

{ "type": "p", "children": [], "text": "\nImmunizations\n" }

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

{ "type": "p", "children": [], "text": "Inform patients that IMULDOSA can interfere with the usual response to immunizations and that they should avoid live vaccines \n [see Warnings and Precautions (5.7)].\n" }

Administration

{ "type": "p", "children": [], "text": "\nAdministration\n" }

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

{ "type": "p", "children": [], "text": "Instruct patients to follow sharps disposal recommendations, as described in the Instructions for Use." }

Manufactured by: Accord BioPharma Inc. 8041 Arco Corporate Drive, Suite 200, Raleigh, North Carolina (NC), 27617 USA US License No. 2105

{ "type": "p", "children": [], "text": "Manufactured by: Accord BioPharma Inc.\n \n8041 Arco Corporate Drive, Suite 200,\n \nRaleigh, North Carolina (NC), 27617 USA\n \nUS License No. 2105\n " }

Marketed by:

{ "type": "p", "children": [], "text": "Marketed by:" }

GSMS, Inc. Camarillo, CA 93012 USA

{ "type": "p", "children": [], "text": "GSMS, Inc.\n \nCamarillo, CA 93012 USA\n " }

<div class="scrollingtable"><table width="100%"> <tfoot> <tr class="First First Last Last"> <td align="left" valign="top">This Medication Guide has been approved by the U.S. Food and Drug Administration</td><td align="right" valign="bottom">Issued: 03/2025</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First First"> <td align="center" class="Lrule Rrule" colspan="4" valign="middle"><span class="Bold">MEDICATION GUIDE</span> <br/> <span class="Bold">IMULDOSA (im ul doe' sah)</span> <br/> <span class="Bold">(ustekinumab-srlf)</span> <br/> <span class="Bold">injection, for subcutaneous or intravenous use</span></td> </tr> <tr> <td class="Lrule Rrule" colspan="4"><span class="Bold">What is the most important information I should know about IMULDOSA?</span> <br/> IMULDOSA is a medicine that affects your immune system. IMULDOSA can increase your risk of having serious side effects, including: <br/> <span class="Bold">Serious infections. </span>IMULDOSA may lower the ability of your immune system to fight infections and may increase your risk of infections. Some people have serious infections while taking ustekinumab products, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their infection. <ul class="Disc"> <li>Your doctor should check you for TB before starting IMULDOSA.</li> <li>If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with IMULDOSA and during treatment with IMULDOSA.</li> <li>Your doctor should watch you closely for signs and symptoms of TB while you are being treated with IMULDOSA.</li> </ul> You should not start taking IMULDOSA if you have any kind of infection unless your doctor says it is okay. <br/> <br/> <span class="Bold">Before starting IMULDOSA, tell your doctor if you:</span> <ul class="Disc"> <li>think you have an infection or have symptoms of an infection such as:</li> </ul> </td> </tr> <tr> <td class="Lrule"> <ul class="Circle"> <li>fever, sweat, or chills</li> <li>muscle aches</li> <li>cough</li> <li>shortness of breath</li> <li>blood in phlegm</li> </ul> </td><td class="Rrule" colspan="4"> <ul class="Circle"> <li>weight loss</li> <li>warm, red, or painful skin or sores on your body</li> <li>diarrhea or stomach pain</li> <li>burning when you urinate or urinate more often than normal</li> <li>feel very tired</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2" valign="middle"> <ul class="Disc"> <li>are being treated for an infection or have any open cuts.</li> <li>get a lot of infections or have infections that keep coming back.</li> <li>have TB, or have been in close contact with someone with TB.</li> </ul> <span class="Bold">After starting IMULDOSA, </span>call your doctor right away if you have any symptoms of an infection (see above). These may be signs of infections such as chest infections, or skin infections or shingles that could have serious complications. IMULDOSA can make you more likely to get infections or make an infection that you have worse. <br/> People who have a genetic problem where the body does not make any of the proteins interleukin 12 (IL-12) and interleukin 23 (IL-23) are at a higher risk for certain serious infections. These infections can spread throughout the body and cause death. People who take IMULDOSA may also be more likely to get these infections. <br/> <span class="Bold">Cancers. </span>IMULDOSA may decrease the activity of your immune system and increase your risk for certain types of cancers. Tell your doctor if you have ever had any type of cancer. Some people who are receiving ustekinumab products and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with IMULDOSA, tell your doctor if you develop any new skin growths. <br/> <span class="Bold">Posterior Reversible Encephalopathy Syndrome (PRES). </span>PRES is a rare condition that affects the brain and can cause death. The cause of PRES is not known. If PRES is found early and treated, most people recover. Tell your doctor right away if you have any new or worsening medical problems including: </td> </tr> <tr> <td class="Lrule"> <ul class="Circle"> <li>headache</li> <li>seizures</li> </ul> </td><td class="Rrule" colspan="4"> <ul class="Circle"> <li>confusion</li> <li>vision problems</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"> <br/> <span class="Bold">What is IMULDOSA?</span> <br/> IMULDOSA is a prescription medicine used to treat: <ul class="Disc"> <li>adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).</li> <li>adults and children 6 years and older with active psoriatic arthritis.</li> <li>adults 18 years and older with moderately to severely active Crohn’s disease.</li> <li>adults 18 years and older with moderately to severely active ulcerative colitis.</li> </ul> It is not known if IMULDOSA is safe and effective in children less than 6 years of age. </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Do not take IMULDOSA if you are </span>allergic to ustekinumab products or any of the ingredients in IMULDOSA. See the end of this Medication Guide for a complete list of ingredients in IMULDOSA. </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Before you receive IMULDOSA, tell your doctor about all of your medical conditions, including if you:</span> <ul class="Disc"> <li>have any of the conditions or symptoms listed in the section <span class="Bold">“What is the most important information I should know about IMULDOSA?”</span> </li> <li>ever had an allergic reaction to ustekinumab products. Ask your doctor if you are not sure.</li> <li>have recently received or are scheduled to receive an immunization (vaccine). People who take IMULDOSA should not receive live vaccines. Tell your doctor if anyone in your house needs a live vaccine. The viruses used in some types of live vaccines can spread to people with a weakened immune system, and can cause serious problems. You should not receive the BCG vaccine during the one year before receiving IMULDOSA or one year after you stop receiving IMULDOSA.</li> <li>have any new or changing lesions within psoriasis areas or on normal skin.</li> <li>are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as well for you during treatment with IMULDOSA. IMULDOSA may also increase your risk of having an allergic reaction to an allergy shot.</li> <li>receive or have received phototherapy for your psoriasis.</li> <li>are pregnant or plan to become pregnant. It is not known if IMULDOSA can harm your unborn baby. You and your doctor should decide if you will receive IMULDOSA. See “What should I avoid while using IMULDOSA?”</li> <li>received IMULDOSA while you were pregnant. It is important that you tell your baby’s healthcare provider before any vaccinations are given to your baby.</li> <li>are breastfeeding or plan to breastfeed. IMULDOSA can pass into your breast milk.</li> <li>Talk to your doctor about the best way to feed your baby if you receive IMULDOSA.</li> </ul> <span class="Bold">Tell your doctor about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements. <br/> Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">How should I use IMULDOSA?</span> <ul class="Disc"> <li>Use IMULDOSA exactly as your doctor tells you to.</li> <li>Adults with Crohn’s disease and ulcerative colitis will receive the first dose of IMULDOSA through a vein in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour to receive the full dose of medicine. You will then receive IMULDOSA as an injection under the skin (subcutaneous injection) 8 weeks after the first dose of IMULDOSA, as described below.</li> <li>Adults with psoriasis or psoriatic arthritis, and children 6 years and older with psoriasis or psoriatic arthritis will receive IMULDOSA as an injection under the skin (subcutaneous injection) as described below.</li> <li> <span class="Bold">Injecting IMULDOSA under your skin</span> <ul class="Circle"> <li>IMULDOSA is intended for use under the guidance and supervision of your doctor. In children 6 years and older, it is recommended that IMULDOSA be administered by a healthcare provider. If your doctor decides that you or a caregiver may give your injections of IMULDOSA at home, you should receive training on the right way to prepare and inject IMULDOSA. Your doctor will determine the right dose of IMULDOSA for you, the amount for each injection, and how often you should receive it. Do not try to inject IMULDOSA yourself until you or your caregiver have been shown how to inject IMULDOSA by your doctor or nurse.</li> <li>Inject IMULDOSA under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs (thighs) or stomach area (abdomen). </li> <li>Do not give an injection in an area of the skin that is tender, bruised, red or hard. </li> <li>Use a different injection site each time you use IMULDOSA. </li> <li>If you inject more IMULDOSA than prescribed, call your doctor right away. </li> <li>Be sure to keep all of your scheduled follow-up appointments.</li> </ul> </li> </ul> <span class="Bold">Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to prepare and inject a dose of IMULDOSA, and how to properly throw away (dispose of) used needles and syringes. The syringe, needle and vial must never be re-used. After the rubber stopper is punctured, IMULDOSA can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused portion of IMULDOSA.</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">What should I avoid while using IMULDOSA?</span> <br/> You should not receive a live vaccine while taking IMULDOSA. See <span class="Bold">“Before you receive IMULDOSA, tell your doctor about all of your medical conditions, including if you:”</span></td> </tr> <tr> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">What are the possible side effects of IMULDOSA?</span> <br/> IMULDOSA may cause serious side effects, including: <ul class="Disc"> <li>See “What is the most important information I should know about IMULDOSA?”</li> <li>Serious allergic reactions. Serious allergic reactions can occur with IMULDOSA. Stop using IMULDOSA and get medical help right away if you have any of the following symptoms of a serious allergic reaction:</li> </ul> </td> </tr> <tr> <td class="Lrule"> <ul class="Circle"> <li>feeling faint</li> <li>swelling of your face, eyelids, tongue, or throat</li> </ul> </td><td class="Rrule" colspan="4"> <ul class="Circle"> <li>chest tightness</li> <li>skin rash</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2" valign="middle"> <ul class="Disc"> <li> <span class="Bold">Lung inflammation</span>. Cases of lung inflammation have happened in some people who receive ustekinumab products, and may be serious. <br/> These lung problems may need to be treated in a hospital. Tell your doctor right away if you develop shortness of breath or a cough that doesn’t go away during treatment with IMULDOSA. </li> </ul> <br/> <span class="Bold">Common side effects of IMULDOSA include:</span></td> </tr> <tr> <td class="Lrule"> <ul class="Circle"> <li>nasal congestion, sore throat, and runny nose</li> <li>upper respiratory infections</li> <li>fever</li> <li>headache</li> <li>tiredness</li> <li>itching</li> <li>nausea and vomiting</li> </ul> </td><td class="Rrule" colspan="4"> <ul class="Circle"> <li>redness at the injection site</li> <li>vaginal yeast infections</li> <li>urinary tract infections</li> <li>sinus infection</li> <li>bronchitis</li> <li>diarrhea</li> <li>stomach pain</li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"> <br/> These are not all of the possible side effects of IMULDOSA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <br/> You may also report side effects to Accord BioPharma, Inc. at 1-866-941-7875. </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"> <br/> <span class="Bold">How should I store IMULDOSA?</span> <ul class="Disc"> <li>Store IMULDOSA vials and prefilled syringes in a refrigerator between 36°F to 46°F (2°C to 8°C).</li> <li>Store IMULDOSA vials standing up straight.</li> <li>Store IMULDOSA in the original carton to protect it from light until time to use it.</li> <li>Do not freeze IMULDOSA.</li> <li>Do not shake IMULDOSA.</li> </ul> If needed, individual IMULDOSA prefilled syringes may also be stored at room temperature up to 86ºF (30°C) for a maximum single period of up to 30 days in the original carton to protect from light. Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided. Once a syringe has been stored at room temperature, it should not be returned to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage. Do not use IMULDOSA after the expiration date on the carton or on the prefilled syringe. <br/> <span class="Bold">Keep IMULDOSA and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"> <br/> <span class="Bold">General information about the safe and effective use of IMULDOSA.</span> <br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use IMULDOSA for a condition for which it was not prescribed. Do not give IMULDOSA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about IMULDOSA that was written for health professionals. </td> </tr> <tr class="Botrule Last Last"> <td class="Lrule Rrule" colspan="2" valign="middle"> <p class="First"> <br/> <span class="Bold">What are the ingredients in IMULDOSA?</span> <br/> <span class="Bold">Active ingredient: </span>ustekinumab-srlf <br/> <span class="Bold">Inactive ingredients:</span><span class="Bold">Single-dose prefilled syringe for subcutaneous use</span>contains histidine, L-histidine hydrochloride monohydrate, polysorbate 80, and sucrose. <span class="Bold">Single-dose vial for intravenous infusion</span>contains edetate disodium, histidine, L-histidine hydrochloride monohydrate, methionine, polysorbate 80, and sucrose. <br/> <br/> Manufactured by: Accord BioPharma Inc. 8041 Arco Corporate Drive, Suite 200, Raleigh, North Carolina (NC), 27617 USA. <br/> US License No. 2105 <br/> <br/> For more information go to www.imuldosa.com or call 1-866-941-7875. </p> <p></p> <p>Marketed by:</p> <p>GSMS, Inc. <br/> Camarillo, CA 93012 USA </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<tfoot>\n<tr class=\"First First Last Last\">\n<td align=\"left\" valign=\"top\">This Medication Guide has been approved by the U.S. Food and Drug Administration</td><td align=\"right\" valign=\"bottom\">Issued: 03/2025</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"4\" valign=\"middle\"><span class=\"Bold\">MEDICATION GUIDE</span>\n<br/>\n<span class=\"Bold\">IMULDOSA (im ul doe' sah)</span>\n<br/>\n<span class=\"Bold\">(ustekinumab-srlf)</span>\n<br/>\n<span class=\"Bold\">injection, for subcutaneous or intravenous use</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">What is the most important information I should know about IMULDOSA?</span>\n<br/>\n\t\t\tIMULDOSA is a medicine that affects your immune system. IMULDOSA can increase your risk of having serious side effects, including:\n <br/>\n<span class=\"Bold\">Serious infections. </span>IMULDOSA may lower the ability of your immune system to fight infections and may increase your risk of infections. Some people have serious infections while taking ustekinumab products, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their infection.\n\t\t\t\n <ul class=\"Disc\">\n<li>Your doctor should check you for TB before starting IMULDOSA.</li>\n<li>If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with IMULDOSA and during treatment with IMULDOSA.</li>\n<li>Your doctor should watch you closely for signs and symptoms of TB while you are being treated with IMULDOSA.</li>\n</ul>\n\t\t\tYou should not start taking IMULDOSA if you have any kind of infection unless your doctor says it is okay.\n <br/>\n<br/>\n<span class=\"Bold\">Before starting IMULDOSA, tell your doctor if you:</span>\n<ul class=\"Disc\">\n<li>think you have an infection or have symptoms of an infection such as:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\">\n<ul class=\"Circle\">\n<li>fever, sweat, or chills</li>\n<li>muscle aches</li>\n<li>cough</li>\n<li>shortness of breath</li>\n<li>blood in phlegm</li>\n</ul>\n</td><td class=\"Rrule\" colspan=\"4\">\n<ul class=\"Circle\">\n<li>weight loss</li>\n<li>warm, red, or painful skin or sores on your body</li>\n<li>diarrhea or stomach pain</li>\n<li>burning when you urinate or urinate more often than normal</li>\n<li>feel very tired</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\">\n<ul class=\"Disc\">\n<li>are being treated for an infection or have any open cuts.</li>\n<li>get a lot of infections or have infections that keep coming back.</li>\n<li>have TB, or have been in close contact with someone with TB.</li>\n</ul>\n<span class=\"Bold\">After starting IMULDOSA, </span>call your doctor right away if you have any symptoms of an infection (see above). These may be signs of infections such as chest infections, or skin infections or shingles that could have serious complications. IMULDOSA can make you more likely to get infections or make an infection that you have worse.\n <br/>\n\t\t\tPeople who have a genetic problem where the body does not make any of the proteins interleukin 12 (IL-12) and interleukin 23 (IL-23) are at a higher risk for certain serious infections. These infections can spread throughout the body and cause death. People who take IMULDOSA may also be more likely to get these infections.\n <br/>\n<span class=\"Bold\">Cancers. </span>IMULDOSA may decrease the activity of your immune system and increase your risk for certain types of cancers. Tell your doctor if you have ever had any type of cancer. Some people who are receiving ustekinumab products and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with IMULDOSA, tell your doctor if you develop any new skin growths.\n <br/>\n<span class=\"Bold\">Posterior Reversible Encephalopathy Syndrome (PRES). </span>PRES is a rare condition that affects the brain and can cause death. The cause of PRES is not known. If PRES is found early and treated, most people recover. Tell your doctor right away if you have any new or worsening medical problems including:\n </td>\n</tr>\n<tr>\n<td class=\"Lrule\">\n<ul class=\"Circle\">\n<li>headache</li>\n<li>seizures</li>\n</ul>\n</td><td class=\"Rrule\" colspan=\"4\">\n<ul class=\"Circle\">\n<li>confusion</li>\n<li>vision problems</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\">\n<br/>\n<span class=\"Bold\">What is IMULDOSA?</span>\n<br/>\n\t\t\tIMULDOSA is a prescription medicine used to treat:\n\t\t\t\n <ul class=\"Disc\">\n<li>adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).</li>\n<li>adults and children 6 years and older with active psoriatic arthritis.</li>\n<li>adults 18 years and older with moderately to severely active Crohn’s disease.</li>\n<li>adults 18 years and older with moderately to severely active ulcerative colitis.</li>\n</ul>\n\t\t\tIt is not known if IMULDOSA is safe and effective in children less than 6 years of age.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">Do not take IMULDOSA if you are </span>allergic to ustekinumab products or any of the ingredients in IMULDOSA. See the end of this Medication Guide for a complete list of ingredients in IMULDOSA.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">Before you receive IMULDOSA, tell your doctor about all of your medical conditions, including if you:</span>\n<ul class=\"Disc\">\n<li>have any of the conditions or symptoms listed in the section \n <span class=\"Bold\">“What is the most important information I should know about IMULDOSA?”</span>\n</li>\n<li>ever had an allergic reaction to ustekinumab products. Ask your doctor if you are not sure.</li>\n<li>have recently received or are scheduled to receive an immunization (vaccine). People who take IMULDOSA should not receive live vaccines. Tell your doctor if anyone in your house needs a live vaccine. The viruses used in some types of live vaccines can spread to people with a weakened immune system, and can cause serious problems. You should not receive the BCG vaccine during the one year before receiving IMULDOSA or one year after you stop receiving IMULDOSA.</li>\n<li>have any new or changing lesions within psoriasis areas or on normal skin.</li>\n<li>are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as well for you during treatment with IMULDOSA. IMULDOSA may also increase your risk of having an allergic reaction to an allergy shot.</li>\n<li>receive or have received phototherapy for your psoriasis.</li>\n<li>are pregnant or plan to become pregnant. It is not known if IMULDOSA can harm your unborn baby. You and your doctor should decide if you will receive IMULDOSA. See “What should I avoid while using IMULDOSA?”</li>\n<li>received IMULDOSA while you were pregnant. It is important that you tell your baby’s healthcare provider before any vaccinations are given to your baby.</li>\n<li>are breastfeeding or plan to breastfeed. IMULDOSA can pass into your breast milk.</li>\n<li>Talk to your doctor about the best way to feed your baby if you receive IMULDOSA.</li>\n</ul>\n<span class=\"Bold\">Tell your doctor about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements.\n <br/>\n\t\t\tKnow the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">How should I use IMULDOSA?</span>\n<ul class=\"Disc\">\n<li>Use IMULDOSA exactly as your doctor tells you to.</li>\n<li>Adults with Crohn’s disease and ulcerative colitis will receive the first dose of IMULDOSA through a vein in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour to receive the full dose of medicine. You will then receive IMULDOSA as an injection under the skin (subcutaneous injection) 8 weeks after the first dose of IMULDOSA, as described below.</li>\n<li>Adults with psoriasis or psoriatic arthritis, and children 6 years and older with psoriasis or psoriatic arthritis will receive IMULDOSA as an injection under the skin (subcutaneous injection) as described below.</li>\n<li>\n<span class=\"Bold\">Injecting IMULDOSA under your skin</span>\n<ul class=\"Circle\">\n<li>IMULDOSA is intended for use under the guidance and supervision of your doctor. In children 6 years and older, it is recommended that IMULDOSA be administered by a healthcare provider. If your doctor decides that you or a caregiver may give your injections of IMULDOSA at home, you should receive training on the right way to prepare and inject IMULDOSA. Your doctor will determine the right dose of IMULDOSA for you, the amount for each injection, and how often you should receive it. Do not try to inject IMULDOSA yourself until you or your caregiver have been shown how to inject IMULDOSA by your doctor or nurse.</li>\n<li>Inject IMULDOSA under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs (thighs) or stomach area (abdomen). </li>\n<li>Do not give an injection in an area of the skin that is tender, bruised, red or hard. </li>\n<li>Use a different injection site each time you use IMULDOSA. </li>\n<li>If you inject more IMULDOSA than prescribed, call your doctor right away. </li>\n<li>Be sure to keep all of your scheduled follow-up appointments.</li>\n</ul>\n</li>\n</ul>\n<span class=\"Bold\">Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to prepare and inject a dose of IMULDOSA, and how to properly throw away (dispose of) used needles and syringes. The syringe, needle and vial must never be re-used. After the rubber stopper is punctured, IMULDOSA can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused portion of IMULDOSA.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">What should I avoid while using IMULDOSA?</span>\n<br/>\n\t\t\tYou should not receive a live vaccine while taking IMULDOSA. See \n <span class=\"Bold\">“Before you receive IMULDOSA, tell your doctor about all of your medical conditions, including if you:”</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">What are the possible side effects of IMULDOSA?</span>\n<br/>\n\t\t\tIMULDOSA may cause serious side effects, including:\n\t\t\t\n <ul class=\"Disc\">\n<li>See “What is the most important information I should know about IMULDOSA?”</li>\n<li>Serious allergic reactions. Serious allergic reactions can occur with IMULDOSA. Stop using IMULDOSA and get medical help right away if you have any of the following symptoms of a serious allergic reaction:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\">\n<ul class=\"Circle\">\n<li>feeling faint</li>\n<li>swelling of your face, eyelids, tongue, or throat</li>\n</ul>\n</td><td class=\"Rrule\" colspan=\"4\">\n<ul class=\"Circle\">\n<li>chest tightness</li>\n<li>skin rash</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Lung inflammation</span>. Cases of lung inflammation have happened in some people who receive ustekinumab products, and may be serious.\n <br/>\n\t\t\t\tThese lung problems may need to be treated in a hospital. Tell your doctor right away if you develop shortness of breath or a cough that doesn’t go away during treatment with IMULDOSA.\n </li>\n</ul>\n<br/>\n<span class=\"Bold\">Common side effects of IMULDOSA include:</span></td>\n</tr>\n<tr>\n<td class=\"Lrule\">\n<ul class=\"Circle\">\n<li>nasal congestion, sore throat, and runny nose</li>\n<li>upper respiratory infections</li>\n<li>fever</li>\n<li>headache</li>\n<li>tiredness</li>\n<li>itching</li>\n<li>nausea and vomiting</li>\n</ul>\n</td><td class=\"Rrule\" colspan=\"4\">\n<ul class=\"Circle\">\n<li>redness at the injection site</li>\n<li>vaginal yeast infections</li>\n<li>urinary tract infections</li>\n<li>sinus infection</li>\n<li>bronchitis</li>\n<li>diarrhea</li>\n<li>stomach pain</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\">\n<br/>\n\t\t\tThese are not all of the possible side effects of IMULDOSA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n <br/>\n\t\t\tYou may also report side effects to Accord BioPharma, Inc. at 1-866-941-7875.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\">\n<br/>\n<span class=\"Bold\">How should I store IMULDOSA?</span>\n<ul class=\"Disc\">\n<li>Store IMULDOSA vials and prefilled syringes in a refrigerator between 36°F to 46°F (2°C to 8°C).</li>\n<li>Store IMULDOSA vials standing up straight.</li>\n<li>Store IMULDOSA in the original carton to protect it from light until time to use it.</li>\n<li>Do not freeze IMULDOSA.</li>\n<li>Do not shake IMULDOSA.</li>\n</ul>\n\t\t\tIf needed, individual IMULDOSA prefilled syringes may also be stored at room temperature up to 86ºF (30°C) for a maximum single period of up to 30 days in the original carton to protect from light. Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided. Once a syringe has been stored at room temperature, it should not be returned to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage. Do not use IMULDOSA after the expiration date on the carton or on the prefilled syringe.\n <br/>\n<span class=\"Bold\">Keep IMULDOSA and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\">\n<br/>\n<span class=\"Bold\">General information about the safe and effective use of IMULDOSA.</span>\n<br/>\n\t\t\tMedicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use IMULDOSA for a condition for which it was not prescribed. Do not give IMULDOSA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about IMULDOSA that was written for health professionals.\n </td>\n</tr>\n<tr class=\"Botrule Last Last\">\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"middle\">\n<p class=\"First\">\n<br/>\n<span class=\"Bold\">What are the ingredients in IMULDOSA?</span>\n<br/>\n<span class=\"Bold\">Active ingredient: </span>ustekinumab-srlf\n <br/>\n<span class=\"Bold\">Inactive ingredients:</span><span class=\"Bold\">Single-dose prefilled syringe for subcutaneous use</span>contains histidine, L-histidine hydrochloride monohydrate, polysorbate 80, and sucrose. \n <span class=\"Bold\">Single-dose vial for intravenous infusion</span>contains edetate disodium, histidine, L-histidine hydrochloride monohydrate, methionine, polysorbate 80, and sucrose.\n <br/>\n<br/>\n\t\t\tManufactured by: Accord BioPharma Inc. 8041 Arco Corporate Drive, Suite 200, Raleigh, North Carolina (NC), 27617 USA.\n <br/>\n\t\t\tUS License No. 2105\n <br/>\n<br/>\n\t\t\tFor more information go to www.imuldosa.com or call 1-866-941-7875.\n </p>\n<p></p>\n<p>Marketed by:</p>\n<p>GSMS, Inc.\n <br/>\n\t\t\tCamarillo, CA 93012 USA\n </p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <tbody class="Headless"> <tr class="First First Last Last"> <td align="center"> <p class="First"> <br/> <span class="Bold">INSTRUCTIONS FOR USE <br/> IMULDOSA (im ul doe' sah) <br/> (ustekinumab-srlf) <br/> injection, for subcutaneous use <br/> Instructions for injecting IMULDOSA using a prefilled syringe. </span> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<tbody class=\"Headless\">\n<tr class=\"First First Last Last\">\n<td align=\"center\">\n<p class=\"First\">\n<br/>\n<span class=\"Bold\">INSTRUCTIONS FOR USE\n <br/>\n\t\t\tIMULDOSA (im ul doe' sah)\n <br/>\n\t\t\t(ustekinumab-srlf)\n <br/>\n\t\t\tinjection, for subcutaneous use\n <br/>\n\t\t\tInstructions for injecting IMULDOSA using a prefilled syringe.\n </span>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Read this Instructions for Use before you start using IMULDOSA. Your doctor or nurse should show you how to prepare and give your injection of IMULDOSA the right way.

{ "type": "p", "children": [], "text": "\nRead this Instructions for Use before you start using IMULDOSA.\n \nYour doctor or nurse should show you how to prepare and give your injection of IMULDOSA the right way.\n \n" }

If you cannot give yourself the injection:

{ "type": "p", "children": [], "text": "If you cannot give yourself the injection:" }

{ "type": "ul", "children": [ "ask your doctor or nurse to help you, or", "ask someone who has been trained by a doctor or nurse to give your injections." ], "text": "" }

Do not try to inject IMULDOSA yourself until you have been shown how to inject IMULDOSA by your doctor, nurse or health professional.

{ "type": "p", "children": [], "text": "Do not try to inject IMULDOSA yourself until you have been shown how to inject IMULDOSA by your doctor, nurse or health professional." }

Important information:

{ "type": "p", "children": [], "text": "\nImportant information:\n" }

{ "type": "ul", "children": [ "Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by your doctor.\n\t\n \nIf your dose is 45 mg, you will receive one 45 mg prefilled syringe.\nIf your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes.\n \nIf you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself two injections, one right after the other.\n\n\n", "Children 12 years of age and older with psoriasis who weigh 132 pounds or more may use a prefilled syringe.", "\nStore IMULDOSAin a refrigerator between 36ºF to 46ºF (2ºC to 8ºC) in the original carton to protect from light.\n ", "If needed, individual IMULDOSA prefilled syringes may be stored at room temperature up to 86°F (30°C) for a maximum 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. If a syringe has been stored at room temperature, it should not be returned to the refrigerator.", "Check the expiration date on the prefilled syringe and carton. If the expiration date has passed or if the prefilled syringe has been kept at room temperature up to 86°F (30°C) for longer than a maximum single period of 30 days or if the prefilled syringe has been stored above 86°F (30°C), do not use it. If the expiration date has passed or if the prefilled syringe has been stored above 86°F (30°C), call your doctor or pharmacist, or call 1-866-941-7875 for help.", "Make sure the syringe is not damaged.", "Check your prefilled syringe for any particles or discoloration. Your prefilled syringe should look clear to slightly clear and colorless to slightly yellow solution.", "Do not use if it is frozen, discolored, cloudy or has particles. Get a new prefilled syringe.", "\nDo not shake the prefilled syringe at any time.Shaking your prefilled syringe may damage your IMULDOSA medicine. If your prefilled syringe has been shaken, do not use it. Get a new prefilled syringe.\n ", "To reduce the risk of accidental needle sticks, each prefilled syringe has a needle guard that is automatically activated to cover the needle after you have given your injection. Do not pull back on the plunger at any time." ], "text": "" }

Gather the supplies you will need to prepare IMULDOSA and to give your injection. (See Figure A) You will need:

{ "type": "p", "children": [], "text": "\nGather the supplies you will need to prepare IMULDOSA and to give your injection. (See Figure A)\n\nYou will need:\n " }

{ "type": "ul", "children": [ "antiseptic wipes", "cotton balls or gauze pads", "adhesive bandage", "your prescribed dose of IMULDOSA ( \n See Figure B)\n ", "FDA-cleared sharps disposal container. \n See “Step 4: Dispose of the syringe.”\n" ], "text": "" }

Figure A

{ "type": "p", "children": [], "text": "\nFigure A\n" }

Figure B

{ "type": "p", "children": [], "text": "\nFigure B\n" }

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

{ "type": "p", "children": [], "text": "\nTo prevent premature activation of the needle safety guard, do not touch the needle guard activation CLIPS at any time during use.\n" }

Step 1: Prepare the injection.

{ "type": "p", "children": [], "text": "\nStep 1: Prepare the injection.\n" }

{ "type": "ul", "children": [ "Choose a well-lit, clean, flat work surface.", "Wash your hands well with soap and warm water.", "Hold the prefilled syringe with the covered needle pointing upward." ], "text": "" }

Step 2: Prepare your injection site

{ "type": "p", "children": [], "text": "\nStep 2: Prepare your injection site\n" }

{ "type": "ul", "children": [ "Choose an injection site around your stomach area (abdomen), buttocks, upper legs (thighs). If a caregiver is giving you the injection, the outer area of the upper arms may also be used. \n (See \n Figure C) \n \n", "\nUse a different injection site for each injection. Do notgive an injection in an area of the skin that is tender, bruised, red or hard.\n ", "Clean the skin with an antiseptic wipe where you plan to give your injection.", "\nDo nottouch this area again before giving the injection. Let your skin dry before injecting.\n ", "\nDo notfan or blow on the clean area.\n " ], "text": "" }

Figure C

{ "type": "p", "children": [], "text": "\nFigure C\n" }

*Areas in gray are recommended injection sites.

{ "type": "p", "children": [], "text": "*Areas in gray are recommended injection sites." }

Step 3: Inject IMULDOSA

{ "type": "p", "children": [], "text": "\nStep 3: Inject IMULDOSA\n" }

{ "type": "ul", "children": [ "Remove the needle cover when you are ready to inject your IMULDOSA.", "\nDo notthe plunger or the plunger head while removing the needle cover.\n ", "Hold the body of the prefilled syringe with one hand and pull the needle cover straight off. \n (See \n Figure D) \n \n", "Put the needle cover in the trash.", "You may also see a drop of liquid at the end of the needle. This is normal.", "\nDo nottouch the needle or let it touch anything.\n ", "\nDo notuse the prefilled syringe if it is dropped without the needle cover in place. Call your doctor, nurse or health professional for instructions.\n " ], "text": "" }

Figure D

{ "type": "p", "children": [], "text": "\nFigure D\n" }

{ "type": "ul", "children": [ "Hold the body of the prefilled syringe in one hand between the thumb and index fingers. \n (See \n Figure E) \n \n" ], "text": "" }

Figure E

{ "type": "p", "children": [], "text": "\nFigure E\n" }

{ "type": "ul", "children": [ "\nDo notpull back on the plunger at any time.\n ", "Use the other hand to gently pinch the cleaned area of skin. Hold firmly.", "Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree angle. \n (See \n Figure F) \n \n" ], "text": "" }

Figure F

{ "type": "p", "children": [], "text": "\nFigure F\n" }

{ "type": "ul", "children": [ "Inject all of the liquid by using your thumb to push in the plunger until the plunger head is completely between the needle guard wings. \n (See \n Figure G) \n \n" ], "text": "" }

Figure G

{ "type": "p", "children": [], "text": "\nFigure G\n" }

{ "type": "ul", "children": [ "When the plunger is pushed as far as it will go, keep pressure on the plunger head. Take the needle out of the skin and let go of the skin.", "Slowly take your thumb off the plunger head. This will let the empty syringe move up until the entire needle is covered by the needle guard. \n (See \n Figure H) \n \n" ], "text": "" }

Figure H

{ "type": "p", "children": [], "text": "\nFigure H\n" }

{ "type": "ul", "children": [ "When the needle is pulled out of your skin, there may be a little bleeding at the injection site. This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary." ], "text": "" }

If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself a second injection right after the first. Repeat Steps 1 to 3 for the second injection using a new syringe. Choose a different site for the second injection.

{ "type": "p", "children": [], "text": "\nIf your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself a second injection right after the first. Repeat Steps 1 to 3 for the second injection using a new syringe. Choose a different site for the second injection.\n" }

Step 4: Dispose of the syringe.

{ "type": "p", "children": [], "text": "\nStep 4: Dispose of the syringe.\n" }

{ "type": "ul", "children": [ "Put the syringe in a FDA-cleared sharps disposal container right away after use. \n Do not throw away (dispose of) loose syringes in your household trash.\n", "If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:\n\t\n \nmade of heavy-duty plastic.\ncan be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out.\nupright and stable during use,\nleak-resistant,\nand properly labeled to warn of hazardous waste inside the container.\n\n", "When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.", "Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container.", "If you have any questions, talk to your doctor or pharmacist." ], "text": "" }

Keep IMULDOSA and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep IMULDOSA and all medicines out of the reach of children.\n" }

Manufactured by: Accord BioPharma Inc. 8041 Arco Corporate Drive, Suite 200, Raleigh, North Carolina (NC), 27617 USA US License No. 2105

{ "type": "p", "children": [], "text": "Manufactured by:\n \nAccord BioPharma Inc. 8041 Arco Corporate Drive, Suite 200, Raleigh, North Carolina (NC), 27617 USA\n \nUS License No. 2105\n " }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

Approved: 03/2025

{ "type": "p", "children": [], "text": "Approved: 03/2025" }

Marketed by:

{ "type": "p", "children": [], "text": "Marketed by:" }

GSMS, Inc. Camarillo, CA 93012 USA

{ "type": "p", "children": [], "text": "GSMS, Inc.\n \nCamarillo, CA 93012 USA\n " }

Carton Label

{ "type": "p", "children": [], "text": "Carton Label" }

45 mg/0.5 mL

{ "type": "p", "children": [], "text": "45 mg/0.5 mL" }

(NDC 51407-929-11)

{ "type": "p", "children": [], "text": "(NDC 51407-929-11)" }

Carton Label

{ "type": "p", "children": [], "text": "Carton Label" }

90 mg/mL (NDC 51407-930-11)

{ "type": "p", "children": [], "text": "90 mg/mL\n \n(NDC 51407-930-11)\n " }

Carton Label

{ "type": "p", "children": [], "text": "Carton Label" }

130 mg/26 mL (5 mg/mL)

{ "type": "p", "children": [], "text": "130 mg/26 mL (5 mg/mL)" }

(NDC 51407-931-11)

{ "type": "p", "children": [], "text": "(NDC 51407-931-11)" }

SELARSDI™ 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.

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

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

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

Subcutaneous Adult Dosage Regimen

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

The recommended dose of SELARSDI for pediatric patients (6 to 17 years old) with plaque psoriasis based on body weight is shown below (Table 1).

<div class="scrollingtable"><table> <caption> <span>Table 1: Recommended Dose of SELARSDI for Subcutaneous Injection in Pediatric Patients (6 to 17 years old) with Plaque Psoriasis</span> </caption> <col width="318.2pt"/> <col width="221.8pt"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Toprule"> <p class="First"> <span class="Bold">Body Weight of Patient at the Time of Dosing</span> </p> </td><td align="center" class="Botrule Toprule"> <p class="First"> <span class="Bold">Recommended Dose</span> </p> </td> </tr> <tr> <td> less than 60 kg</td><td align="center"> <p class="First">0.75 mg/kg</p> </td> </tr> <tr> <td> <p class="First">60 kg to 100 kg</p> </td><td align="center"> <p class="First">45 mg</p> </td> </tr> <tr class="Last"> <td>more than 100 kg </td><td align="center"> 90 mg</td> </tr> </tbody> </table></div>

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 single-dose vial.

<div class="scrollingtable"><table> <caption> <span>Table 2: Injection volumes of SELARSDI 45 mg/0.5 mL single-dose vials for pediatric patients (6 to 17 years old) with plaque psoriasis and pediatric patients (6 to 17 years old) with psoriatic arthritis* weighing less than 60 kg</span> </caption> <col width="181.9pt"/> <col width="181.9pt"/> <col width="181.95pt"/> <tbody class="Headless"> <tr class="First"> <td align="center"> <p class="First"> <span class="Bold">Body Weight (kg) at the time of dosing</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Dose (mg)</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Volume of injection (mL)</span> </p> </td> </tr> <tr> <td align="center" class="Toprule"> <p class="First">15</p> </td><td align="center" class="Toprule"> <p class="First">11.3</p> </td><td align="center" class="Toprule"> <p class="First">0.12</p> </td> </tr> <tr> <td align="center"> <p class="First">16</p> </td><td align="center"> <p class="First">12.0</p> </td><td align="center"> <p class="First">0.13</p> </td> </tr> <tr> <td align="center"> <p class="First">17</p> </td><td align="center"> <p class="First">12.8</p> </td><td align="center"> <p class="First">0.14</p> </td> </tr> <tr> <td align="center"> <p class="First">18</p> </td><td align="center"> <p class="First">13.5</p> </td><td align="center"> <p class="First">0.15</p> </td> </tr> <tr> <td align="center"> <p class="First">19</p> </td><td align="center"> <p class="First">14.3</p> </td><td align="center"> <p class="First">0.16</p> </td> </tr> <tr> <td align="center"> <p class="First">20</p> </td><td align="center"> <p class="First">15.0</p> </td><td align="center"> <p class="First">0.17</p> </td> </tr> <tr> <td align="center"> <p class="First">21</p> </td><td align="center"> <p class="First">15.8</p> </td><td align="center"> <p class="First">0.17</p> </td> </tr> <tr> <td align="center"> <p class="First">22</p> </td><td align="center"> <p class="First">16.5</p> </td><td align="center"> <p class="First">0.18</p> </td> </tr> <tr> <td align="center"> <p class="First">23</p> </td><td align="center"> <p class="First">17.3</p> </td><td align="center"> <p class="First">0.19</p> </td> </tr> <tr> <td align="center"> <p class="First">24</p> </td><td align="center"> <p class="First">18.0</p> </td><td align="center"> <p class="First">0.20</p> </td> </tr> <tr> <td align="center"> <p class="First">25</p> </td><td align="center"> <p class="First">18.8</p> </td><td align="center"> <p class="First">0.21</p> </td> </tr> <tr> <td align="center"> <p class="First">26</p> </td><td align="center"> <p class="First">19.5</p> </td><td align="center"> <p class="First">0.22</p> </td> </tr> <tr> <td align="center"> <p class="First">27</p> </td><td align="center"> <p class="First">20.3</p> </td><td align="center"> <p class="First">0.22</p> </td> </tr> <tr> <td align="center"> <p class="First">28</p> </td><td align="center"> <p class="First">21.0</p> </td><td align="center"> <p class="First">0.23</p> </td> </tr> <tr> <td align="center"> <p class="First">29</p> </td><td align="center"> <p class="First">21.8</p> </td><td align="center"> <p class="First">0.24</p> </td> </tr> <tr> <td align="center"> <p class="First">30</p> </td><td align="center"> <p class="First">22.5</p> </td><td align="center"> <p class="First">0.25</p> </td> </tr> <tr> <td align="center"> <p class="First">31</p> </td><td align="center"> <p class="First">23.3</p> </td><td align="center"> <p class="First">0.26</p> </td> </tr> <tr> <td align="center"> <p class="First">32</p> </td><td align="center"> <p class="First">24</p> </td><td align="center"> <p class="First">0.27</p> </td> </tr> <tr> <td align="center"> <p class="First">33</p> </td><td align="center"> <p class="First">24.8</p> </td><td align="center"> <p class="First">0.27</p> </td> </tr> <tr> <td align="center"> <p class="First">34</p> </td><td align="center"> <p class="First">25.5</p> </td><td align="center"> <p class="First">0.28</p> </td> </tr> <tr> <td align="center"> <p class="First">35</p> </td><td align="center"> <p class="First">26.3</p> </td><td align="center"> <p class="First">0.29</p> </td> </tr> <tr> <td align="center"> <p class="First">36</p> </td><td align="center"> <p class="First">27</p> </td><td align="center"> <p class="First">0.3</p> </td> </tr> <tr> <td align="center"> <p class="First">37</p> </td><td align="center"> <p class="First">27.8</p> </td><td align="center"> <p class="First">0.31</p> </td> </tr> <tr> <td align="center"> <p class="First">38</p> </td><td align="center"> <p class="First">28.5</p> </td><td align="center"> <p class="First">0.32</p> </td> </tr> <tr> <td align="center"> <p class="First">39</p> </td><td align="center"> <p class="First">29.3</p> </td><td align="center"> <p class="First">0.32</p> </td> </tr> <tr> <td align="center"> <p class="First">40</p> </td><td align="center"> <p class="First">30</p> </td><td align="center"> <p class="First">0.33</p> </td> </tr> <tr> <td align="center"> <p class="First">41</p> </td><td align="center"> <p class="First">30.8</p> </td><td align="center"> <p class="First">0.34</p> </td> </tr> <tr> <td align="center"> <p class="First">42</p> </td><td align="center"> <p class="First">31.5</p> </td><td align="center"> <p class="First">0.35</p> </td> </tr> <tr> <td align="center"> <p class="First">43</p> </td><td align="center"> <p class="First">32.3</p> </td><td align="center"> <p class="First">0.36</p> </td> </tr> <tr> <td align="center"> <p class="First">44</p> </td><td align="center"> <p class="First">33</p> </td><td align="center"> <p class="First">0.37</p> </td> </tr> <tr> <td align="center"> <p class="First">45</p> </td><td align="center"> <p class="First">33.8</p> </td><td align="center"> <p class="First">0.37</p> </td> </tr> <tr> <td align="center"> <p class="First">46</p> </td><td align="center"> <p class="First">34.5</p> </td><td align="center"> <p class="First">0.38</p> </td> </tr> <tr> <td align="center"> <p class="First">47</p> </td><td align="center"> <p class="First">35.3</p> </td><td align="center"> <p class="First">0.39</p> </td> </tr> <tr> <td align="center"> <p class="First">48</p> </td><td align="center"> <p class="First">36</p> </td><td align="center"> <p class="First">0.4</p> </td> </tr> <tr> <td align="center"> <p class="First">49</p> </td><td align="center"> <p class="First">36.8</p> </td><td align="center"> <p class="First">0.41</p> </td> </tr> <tr> <td align="center"> <p class="First">50</p> </td><td align="center"> <p class="First">37.5</p> </td><td align="center"> <p class="First">0.42</p> </td> </tr> <tr> <td align="center"> <p class="First">51</p> </td><td align="center"> <p class="First">38.3</p> </td><td align="center"> <p class="First">0.42</p> </td> </tr> <tr> <td align="center"> <p class="First">52</p> </td><td align="center"> <p class="First">39</p> </td><td align="center"> <p class="First">0.43</p> </td> </tr> <tr> <td align="center"> <p class="First">53</p> </td><td align="center"> <p class="First">39.8</p> </td><td align="center"> <p class="First">0.44</p> </td> </tr> <tr> <td align="center"> <p class="First">54</p> </td><td align="center"> <p class="First">40.5</p> </td><td align="center"> <p class="First">0.45</p> </td> </tr> <tr> <td align="center"> <p class="First">55</p> </td><td align="center"> <p class="First">41.3</p> </td><td align="center"> <p class="First">0.46</p> </td> </tr> <tr> <td align="center"> <p class="First">56</p> </td><td align="center"> <p class="First">42</p> </td><td align="center"> <p class="First">0.46</p> </td> </tr> <tr> <td align="center"> <p class="First">57</p> </td><td align="center"> <p class="First">42.8</p> </td><td align="center"> <p class="First">0.47</p> </td> </tr> <tr> <td align="center"> <p class="First">58</p> </td><td align="center"> <p class="First">43.5 </p> </td><td align="center"> <p class="First">0.48</p> </td> </tr> <tr> <td align="center"> <p class="First">59</p> </td><td align="center"> <p class="First">44.3</p> </td><td align="center"> <p class="First">0.49</p> </td> </tr> <tr class="Last"> <td class="Toprule" colspan="3"> <p class="First">* Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen.</p> </td> </tr> </tbody> </table></div>

Subcutaneous Adult Dosage Regimen

Subcutaneous Pediatric Dosage Regimen

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

The recommended dose of SELARSDI for pediatric patients (6 to 17 years old) with psoriatic arthritis, based on body weight, is shown below (Table 3).

<div class="scrollingtable"><table> <caption> <span>Table 3: Recommended Dose of SELARSDI for Subcutaneous Injection in Pediatric Patients (6 to 17 years old) with Psoriatic Arthritis</span> </caption> <col width="400px"/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule"> <p class="First"> <span class="Bold">Body Weight of Patient at the Time of Dosing</span> </p> </td><td align="center" class="Botrule Toprule"> <p class="First"> <span class="Bold">Recommended Dose</span> </p> </td> </tr> <tr> <td> Less than 60 kg*</td><td align="center"> <p class="First">0.75 mg/kg</p> </td> </tr> <tr> <td> <p class="First">60 kg or more</p> </td><td align="center"> <p class="First">45 mg</p> </td> </tr> <tr> <td class="Botrule"> <p class="First">greater than 100 kg with co-existent moderate-to-severe plaque psoriasis</p> </td><td align="center" class="Botrule"> <p class="First">90 mg</p> </td> </tr> <tr class="Last"> <td class="Botrule" colspan="2">* 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 single-dose vial. </td> </tr> </tbody> </table></div>

Intravenous Induction Adult Dosage Regimen

A single intravenous infusion dose of SELARSDI using the weight-based dosage regimen specified in Table 4

[see Instructions for dilution of SELARSDI 130 mg vial for intravenous infusion (2.6)].

<div class="scrollingtable"><table> <caption> <span>Table 4: Initial Intravenous Dosage of SELARSDI</span> </caption> <col width="242.75pt"/> <col width="100pt"/> <col width="202.2pt"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Body Weight of Patient at the time of dosing</span></td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Dose</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Number of 130 mg/26 mL <br/> (5 mg/mL) SELARSDI vials</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">55 kg or less</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">260 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">2</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">more than 55 kg to 85 kg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">390 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">3</td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">more than 85 kg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">520 mg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule">4</td> </tr> </tbody> </table></div>

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.

Refer to the diagram below for the provided instructions.

Hold the SYRINGE 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 SELARSDI subcutaneously as recommended [see Dosage and Administration (2.1, 2.2, 2.3)].

Inject all of the medication by pushing in the PLUNGER HEAD all the way in until the plunger head is completely between the needle guard activation clips. Injection of the entire prefilled syringe contents is necessary to activate the passive safety device 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. The PLUNGER will move up with your thumb and retract the needle into the needle guard, as shown by the illustration below:

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

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

Storage

If necessary, the diluted infusion solution may be kept at room temperature up to 25°C (77°F) for up to 4 hours. Protect the diluted solution from light. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within 4 hours after the dilution in the infusion bag (cumulative time after preparation including the storage and the infusion period). Do not freeze. Discard any unused portion of the infusion solution.

SELARSDI (ustekinumab-aekn) injection is a clear and colorless to slightly yellow solution and free of visible particles.

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Subcutaneous Injection

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

{ "type": "p", "children": [], "text": "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 

{ "type": "p", "children": [], "text": "Injection: 45 mg/0.5 mL solution in a single-dose vial \n" }

Intravenous Infusion

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

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

{ "type": "p", "children": [], "text": "SELARSDI is contraindicated in patients with clinically significant hypersensitivity to ustekinumab products or to any of the excipients in SELARSDI [see Warnings and Precautions (5.5)].\n" }

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

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

Avoid initiating treatment with SELARSDI 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 SELARSDI 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 SELARSDI and discontinue SELARSDI for serious or clinically significant infections until the infection resolves or is adequately treated.

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

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

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

Ustekinumab products are immunosuppressants 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 products 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 products who had pre-existing risk factors for developing non- melanoma skin cancer. Monitor all patients receiving SELARSDI 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)].

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

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 product initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab products.

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

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

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

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

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

Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% with higher rates in the ustekinumab groups during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies (14)].

<div class="scrollingtable"><table> <caption> <span>Table 5: Adverse Reactions, Reported by ≥1% of Subjects with Plaque Psoriasis and at Higher Rates in the ustekinumab groups through Week 12 in Ps STUDY 1 and Ps STUDY 2</span> </caption> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center"></td><td align="center"></td><td align="center" class="Botrule" colspan="2"> <p class="First"> <span class="Bold">Ustekinumab</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">45 mg</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">90 mg</span> </p> </td> </tr> <tr> <td align="center"> <p class="First"> <span class="Bold">Subjects treated</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">665</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">664</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">666</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Nasopharyngitis</p> </td><td align="center" class="Toprule"> <p class="First">51 (8%)</p> </td><td align="center" class="Toprule"> <p class="First">56 (8%)</p> </td><td align="center" class="Toprule"> <p class="First">49 (7%)</p> </td> </tr> <tr> <td> <p class="First">Upper respiratory tract infection</p> </td><td align="center"> <p class="First">30 (5%)</p> </td><td align="center"> <p class="First">36 (5%)</p> </td><td align="center"> <p class="First">28 (4%)</p> </td> </tr> <tr> <td> <p class="First">Headache</p> </td><td align="center"> <p class="First">23 (3%)</p> </td><td align="center"> <p class="First">33 (5%)</p> </td><td align="center"> <p class="First">32 (5%)</p> </td> </tr> <tr> <td> <p class="First">Fatigue</p> </td><td align="center"> <p class="First">14 (2%)</p> </td><td align="center"> <p class="First">18 (3%)</p> </td><td align="center"> <p class="First">17 (3%)</p> </td> </tr> <tr> <td> <p class="First">Back pain</p> </td><td align="center"> <p class="First">8 (1%)</p> </td><td align="center"> <p class="First">9 (1%)</p> </td><td align="center"> <p class="First">14 (2%)</p> </td> </tr> <tr> <td> <p class="First">Dizziness</p> </td><td align="center"> <p class="First">8 (1%)</p> </td><td align="center"> <p class="First">8 (1%)</p> </td><td align="center"> <p class="First">14 (2%)</p> </td> </tr> <tr> <td> <p class="First">Pharyngolaryngeal pain</p> </td><td align="center"> <p class="First">7 (1%)</p> </td><td align="center"> <p class="First">9 (1%)</p> </td><td align="center"> <p class="First">12 (2%)</p> </td> </tr> <tr> <td> <p class="First">Pruritus</p> </td><td align="center"> <p class="First">9 (1%)</p> </td><td align="center"> <p class="First">10 (2%)</p> </td><td align="center"> <p class="First">9 (1%)</p> </td> </tr> <tr> <td> <p class="First">Injection site erythema</p> </td><td align="center"> <p class="First">3 (&lt;1%)</p> </td><td align="center"> <p class="First">6 (1%)</p> </td><td align="center"> <p class="First">13 (2%)</p> </td> </tr> <tr> <td> <p class="First">Myalgia</p> </td><td align="center"> <p class="First">4 (1%)</p> </td><td align="center"> <p class="First">7 (1%)</p> </td><td align="center"> <p class="First">8 (1%)</p> </td> </tr> <tr class="Last"> <td class="Botrule"> <p class="First">Depression</p> </td><td align="center" class="Botrule"> <p class="First">3 (&lt;1%)</p> </td><td align="center" class="Botrule"> <p class="First">8 (1%)</p> </td><td align="center" class="Botrule"> <p class="First">4 (1%)</p> </td> </tr> </tbody> </table></div>

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 adult plaque psoriasis clinical trials [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 placebo-treated subjects and 13.4 weeks for ustekinumab-treated subjects), 27% of ustekinumab-treated subjects reported infections (1.39 per patient-years of follow-up) compared with 24% of placebo-treated subjects (1.21 per patient-years of follow-up). Serious infections occurred in 0.3% of ustekinumab-treated subjects (0.01 per patient-years of follow-up) and in 0.4% of placebo-treated subjects (0.02 per patient-years of follow-up) [see Warnings and Precautions (5.1)].

In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years), representing 8998 patient-years of exposure, 72.3% of ustekinumab-treated subjects reported infections (0.87 per patient-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per patient-years of follow-up).

Malignancies

In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years, representing 8998 patient-years of exposure), 1.7% of ustekinumab-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred patient-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of ustekinumab-treated subjects (0.52 per hundred patient-years of follow-up) [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 ustekinumab-treated subjects during the controlled and uncontrolled portions of trials were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).1

Pediatric Subjects with Plaque Psoriasis

The safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects 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 ustekinumab was assessed in 927 subjects in two randomized, double-blind, placebo-controlled trials in adults with active psoriatic arthritis (PsA). The overall safety profile of ustekinumab in subjects with PsA was consistent with the safety profile seen in adult psoriasis clinical trials. A higher incidence of arthralgia, nausea, and dental infections was observed in ustekinumab-treated subjects when compared with placebo- treated subjects (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical trials.

Crohn’s Disease

The safety of ustekinumab was assessed in 1407 subjects with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] greater than or equal to 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 ustekinumab 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 ustekinumab every 8 weeks, or placebo for 44 weeks in trial CD-3. Subjects in these 3 trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX)], oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn’s disease [see Clinical Studies (14.4)].

The overall safety profile of ustekinumab was consistent with the safety profile seen in the adult psoriasis and psoriatic arthritis clinical trials. Common adverse reactions in trials CD-1 and CD-2 and in trial CD-3 are listed in Tables 6 and 7, respectively.

<div class="scrollingtable"><table> <caption> <span>Table 6: Common adverse reactions through Week 8 in Trials CD-1 and CD-2 occurring in ≥3% of ustekinumab–treated subjects and higher than placebo</span> </caption> <col width="179.8pt"/> <col width="179.85pt"/> <col width="179.85pt"/> <tbody class="Headless"> <tr class="First"> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Ustekinumab</span> </p> <p> <span class="Bold">6 mg/kg single intravenous</span> </p> <p> <span class="Bold">induction dose</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">N=466</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">N=470</span> </p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Toprule"> <p class="First">Vomiting</p> </td><td align="center" class="Botrule Toprule"> <p class="First">3%</p> </td><td align="center" class="Botrule Toprule"> <p class="First">4%</p> </td> </tr> </tbody> </table></div>

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%).

<div class="scrollingtable"><table> <caption> <span>Table 7: Common adverse reactions through Week 44 in Trial CD-3 occurring in ≥3% of ustekinumab-treated subjects and higher than placebo</span> </caption> <col width="191.4pt"/> <col width="163pt"/> <col width="185.1pt"/> <tbody class="Headless"> <tr class="First"> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Ustekinumab<br/> </span><span class="Bold">90 mg subcutaneous<br/> </span><span class="Bold">maintenance dose every<br/> </span><span class="Bold">8 weeks</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">N=133</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">N=131</span> </p> </td> </tr> <tr> <td class="Botrule"> <p class="First">Nasopharyngitis</p> </td><td align="center" class="Botrule"> <p class="First">8%</p> </td><td align="center" class="Botrule"> <p class="First">11%</p> </td> </tr> <tr> <td> <p class="First">Injection site erythema</p> </td><td align="center"> <p class="First">0</p> </td><td align="center"> <p class="First">5%</p> </td> </tr> <tr> <td> <p class="First">Vulvovaginal candidiasis/mycotic infection</p> </td><td align="center"> <p class="First">1%</p> </td><td align="center"> <p class="First">5%</p> </td> </tr> <tr> <td> <p class="First">Bronchitis</p> </td><td align="center"> <p class="First">3%</p> </td><td align="center"> <p class="First">5%</p> </td> </tr> <tr> <td> <p class="First">Pruritus</p> </td><td align="center"> <p class="First">2%</p> </td><td align="center"> <p class="First">4%</p> </td> </tr> <tr> <td> <p class="First">Urinary tract infection</p> </td><td align="center"> <p class="First">2%</p> </td><td align="center"> <p class="First">4%</p> </td> </tr> <tr class="Last"> <td class="Botrule"> <p class="First">Sinusitis</p> </td><td align="center" class="Botrule"> <p class="First">2%</p> </td><td align="center" class="Botrule"> <p class="First">3%</p> </td> </tr> </tbody> </table></div>

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 patient 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 ustekinumab- treated subjects (0.36 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per hundred patient- years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.2% of ustekinumab-treated subjects (0.27 events per hundred patient-years) and in none of the placebo-treated subjects.

Hypersensitivity Reactions Including Anaphylaxis

In CD trials, two subjects reported hypersensitivity reactions following ustekinumab administration. One patient experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness of breath, and flushing) after a single subcutaneous administration (0.1% of subjects receiving subcutaneous ustekinumab). In addition, one subject experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body temperature) after the initial intravenous ustekinumab dose (0.08% of subjects receiving intravenous ustekinumab). These subjects were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour.

Ulcerative Colitis

The safety of ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to severely active ulcerative colitis [see Clinical Studies (14.5)]. The overall safety profile of ustekinumab in subjects with ulcerative colitis was consistent with the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of ustekinumab-treated subjects and at a higher rate than placebo were:

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 ustekinumab-treated subjects (0.48 events per hundred patient-years) and 0.0% of placebo-treated subjects (0.00 events per hundred patient- years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.5% of ustekinumab-treated subjects (0.64 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.40 events per hundred patient-years).

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ustekinumab or of other ustekinumab products.

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.

The following adverse reactions have been reported during post-approval use of ustekinumab products. 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 product 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.

In plaque psoriasis trials the safety of ustekinumab products 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.

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

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

Risk Summary

Limited data from observational studies, published case reports, and postmarketing surveillance on the use of ustekinumab products during pregnancy are insufficient to inform a drug associated risk of major birth defects, miscarriage, and other adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore, ustekinumab products may be transferred to the developing fetus [see Clinical Considerations].  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).

The background risk of major birth defects and miscarriage for the indicated population(s) are unknown. 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

Fetal/Neonatal Adverse Reactions

Because ustekinumab products may theoretically interfere with immune response to infections, consider risks and benefits prior to administering live vaccines to infants exposed to SELARSDI in utero. There are insufficient data regarding exposed infant serum levels of ustekinumab products at birth and the duration of persistence of ustekinumab products in infant serum after birth. Although a specific timeframe to delay administration of live attenuated vaccines in infants exposed in utero is unknown, consider the risks and benefits of delaying a minimum of 6 months after birth because of the clearance of the product.

Data

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.

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 products on milk production. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ustekinumab products are unknown. No adverse effects on the breastfed infant causally related to ustekinumab products 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 SELARSDI and any potential adverse effects on the breastfed child from SELARSDI or from the underlying maternal condition.

Plaque Psoriasis

The safety and effectiveness of SELARSDI have been established for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 to 17 years of age who are candidates for phototherapy or systemic therapy.

Use of SELARSDI in pediatric patients 12 to less than 17 years of age is supported by evidence from a multicenter, randomized, 60week trial (Ps STUDY 3) of ustekinumab that included a 12week, 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 SELARSDI 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) of ustekinumab in 44 subjects [see Adverse Reactions (6.1), Pharmacokinetics (12.3)].

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

Psoriatic Arthritis

The safety and effectiveness of SELARSDI have been established for treatment of psoriatic arthritis in pediatric patients 6 to 17 years old.

Use of SELARSDI in these age groups is supported by evidence from adequate and well controlled trials of ustekinumab in adults with psoriasis and PsA, pharmacokinetic data from adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and safety data of ustekinumab from two clinical trials in 44 pediatric subjects 6 to 11 years old with psoriasis and 110 pediatric subjects 12 to 17 years old 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 SELARSDI 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 SELARSDI have not been established in pediatric patients with Crohn’s disease or ulcerative colitis.

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.

Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity. In case of overdosage, monitor the patient for any signs or symptoms of adverse reactions or effects and institute appropriate symptomatic treatment immediately. Consider contacting the Poison Help line (1-800- 222-1222) or a medical toxicologist for additional overdose management recommendations.

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

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

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

{ "type": "p", "children": [], "text": "SELARSDI (ustekinumab-aekn) injection is a sterile, preservative-free, clear and colorless to slightly yellow solution free of visible particles with pH of 5.7 to 6.3." }

SELARSDI for Subcutaneous Use

{ "type": "p", "children": [], "text": "\nSELARSDI for Subcutaneous Use\n" }

Available as 45 mg of ustekinumab-aekn in 0.5 mL and 90 mg of ustekinumab-aekn in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 29-gauge fixed 1/2 inch needle and as 45 mg of ustekinumab-aekn in 0.5 mL in a single-dose borosilicate Type I glass vial with a rubber stopper. Not made with natural rubber latex.

{ "type": "p", "children": [], "text": "Available as 45 mg of ustekinumab-aekn in 0.5 mL and 90 mg of ustekinumab-aekn in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 29-gauge fixed 1/2 inch needle and as 45 mg of ustekinumab-aekn in 0.5 mL in a single-dose borosilicate Type I glass vial with a rubber stopper. Not made with natural rubber latex." }

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

{ "type": "p", "children": [], "text": "Each 0.5 mL prefilled syringe or vial delivers 45 mg ustekinumab-aekn, histidine (0.122 mg), L-histidine monohydrochloride monohydrate (0.507 mg), polysorbate 80 (0.02 mg), sucrose (38 mg) and water for injection (q.s)." }

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

{ "type": "p", "children": [], "text": "Each 1 mL prefilled syringe delivers 90 mg ustekinumab-aekn, histidine (0.243 mg), L-histidine monohydrochloride monohydrate (1.013 mg), polysorbate 80 (0.04 mg), sucrose (76 mg) and water for injection (q.s)." }

SELARSDI for Intravenous Infusion

{ "type": "p", "children": [], "text": "\nSELARSDI for Intravenous Infusion\n" }

 Available as 130 mg of ustekinumab-aekn in 26 mL, supplied as a single-dose borosilicate type I glass vial with a rubber stopper. Not made with natural rubber latex.

{ "type": "p", "children": [], "text": "\n Available as 130 mg of ustekinumab-aekn in 26 mL, supplied as a single-dose borosilicate type I glass vial with a rubber stopper. Not made with natural rubber latex." }

Each 26 mL vial delivers 130 mg ustekinumab-aekn, edetate disodium (0.47 mg), histidine (20.02 mg), L- histidine monohydrochloride monohydrate (27.04 mg), methionine (10.4 mg), polysorbate 80 (10.4 mg), sucrose (2,210 mg), and water for injection (q.s).

{ "type": "p", "children": [], "text": "Each 26 mL vial delivers 130 mg ustekinumab-aekn, edetate disodium (0.47 mg), histidine (20.02 mg), L- histidine monohydrochloride monohydrate (27.04 mg), methionine (10.4 mg), polysorbate 80 (10.4 mg), sucrose (2,210 mg), and water for injection (q.s)." }

Ustekinumab products are human IgG1κ monoclonal antibodies that bind with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab products were shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell- surface receptor chain, IL-12Rβ1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn’s disease and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab products, was shown to be protective.

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)].

Absorption

In adult subjects with plaque psoriasis, the median time to reach the maximum serum concentration (Tmax) 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 Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in subjects with plaque psoriasis.

Following multiple subcutaneous doses of ustekinumab in adult subjects with plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state trough serum ustekinumab concentrations were 0.69 ± 0.69 mcg/mL for subjects less than or equal to 100 kg receiving a 45 mg dose and 0.74 ± 0.78 mcg/mL for subjects greater than 100 kg receiving a 90 mg dose. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.

Following the recommended intravenous induction dose, mean ±SD peak serum ustekinumab concentration was 125.2 ± 33.6 mcg/mL in subjects with Crohn’s disease, and 129.1 ± 27.6 mcg/mL in subjects with ulcerative colitis. Starting at Week 8, the recommended subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 weeks. Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. There was no apparent accumulation in ustekinumab concentration over time when given subcutaneously every 8 weeks. Mean ±SD steady-state trough concentration was 2.5 ± 2.1 mcg/mL in subjects with Crohn’s disease, and 3.3 ± 2.3 mcg/mL in subjects with ulcerative colitis for 90 mg ustekinumab administered every 8 weeks.

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 plaque psoriasis trials 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 products have not been characterized. As a human IgG1κ monoclonal antibody, ustekinumab products are expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

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 ustekinumab in pediatric subjects 6 to 17 years of age 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 to 17 years of age.

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

Drug Interaction Studies

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

No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with ustekinumab at the approved recommended dosage in subjects with Crohn’s disease [see Drug Interactions (7.2)].

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

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

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

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.

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.

Clinical Response

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

<div class="scrollingtable"><table> <caption> <span>Table 8: Clinical Outcomes at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2</span> </caption> <col/> <col/> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule"> </td><td align="center" class="Toprule"></td><td align="center" class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Ps STUDY 1</span> </p> </td><td align="center" class="Toprule"></td><td align="center" class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Ps STUDY 2</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center" class="Botrule"></td><td align="center" class="Botrule" colspan="2"> <p class="First"> <span class="Bold">Ustekinumab</span> </p> </td><td align="center" class="Botrule"></td><td align="center" class="Botrule" colspan="2"> <p class="First"> <span class="Bold">Ustekinumab</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">45 mg</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">90 mg</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">45 mg</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">90 mg</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Subjects randomized</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">255</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">255</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">256</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">410</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">409</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">411</span> </p> </td> </tr> <tr> <td> <p class="First">PASI 75 response</p> </td><td align="center"> <p class="First">8 (3%)</p> </td><td align="center"> <p class="First">171 (67%)</p> </td><td align="center"> <p class="First">170 (66%)</p> </td><td align="center"> <p class="First">15 (4%)</p> </td><td align="center"> <p class="First">273 (67%)</p> </td><td align="center"> <p class="First">311 (76%)</p> </td> </tr> <tr class="Last"> <td class="Botrule"> <p class="First">PGA of Cleared or Minimal</p> </td><td align="center" class="Botrule"> <p class="First">10 (4%)</p> </td><td align="center" class="Botrule"> <p class="First">151 (59%)</p> </td><td align="center" class="Botrule"> <p class="First">156 (61%)</p> </td><td align="center" class="Botrule"> <p class="First">18 (4%)</p> </td><td align="center" class="Botrule"> <p class="First">277 (68%)</p> </td><td align="center" class="Botrule"> <p class="First">300 (73%)</p> </td> </tr> </tbody> </table></div>

Examination of age, gender, and race subgroups did not identify differences in response to ustekinumab 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).

<div class="scrollingtable"><table> <caption> <span>Table 9: Clinical Outcomes by Weight at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2</span> </caption> <col/> <col/> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule"></td><td align="center" class="Toprule" colspan="3"> <p class="First"> <span class="Bold">Ps STUDY 1</span> </p> </td><td align="center" class="Toprule" colspan="3"> <p class="First"> <span class="Bold">Ps STUDY 2</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center" class="Botrule"></td><td align="center" class="Botrule" colspan="2"> <p class="First"> <span class="Bold">Ustekinumab</span> </p> </td><td align="center" class="Botrule"></td><td align="center" class="Botrule" colspan="2"> <p class="First"> <span class="Bold">Ustekinumab</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">45 mg</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">90 mg</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">45 mg</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">90 mg</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Subjects randomized</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">255</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">255</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">256</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">410</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">409</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">411</span> </p> </td> </tr> <tr> <td colspan="7"> <p class="First"> <span class="Bold">PASI 75 response<span class="Sup">*</span></span> </p> </td> </tr> <tr> <td align="center"> <p class="First">≤100 kg</p> </td><td align="center"> <p class="First">4%</p> </td><td align="center"> <p class="First">74%</p> </td><td align="center"> <p class="First">65%</p> </td><td align="center"> <p class="First">4%</p> </td><td align="center"> <p class="First">73%</p> </td><td align="center"> <p class="First">78%</p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First">6/166</p> </td><td align="center"> <p class="First">124/168</p> </td><td align="center"> <p class="First">107/164</p> </td><td align="center"> <p class="First">12/290</p> </td><td align="center"> <p class="First">218/297</p> </td><td align="center"> <p class="First">225/289</p> </td> </tr> <tr> <td align="center"> <p class="First">&gt;100 kg</p> </td><td align="center"> <p class="First">2%</p> </td><td align="center"> <p class="First">54%</p> </td><td align="center"> <p class="First">68%</p> </td><td align="center"> <p class="First">3%</p> </td><td align="center"> <p class="First">49%</p> </td><td align="center"> <p class="First">71%</p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First">2/89</p> </td><td align="center"> <p class="First">47/87</p> </td><td align="center"> <p class="First">63/92</p> </td><td align="center"> <p class="First">3/120</p> </td><td align="center"> <p class="First">55/112</p> </td><td align="center"> <p class="First">86/121</p> </td> </tr> <tr> <td colspan="7"> <p class="First"> <span class="Bold">PGA of Cleared or Minimal<span class="Sup">*</span></span> </p> </td> </tr> <tr> <td align="center"> <p class="First">≤100 kg</p> </td><td align="center"> <p class="First">4%</p> </td><td align="center"> <p class="First">64%</p> </td><td align="center"> <p class="First">63%</p> </td><td align="center"> <p class="First">5%</p> </td><td align="center"> <p class="First">74%</p> </td><td align="center"> <p class="First">75%</p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First">7/166</p> </td><td align="center"> <p class="First">108/168</p> </td><td align="center"> <p class="First">103/164</p> </td><td align="center"> <p class="First">14/290</p> </td><td align="center"> <p class="First">220/297</p> </td><td align="center"> <p class="First">216/289</p> </td> </tr> <tr> <td align="center"> <p class="First">&gt;100 kg</p> </td><td align="center"> <p class="First">3%</p> </td><td align="center"> <p class="First">49%</p> </td><td align="center"> <p class="First">58%</p> </td><td align="center"> <p class="First">3%</p> </td><td align="center"> <p class="First">51%</p> </td><td align="center"> <p class="First">69%</p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First">3/89</p> </td><td align="center"> <p class="First">43/87</p> </td><td align="center"> <p class="First">53/92</p> </td><td align="center"> <p class="First">4/120</p> </td><td align="center"> <p class="First">57/112</p> </td><td align="center"> <p class="First">84/121</p> </td> </tr> <tr class="Last"> <td class="Toprule" colspan="7"> <p class="First"> <span class="Sup">* Subjects were dosed with trial medication at Weeks 0 and 4.</span> </p> </td> </tr> </tbody> </table></div>

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 ustekinumab (ustekinumab at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomized to ustekinumab 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.

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.

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

<div class="scrollingtable"><table> <caption> <span>Table 10: Efficacy Results at Week 12 in Pediatric Subjects 12 to 17 years with Plaque Psoriasis in Ps STUDY 3</span> </caption> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule"></td><td align="center" class="Botrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Ps STUDY 3</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Ustekinumab*</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">n (%)</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">n (%)</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">37</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">36</span> </p> </td> </tr> <tr> <td> <p class="First"> <span class="Bold">PGA</span> </p> </td><td align="center"></td><td align="center"></td> </tr> <tr> <td> <p class="First">PGA of cleared (0) or minimal (1)</p> </td><td align="center"> <p class="First">2 (5.4%)</p> </td><td align="center"> <p class="First">25 (69.4%)</p> </td> </tr> <tr> <td> <p class="First"> <span class="Bold">PASI</span> </p> </td><td align="center"></td><td align="center"></td> </tr> <tr> <td> <p class="First">PASI 75 responders</p> </td><td align="center"> <p class="First">4 (10.8%)</p> </td><td align="center"> <p class="First">29 (80.6%)</p> </td> </tr> <tr> <td> <p class="First">PASI 90 responders</p> </td><td align="center"> <p class="First">2 (5.4%)</p> </td><td align="center"> <p class="First">22 (61.1%)</p> </td> </tr> <tr class="Last"> <td class="Toprule" colspan="3"> <p class="First"> <span class="Sup">*</span> Using the weight-based dosage regimen specified in Table 1 and Table 2.</p> </td> </tr> </tbody> </table></div>

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 subjects, 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.

<div class="scrollingtable"><table> <caption> <span>Table 11: ACR 20, ACR 50, ACR 70 and PASI 75 responses in PsA STUDY 1 and PsA STUDY 2 at Week 24</span> </caption> <col/> <col/> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule"></td><td align="center" class="Toprule" colspan="3"> <p class="First"> <span class="Bold">PsA STUDY 1</span> </p> </td><td align="center" class="Toprule" colspan="3"> <p class="First"> <span class="Bold">PsA STUDY 2</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center" class="Botrule"></td><td align="center" class="Botrule" colspan="2"> <p class="First"> <span class="Bold">Ustekinumab</span> </p> </td><td align="center" class="Botrule"></td><td align="center" class="Botrule" colspan="2"> <p class="First"> <span class="Bold">Ustekinumab</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">45 mg</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">90 mg</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">45 mg</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">90 mg</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Number of subjects randomized</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">206</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">205</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">204</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">104</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">103</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">105</span> </p> </td> </tr> <tr> <td> <p class="First">ACR 20 response, N (%)</p> </td><td align="center"> <p class="First">47 (23%)</p> </td><td align="center"> <p class="First">87 (42%)</p> </td><td align="center"> <p class="First">101 (50%)</p> </td><td align="center"> <p class="First">21 (20%)</p> </td><td align="center"> <p class="First">45 (44%)</p> </td><td align="center"> <p class="First">46 (44%)</p> </td> </tr> <tr> <td> <p class="First">ACR 50 response, N (%)</p> </td><td align="center"> <p class="First">18 (9%)</p> </td><td align="center"> <p class="First">51 (25%)</p> </td><td align="center"> <p class="First">57 (28%)</p> </td><td align="center"> <p class="First">7 (7%)</p> </td><td align="center"> <p class="First">18 (17%)</p> </td><td align="center"> <p class="First">24 (23%)</p> </td> </tr> <tr> <td> <p class="First">ACR 70 response, N (%)</p> </td><td align="center"> <p class="First">5 (2%)</p> </td><td align="center"> <p class="First">25 (12%)</p> </td><td align="center"> <p class="First">29 (14%)</p> </td><td align="center"> <p class="First">3 (3%)</p> </td><td align="center"> <p class="First">7 (7%)</p> </td><td align="center"> <p class="First">9 (9%)</p> </td> </tr> <tr> <td> <p class="First"> <span class="Bold">Number of subjects with ≥ 3% BSA<span class="Sup">a</span></span> </p> </td><td align="center"> <p class="First"> <span class="Bold">146</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">145</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">149</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">80</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">80</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">81</span> </p> </td> </tr> <tr> <td> <p class="First">PASI 75 response, N (%)</p> </td><td align="center"> <p class="First">16 (11%)</p> </td><td align="center"> <p class="First">83 (57%)</p> </td><td align="center"> <p class="First">93 (62%)</p> </td><td align="center"> <p class="First">4 (5%)</p> </td><td align="center"> <p class="First">41 (51%)</p> </td><td align="center"> <p class="First">45 (56%)</p> </td> </tr> <tr class="Last"> <td class="Toprule" colspan="7"> <p class="First"> <span class="Sup">a</span> Number of subjects with ≥ 3% BSA psoriasis skin involvement at baseline</p> </td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table> <caption> <span>Table 12: Mean change from baseline in ACR components at Week 24</span> </caption> <col width="188.05pt"/> <col width="110.1pt"/> <col width="119pt"/> <col width="122.85pt"/> <tbody class="Headless"> <tr class="First"> <td align="center"></td><td align="center"></td><td align="center"> <p class="First"> <span class="Bold">PsA STUDY 1</span> </p> </td><td align="center"></td> </tr> <tr> <td align="center"></td><td align="center" class="Botrule" colspan="3"> <p class="First"> <span class="Bold">Ustekinumab</span> </p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(N = 206)</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">45 mg</span> </p> <p> <span class="Bold">(N = 205)</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">90 mg</span> </p> <p> <span class="Bold">(N = 204)</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First">Number of swollen joints<span class="Sup">a</span> </p> </td><td align="center" class="Toprule"></td><td align="center" class="Toprule"></td><td align="center" class="Toprule"></td> </tr> <tr> <td> <p class="First">    Baseline</p> </td><td align="center"> <p class="First">15</p> </td><td align="center"> <p class="First">12</p> </td><td align="center"> <p class="First">13</p> </td> </tr> <tr> <td> <p class="First">    Mean Change at Week 24</p> </td><td align="center"> <p class="First">-3</p> </td><td align="center"> <p class="First">-5</p> </td><td align="center"> <p class="First">-6</p> </td> </tr> <tr> <td> <p class="First">Number of tender joints<span class="Sup">b</span> </p> </td><td align="center"></td><td align="center"></td><td align="center"></td> </tr> <tr> <td> <p class="First">     Baseline</p> </td><td align="center"> <p class="First">25</p> </td><td align="center"> <p class="First">22</p> </td><td align="center"> <p class="First">23</p> </td> </tr> <tr> <td> <p class="First">     Mean Change at Week 24</p> </td><td align="center"> <p class="First">-4</p> </td><td align="center"> <p class="First">-8</p> </td><td align="center"> <p class="First">-9</p> </td> </tr> <tr> <td> <p class="First">Subject’s assessment of pain<span class="Sup">c</span> </p> </td><td align="center"></td><td align="center"></td><td align="center"></td> </tr> <tr> <td> <p class="First">     Baseline</p> </td><td align="center"> <p class="First">6.1</p> </td><td align="center"> <p class="First">6.2</p> </td><td align="center"> <p class="First">6.6</p> </td> </tr> <tr> <td> <p class="First">     Mean Change at Week 24</p> </td><td align="center"> <p class="First">-0.5</p> </td><td align="center"> <p class="First">-2.0</p> </td><td align="center"> <p class="First">-2.6</p> </td> </tr> <tr> <td> <p class="First">Subject global assessment<span class="Sup">c</span> </p> </td><td align="center"></td><td align="center"></td><td align="center"></td> </tr> <tr> <td> <p class="First">     Baseline</p> </td><td align="center"> <p class="First">6.1</p> </td><td align="center"> <p class="First">6.3</p> </td><td align="center"> <p class="First">6.4</p> </td> </tr> <tr> <td> <p class="First">     Mean Change at Week 24</p> </td><td align="center"> <p class="First">-0.5</p> </td><td align="center"> <p class="First">-2.0</p> </td><td align="center"> <p class="First">-2.5</p> </td> </tr> <tr> <td> <p class="First">Physician global assessment<span class="Sup">c</span> </p> </td><td align="center"></td><td align="center"></td><td align="center"></td> </tr> <tr> <td> <p class="First">     Baseline</p> </td><td align="center"> <p class="First">5.8</p> </td><td align="center"> <p class="First">5.7</p> </td><td align="center"> <p class="First">6.1</p> </td> </tr> <tr> <td> <p class="First">     Mean Change at Week 24</p> </td><td align="center"> <p class="First">-1.4</p> </td><td align="center"> <p class="First">-2.6</p> </td><td align="center"> <p class="First">-3.1</p> </td> </tr> <tr> <td> <p class="First">Disability index (HAQ)<span class="Sup">d</span> </p> </td><td align="center"></td><td align="center"></td><td align="center"></td> </tr> <tr> <td> <p class="First">     Baseline</p> </td><td align="center"> <p class="First">1.2</p> </td><td align="center"> <p class="First">1.2</p> </td><td align="center"> <p class="First">1.2</p> </td> </tr> <tr> <td> <p class="First">     Mean Change at Week 24</p> </td><td align="center"> <p class="First">-0.1</p> </td><td align="center"> <p class="First">-0.3</p> </td><td align="center"> <p class="First">-0.4</p> </td> </tr> <tr> <td> <p class="First">CRP (mg/dL)<span class="Sup">e</span> </p> </td><td align="center"></td><td align="center"></td><td align="center"></td> </tr> <tr> <td> <p class="First">     Baseline</p> </td><td align="center"> <p class="First">1.6</p> </td><td align="center"> <p class="First">1.7</p> </td><td align="center"> <p class="First">1.8</p> </td> </tr> <tr> <td> <p class="First">     Mean Change at Week 24</p> </td><td align="center"> <p class="First">0.01</p> </td><td align="center"> <p class="First">-0.5</p> </td><td align="center"> <p class="First">-0.8</p> </td> </tr> <tr> <td class="Toprule" colspan="4"> <p class="First"> <span class="Sup">a</span> Number of swollen joints counted (0-66)</p> </td> </tr> <tr> <td colspan="4"> <p class="First"> <span class="Sup">b</span> Number of tender joints counted (0-68)</p> </td> </tr> <tr> <td colspan="4"> <p class="First"> <span class="Sup">c</span> Visual analogue scale; 0= best, 10=worst.</p> </td> </tr> <tr> <td colspan="4"> <p class="First"> <span class="Sup">d</span> 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.</p> </td> </tr> <tr class="Last"> <td colspan="4"> <p class="First"> <span class="Sup">e</span> CRP: (Normal Range 0.0-1.0 mg/dL)</p> </td> </tr> </tbody> </table></div>

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

Physical Function

Ustekinumab-treated subjects showed improvement in physical function compared to subjects treated with 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 ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24.

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.

Trials CD-1 and CD-2

In trials CD-1 and CD-2, 1409 subjects were randomized, of whom 1368 (CD-1, n=741; CD-2, n=627) were included in the final efficacy analysis. Induction of clinical response (defined as a reduction in CDAI score of greater than or equal to 100 points or CDAI score of less than 150) at Week 6 and clinical remission (defined as a CDAI score of less than 150) at Week 8 were evaluated. In both trials, subjects were randomized to receive a single intravenous administration of ustekinumab at either approximately 6 mg/kg, placebo (see Table 4), or 130 mg (a lower dose than recommended).

In trial CD-1, subjects had failed or were intolerant to prior treatment with a TNF blocker: 29% subjects had an inadequate initial response (primary non-responders), 69% responded but subsequently lost response (secondary non-responders) and 36% were intolerant to a TNF blocker. Of these subjects, 48% failed or were intolerant to one TNF blocker and 52% had failed 2 or 3 prior TNF blockers. At baseline and throughout the trial, approximately 46% of the subjects were receiving corticosteroids and 31% of the subjects were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score was 319 in the ustekinumab approximately 6 mg/kg group and 313 in the placebo group.

In trial CD-2, subjects had failed or were intolerant to prior treatment with corticosteroids (81% of subjects), at least one immunomodulator (6-MP, AZA, MTX; 68% of subjects), or both (49% of subjects). Additionally, 69% never received a TNF blocker and 31% previously received but had not failed a TNF blocker. At baseline, and throughout the trial, approximately 39% of the subjects were receiving corticosteroids and 35% of the subjects were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score was 286 in the ustekinumab and 290 in the placebo group.

In these induction trials, a greater proportion of subjects treated with ustekinumab (at the recommended dose of approximately 6 mg/kg dose) achieved clinical response at Week 6 and clinical remission at Week 8 compared to placebo (see Table 13 for clinical response and remission rates). Clinical response and remission were significant as early as Week 3 in ustekinumab-treated subjects and continued to improve through Week 8.

<div class="scrollingtable"><table> <caption> <span>Table 13: Induction of Clinical Response and Remission in CD-1* and CD-2**</span> </caption> <col width="103.5pt"/> <col width="59.55pt"/> <col width="92.1pt"/> <col width="78pt"/> <col width="49.6pt"/> <col width="88.15pt"/> <col width="68.6pt"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule"></td><td align="center" class="Toprule"></td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">CD-1</span> </p> <p> <span class="Bold">n = 741</span> </p> </td><td align="center" class="Toprule"></td><td align="center" class="Toprule"></td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">CD-2</span> </p> <p> <span class="Bold">n = 627</span> </p> </td><td align="center" class="Toprule"></td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">N = 247</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Ustekinumab</span><span class="Bold"><span class="Sup">†</span></span> </p> <p> <span class="Bold">N = 249</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Treatment difference</span> </p> <p> <span class="Bold">and 95% CI</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">N = 209</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Ustekinumab<span class="Sup">†</span></span> </p> <p> <span class="Bold">N = 209</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Treatment difference</span> </p> <p> <span class="Bold">and 95% CI</span> </p> </td> </tr> <tr> <td align="center" class="Toprule" rowspan="2"> <p class="First">Clinical Response</p> <p>(100 point), Week 6</p> </td><td align="center" class="Toprule"> <p class="First">53 (21%)</p> </td><td align="center" class="Toprule"> <p class="First">84 (34%)<span class="Sup">a</span> </p> </td><td align="center" class="Toprule"> <p class="First">12%</p> </td><td align="center" class="Toprule"> <p class="First">60 (29%)</p> </td><td align="center" class="Toprule"> <p class="First">116 (56%)<span class="Sup">b</span> </p> </td><td align="center" class="Toprule"> <p class="First">27%</p> </td> </tr> <tr> <td align="center"></td><td align="center"></td><td align="center"> <p class="First">(4%, 20%)</p> </td><td align="center"></td><td align="center"></td><td align="center"> <p class="First">(18%, 36%)</p> </td> </tr> <tr> <td align="center" rowspan="2"> <p class="First">Clinical Remission,</p> <p>Week 8</p> </td><td align="center"> <p class="First">18 (7%)</p> </td><td align="center"> <p class="First">52 (21%)<span class="Sup">b</span> </p> </td><td align="center"> <p class="First">14%</p> </td><td align="center"> <p class="First">41 (20%)</p> </td><td align="center"> <p class="First">84 (40%)<span class="Sup">b</span> </p> </td><td align="center"> <p class="First">21%</p> </td> </tr> <tr> <td align="center"></td><td align="center"></td><td align="center"> <p class="First">(8%, 20%)</p> </td><td align="center"></td><td align="center"></td><td align="center"> <p class="First">(12%, 29%)</p> </td> </tr> <tr> <td align="center" rowspan="2"> <p class="First">Clinical Response</p> <p>(100 point), Week 8</p> </td><td align="center"> <p class="First">50 (20%)</p> </td><td align="center"> <p class="First">94 (38%)<span class="Sup">b</span> </p> </td><td align="center"> <p class="First">18%</p> </td><td align="center"> <p class="First">67 (32%)</p> </td><td align="center"> <p class="First">121 (58%)<span class="Sup">b</span> </p> </td><td align="center"> <p class="First">26%</p> </td> </tr> <tr> <td align="center"></td><td align="center"></td><td align="center"> <p class="First">(10%, 25%)</p> </td><td align="center"></td><td align="center"></td><td align="center"> <p class="First">(17%, 35%)</p> </td> </tr> <tr> <td align="center" rowspan="2"> <p class="First">70 Point Response,</p> <p>Week 6</p> </td><td align="center"> <p class="First">75 (30%)</p> </td><td align="center"> <p class="First">109 (44%)<span class="Sup">a</span> </p> </td><td align="center"> <p class="First">13%</p> </td><td align="center"> <p class="First">81 (39%)</p> </td><td align="center"> <p class="First">135 (65%)<span class="Sup">b</span> </p> </td><td align="center"> <p class="First">26%</p> </td> </tr> <tr> <td align="center"></td><td align="center"></td><td align="center"> <p class="First">(5%, 22%)</p> </td><td align="center"></td><td align="center"></td><td align="center"> <p class="First">(17%, 35%)</p> </td> </tr> <tr> <td align="center" rowspan="2"> <p class="First">70 Point Response,</p> <p>Week 3</p> </td><td align="center"> <p class="First">67 (27%)</p> </td><td align="center"> <p class="First">101 (41%)<span class="Sup">a</span> </p> </td><td align="center"> <p class="First">13%</p> </td><td align="center"> <p class="First">66 (32%)</p> </td><td align="center"> <p class="First">106 (51%)<span class="Sup">b</span> </p> </td><td align="center"> <p class="First">19%</p> </td> </tr> <tr> <td align="center"></td><td align="center"></td><td align="center"> <p class="First">(5%, 22%)</p> </td><td align="center"></td><td align="center"></td><td align="center"> <p class="First">(10%, 28%)</p> </td> </tr> <tr> <td class="Toprule" colspan="7"> <p class="First">Clinical remission is defined as CDAI score &lt; 150; Clinical response is defined as reduction in CDAI score by at least 100 points or being in clinical remission: 70 point response is defined as reduction in CDAI score by at least 70 points</p> </td> </tr> <tr> <td colspan="7"> <p class="First"> <span class="Sup">*</span> Patient population consisted of subjects who failed or were intolerant to TNF blocker therapy</p> </td> </tr> <tr> <td colspan="7"> <p class="First"> <span class="Sup">**</span> Patient population consisted of subjects who failed or were intolerant to corticosteroids or immunomodulators (e.g., 6-MP, AZA, MTX) and previously received but not failed a TNF blocker or were never treated with a TNF blocker.</p> </td> </tr> <tr> <td colspan="7"> <p class="First"> <span class="Sup">†</span> Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4.</p> </td> </tr> <tr> <td colspan="7"> <p class="First"> <span class="Sup">a</span> 0.001≤ p &lt; 0.01</p> </td> </tr> <tr class="Last"> <td colspan="7"> <p class="First"> <span class="Sup">b</span> p &lt; 0.001</p> </td> </tr> </tbody> </table></div>

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 ustekinumab in trials CD-1 or CD-2. Subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks or placebo for 44 weeks (see Table 14).

<div class="scrollingtable"><table> <caption> <span>Table 14: Clinical Response and Remission in CD-3 (Week 44; 52 weeks from initiation of the induction dose)</span> </caption> <col width="171.4pt"/> <col width="107.15pt"/> <col width="123.1pt"/> <col width="138.35pt"/> <tbody class="Headless"> <tr class="First"> <td align="center" rowspan="3"></td><td align="center"></td><td align="center"> <p class="First"> <span class="Bold">90 mg Ustekinumab</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">Treatment </span> </p> </td> </tr> <tr> <td align="center"> <p class="First"> <span class="Bold">Placebo<span class="Sup">*</span></span> </p> </td><td align="center"> <p class="First"> <span class="Bold">every 8 weeks </span> </p> </td><td align="center"> <p class="First"> <span class="Bold">difference and</span> </p> </td> </tr> <tr> <td align="center" class="Botrule"> <p class="First"> <span class="Bold">N = 131<span class="Sup">†</span></span> </p> </td><td align="center" class="Botrule"> <p class="First"> <span class="Bold">N = 128<span class="Sup">†</span></span> </p> </td><td align="center" class="Botrule"> <p class="First"> <span class="Bold">95% CI</span> </p> </td> </tr> <tr> <td> <p class="First">Clinical Remission</p> </td><td align="center"> <p class="First">47 (36%)</p> </td><td align="center"> <p class="First">68 (53%)<span class="Sup">a</span> </p> </td><td align="center"> <p class="First">17% (5%, 29%)</p> </td> </tr> <tr> <td> <p class="First">Clinical Response</p> </td><td align="center"> <p class="First">58 (44%)</p> </td><td align="center"> <p class="First">76 (59%)<span class="Sup">b</span> </p> </td><td align="center"> <p class="First">15% (3%, 27%)</p> </td> </tr> <tr> <td> <p class="First">Clinical Remission in subjects in remission at the start of maintenance therapy<span class="Sup">**</span> </p> </td><td align="center"> <p class="First">36/79 (46%)</p> </td><td align="center"> <p class="First">52/78 (67%)<span class="Sup">a</span> </p> </td><td align="center"> <p class="First">21% (6%, 36%)</p> </td> </tr> <tr> <td class="Toprule" colspan="4"> <p class="First">Clinical remission is defined as CDAI score &lt; 150; Clinical response is defined as reduction in CDAI of at least 100 points or being in clinical remission</p> </td> </tr> <tr class="Last"> <td colspan="4"> <p class="First"> <span class="Sup">*</span> The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the start of maintenance therapy.</p> <p> <span class="Sup">**</span> 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.</p> <p> <span class="Sup">†</span> Subjects who achieved clinical response to ustekinumab at the end of the induction trial.</p> <p> <span class="Sup">a</span> p &lt; 0.01</p> <p> <span class="Sup">b</span> 0.01≤ p &lt; 0.05</p> </td> </tr> </tbody> </table></div>

At Week 44, 47% of subjects who received ustekinumab 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%) ustekinumab-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%) ustekinumab-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 ustekinumab-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 ustekinumab 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 ustekinumab 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.

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).

Trial UC-1

In UC-1, 961 subjects were randomized at Week 0 to a single intravenous administration of ustekinumab 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 ustekinumab (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).

<div class="scrollingtable"><table> <caption> <span>Table 15: Proportion of Subjects Meeting Efficacy Endpoints at Week 8 in UC-1</span> </caption> <col/> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center"> <p class="First"> <span class="Bold">Endpoint</span> </p> </td><td align="center" colspan="2"> <p class="First"> <span class="Bold">Placebo</span> </p> <p>N = 319</p> </td><td align="center" colspan="2"> <p class="First"> <span class="Bold">Ustekinumab<span class="Sup">†</span></span> </p> <p>N = 322</p> </td><td align="center" rowspan="2"> <p class="First"> <span class="Bold">Treatment difference and</span> </p> <p> <span class="Bold">97.5% CI <span class="Sup">a</span></span> </p> </td> </tr> <tr> <td align="center"></td><td align="center"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">%</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">%</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Clinical Remission*</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">22</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">7%</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">62</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">19%</span> </p> </td><td align="center" class="Toprule"> <p class="First">12%</p> <p>(7%, 18%) <span class="Sup">b</span> </p> </td> </tr> <tr> <td> <p class="First">     Bio-naïve<span class="Sup">⸸</span> </p> </td><td align="center"> <p class="First">14/151</p> </td><td align="center"> <p class="First">9%</p> </td><td align="center"> <p class="First">36/147</p> </td><td align="center"> <p class="First">24%</p> </td><td align="center" rowspan="2"></td> </tr> <tr> <td> <p class="First">     Prior biologic failure</p> </td><td align="center"> <p class="First">7/161</p> </td><td align="center"> <p class="First">4%</p> </td><td align="center"> <p class="First">24/166</p> </td><td align="center"> <p class="First">14%</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Endoscopic Improvement<span class="Sup">§</span></span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">40</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">13%</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">80</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">25%</span> </p> </td><td align="center" class="Toprule"> <p class="First">12%</p> </td> </tr> <tr> <td> <p class="First">     Bio-naïve<span class="Sup">⸸</span> </p> </td><td align="center"> <p class="First">28/151</p> </td><td align="center"> <p class="First">19%</p> </td><td align="center"> <p class="First">43/147</p> </td><td align="center"> <p class="First">29%</p> </td><td align="center"> <p class="First">(6%, 19%)<span class="Sup">b</span> </p> </td> </tr> <tr> <td> <p class="First">     Prior biologic failure</p> </td><td align="center"> <p class="First">11/161</p> </td><td align="center"> <p class="First">7%</p> </td><td align="center"> <p class="First">34/166</p> </td><td align="center"> <p class="First">20%</p> </td><td align="center"></td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Clinical Response<span class="Sup">†</span></span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">99</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">31%</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">186</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">58%</span> </p> </td><td align="center" class="Toprule"> <p class="First">27%<br/> (18%, 35%) <span class="Sup">b</span> </p> </td> </tr> <tr> <td> <p class="First">     Bio-naïve<span class="Sup">⸸</span> </p> </td><td align="center"> <p class="First">55/151</p> </td><td align="center"> <p class="First">36%</p> </td><td align="center"> <p class="First">94/147</p> </td><td align="center"> <p class="First">64%</p> </td><td align="center" rowspan="2"></td> </tr> <tr> <td> <p class="First">     Prior biologic failure</p> </td><td align="center"> <p class="First">42/161</p> </td><td align="center"> <p class="First">26%</p> </td><td align="center"> <p class="First">86/166</p> </td><td align="center"> <p class="First">52%</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Histologic-Endoscopic </span><span class="Bold">Mucosal Improvement<span class="Sup">‡</span></span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">26</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">8%</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">54</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">17%</span> </p> </td><td align="center" class="Toprule"> <p class="First">9%<br/> (3%, 14%) <span class="Sup">b</span> </p> </td> </tr> <tr> <td> <p class="First">     Bio-naïve<span class="Sup">⸸</span> </p> </td><td align="center"> <p class="First">19/151</p> </td><td align="center"> <p class="First">13%</p> </td><td align="center"> <p class="First">30/147</p> </td><td align="center"> <p class="First">20%</p> </td><td align="center" rowspan="2"></td> </tr> <tr> <td> <p class="First">     Prior biologic failure</p> </td><td align="center"> <p class="First">6/161</p> </td><td align="center"> <p class="First">4%</p> </td><td align="center"> <p class="First">21/166</p> </td><td align="center"> <p class="First">13%</p> </td> </tr> <tr class="Last"> <td class="Toprule" colspan="6"> <p class="First"> <span class="Sup">†</span> Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4.</p> <p> <span class="Sup">⸸</span> An additional 7 subjects on placebo and 9 subjects on ustekinumab (6 mg/kg) had been exposed to, but had not failed, biologics.</p> <p> <span class="Sup">* </span>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). </p> <p> <span class="Sup">§</span> Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).</p> <p> <span class="Sup">†</span> 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.</p> <p> <span class="Sup">‡</span><span class="Bold"> </span>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 &lt;5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue).</p> <p> <span class="Sup">a</span> Adjusted treatment difference (97.5% CI)</p> <p> <span class="Sup"> b</span> p &lt; 0.001</p> </td> </tr> </tbody> </table></div>

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 ustekinumab-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 ustekinumab in UC-1. These subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab 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 ustekinumab at the recommended dosage (90 mg every 8 weeks) compared to the placebo are shown in Table 16.

<div class="scrollingtable"><table> <caption> <span>Table 16: Efficacy Endpoints of Maintenance at Week 44 in UC-2 (52 Weeks from Initiation of the Induction Dose)</span> </caption> <col/> <col/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" rowspan="2"> <p class="First"> <span class="Bold">Endpoint</span> </p> </td><td align="center" colspan="2"> <p class="First"> <span class="Bold">Placebo*</span> </p> <p>N = 175<span class="Sup">†</span> </p> </td><td align="center" colspan="2"> <p class="First"> <span class="Bold">90 mg Ustekinumab</span> </p> <p> <span class="Bold">every 8 weeks</span> </p> <p>N = 176</p> </td><td align="center"> <p class="First"> <span class="Bold">Treatment difference and</span> </p> <p> <span class="Bold">95% CI</span> </p> </td> </tr> <tr> <td align="center"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">%</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center"> <p class="First"> <span class="Bold">%</span> </p> </td><td align="center"></td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Clinical Remission</span><span class="Bold"><span class="Sup">**</span></span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">46</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">26%</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">79</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">45%</span> </p> </td><td align="center" class="Toprule"> <p class="First">19%</p> <p>(9%, 28%) <span class="Sup">a</span> </p> </td> </tr> <tr> <td> <p class="First">     Bio-naïve<span class="Sup">⸸</span> </p> </td><td align="center"> <p class="First">30/84</p> </td><td align="center"> <p class="First">36%</p> </td><td align="center"> <p class="First">39/79</p> </td><td align="center"> <p class="First">49%</p> </td><td align="center"></td> </tr> <tr> <td> <p class="First">     Prior biologic failure</p> </td><td align="center"> <p class="First">16/88</p> </td><td align="center"> <p class="First">18%</p> </td><td align="center"> <p class="First">37/91</p> </td><td align="center"> <p class="First">41%</p> </td><td align="center"></td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Maintenance of Clinical Response at Week 44<span class="Sup">†</span></span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">84</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">48%</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">130</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">74%</span> </p> </td><td align="center" class="Toprule"> <p class="First">26%</p> <p>(16%, 36%) <span class="Sup">a</span> </p> </td> </tr> <tr> <td> <p class="First">    Bio-naïve<span class="Sup">⸸</span> </p> </td><td align="center"> <p class="First">49/84</p> </td><td align="center"> <p class="First">58%</p> </td><td align="center"> <p class="First">62/79</p> </td><td align="center"> <p class="First">78%</p> </td><td align="center"></td> </tr> <tr> <td> <p class="First">    Prior biologic failure</p> </td><td align="center"> <p class="First">35/88</p> </td><td align="center"> <p class="First">40%</p> </td><td align="center"> <p class="First">64/91</p> </td><td align="center"> <p class="First">70%</p> </td><td align="center"></td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Endoscopic Improvement<span class="Sup">§</span></span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">47</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">27%</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">83</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">47%</span> </p> </td><td align="center" class="Toprule"> <p class="First">20%</p> <p>(11%, 30%) <span class="Sup">a</span> </p> </td> </tr> <tr> <td> <p class="First">    Bio-naïve<span class="Sup">⸸</span> </p> </td><td align="center"> <p class="First">29/84</p> </td><td align="center"> <p class="First">35%</p> </td><td align="center"> <p class="First">42/79</p> </td><td align="center"> <p class="First">53%</p> </td><td align="center"></td> </tr> <tr> <td> <p class="First">    Prior biologic failure</p> </td><td align="center"> <p class="First">18/88</p> </td><td align="center"> <p class="First">20%</p> </td><td align="center"> <p class="First">38/91</p> </td><td align="center"> <p class="First">42%</p> </td><td align="center"></td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Corticosteroid-free Clinical Remission</span><span class="Bold"><span class="Sup">‡</span></span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">45</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">26%</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">76</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">43%</span> </p> </td><td align="center" class="Toprule"> <p class="First">17%</p> <p>(8%, 27%) <span class="Sup">a</span> </p> </td> </tr> <tr> <td> <p class="First">     Bio-naïve<span class="Sup">⸸</span> </p> </td><td align="center"> <p class="First">30/84</p> </td><td align="center"> <p class="First">36%</p> </td><td align="center"> <p class="First">38/79</p> </td><td align="center"> <p class="First">48%</p> </td><td align="center"></td> </tr> <tr> <td> <p class="First">     Prior biologic failure</p> </td><td align="center"> <p class="First">15/88</p> </td><td align="center"> <p class="First">17%</p> </td><td align="center"> <p class="First">35/91</p> </td><td align="center"> <p class="First">38%</p> </td><td align="center"></td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Maintenance of Clinical Remission at Week 44 in subjects who achieved clinical remission 8 weeks after induction</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">18/50</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">36%</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">27/41</span> </p> </td><td align="center" class="Toprule"> <p class="First"> <span class="Bold">66%</span> </p> </td><td align="center" class="Toprule"> <p class="First">31%</p> <p>(12%, 50%) <span class="Sup">b</span> </p> </td> </tr> <tr> <td> <p class="First">     Bio-naïve<span class="Sup">⸸</span> </p> </td><td align="center"> <p class="First">12/27</p> </td><td align="center"> <p class="First">44%</p> </td><td align="center"> <p class="First">14/20</p> </td><td align="center"> <p class="First">70%</p> </td><td align="center"></td> </tr> <tr> <td> <p class="First">     Prior biologic failure</p> </td><td align="center"> <p class="First">6/23</p> </td><td align="center"> <p class="First">26%</p> </td><td align="center"> <p class="First">12/18</p> </td><td align="center"> <p class="First">67%</p> </td><td align="center"></td> </tr> <tr class="Last"> <td class="Toprule" colspan="6"> <p class="First"> <span class="Sup">⸸ </span>An additional 3 subjects on placebo and 6 subjects on ustekinumab had been exposed to, but had not failed, biologics.</p> <p> <span class="Sup">* </span>The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the start of maintenance therapy.</p> <p> <span class="Sup">**</span> 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).</p> <p> <span class="Sup">†</span> 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.</p> <p> <span class="Sup">§</span> Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).</p> <p> <span class="Sup">‡</span> Corticosteroid-free clinical remission was defined as subjects in clinical remission and not receiving corticosteroids at Week 44.</p> <p> <span class="Sup">a</span> p =&lt;0.001</p> <p> <span class="Sup">b</span> p=0.004</p> </td> </tr> </tbody> </table></div>

Other Endpoints

Week 16 Responders to Ustekinumab Induction

Subjects who were not in clinical response 8 weeks after induction with ustekinumab 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 ustekinumab at Week 8. Of these subjects, 55/101 (54%) achieved clinical response eight weeks later (Week 16) and received ustekinumab 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 ustekinumab 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 ustekinumab 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 ustekinumab and in 32/175 (18%) of subjects in placebo group.

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SELARSDI (ustekinumab-aekn) injection, is a sterile, preservative-free, clear and colorless to slightly yellow solution and free of visible particles for subcutaneous use. It is supplied as individually packaged, single-dose prefilled syringes or single-dose vials.

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For Subcutaneous Use

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Single-dose Prefilled Syringes

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{ "type": "ul", "children": [ "45 mg/0.5 mL NDC 51759-505-32" ], "text": "" }

{ "type": "ul", "children": [ "90 mg/mL NDC 51759-607-32" ], "text": "" }

Each prefilled syringe is equipped with a 29-gauge fixed 1/2 inch needle equipped with a passive safety device and a needle cover. Not made with natural rubber latex.

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Single-dose Vial

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For Intravenous Infusion

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Single-dose Vial

{ "type": "p", "children": [], "text": "\nSingle-dose Vial\n" }

{ "type": "ul", "children": [ "130 mg/26 mL (5 mg/mL) NDC 51759-708-13" ], "text": "" }

Storage and Stability

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Store SELARSDI vials and prefilled syringes refrigerated between 2°C to 8°C (36°F to 46°F). Store SELARSDI vials upright. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake.

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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 SELARSDI after the expiration date on the carton or on the prefilled syringe.

{ "type": "p", "children": [], "text": "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 SELARSDI after the expiration date on the carton or on the prefilled syringe." }

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

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Infections Inform patients that SELARSDI 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)].

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

{ "type": "p", "children": [], "text": "\nMalignancies\nInform patients of the risk of developing malignancies while receiving SELARSDI [see Warnings and Precautions (5.4)].\n" }

Hypersensitivity Reactions Advise patients to seek immediate medical attention if they experience any signs or symptoms of serious hypersensitivity reactions and discontinue SELARSDI [see Warnings and Precautions (5.5)].

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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)].

{ "type": "p", "children": [], "text": "\nPosterior Reversible Encephalopathy Syndrome (PRES)\nInform 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)].\n" }

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

{ "type": "p", "children": [], "text": "\nImmunizations\nInform patients that SELARSDI can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.7)].\n" }

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

{ "type": "p", "children": [], "text": "\nAdministration\nInstruct patients to follow sharps disposal recommendations, as described in the Instructions for Use." }

Brands listed are the trademarks of their respective owners.

{ "type": "p", "children": [], "text": "Brands listed are the trademarks of their respective owners." }

Manufactured By: Alvotech USA Inc. Leesburg, VA 20175 U.S. License No. 2225

{ "type": "p", "children": [], "text": "Manufactured By:\nAlvotech USA Inc.\nLeesburg, VA 20175\nU.S. License No. 2225" }

Product of Iceland

{ "type": "p", "children": [], "text": "Product of Iceland" }

Marketed By: Teva Pharmaceuticals Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Marketed By:\nTeva Pharmaceuticals\nParsippany, NJ 07054" }

<div class="scrollingtable"><table> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="3"> <br/> <p class="First"> <span class="Bold">MEDICATION GUIDE<br/> </span><span class="Bold">SELARSDI™ (seh-LARS-dee)<br/> </span><span class="Bold">(ustekinumab-aekn)<br/> </span><span class="Bold">injection, for subcutaneous or intravenous use</span> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3"> <br/> <p class="First"> <span class="Bold">What is the most important information I should know about SELARSDI?<br/> </span>SELARSDI is a medicine that affects your immune system. SELARSDI can increase your risk of having serious side<br/> effects, including:</p> <p> <span class="Bold">Serious infections. </span>SELARSDI may lower the ability of your immune system to fight infections and may increase your risk of infections. Some people have serious infections while taking ustekinumab products, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their infection.</p> <ul class="Disk"> <li>Your doctor should check you for TB before starting SELARSDI.</li> <li>If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with SELARSDI and during treatment with SELARSDI.</li> <li>Your doctor should watch you closely for signs and symptoms of TB while you are being treated with SELARSDI.</li> </ul> <p>You should not start taking SELARSDI if you have any kind of infection unless your doctor says it is okay.</p> <p> <span class="Bold">Before starting SELARSDI, tell your doctor if you:</span> </p> <ul class="Disk"> <li>think you have an infection or have symptoms of an infection such as:</li> </ul> </td> </tr> <tr> <td class="Lrule" colspan="2"> <br/> <ul class="Circle"> <li>fever, sweat, or chills</li> <li>muscle aches</li> <li>cough</li> <li>shortness of breath</li> <li>blood in phlegm</li> <li>weight loss</li> </ul> </td><td class="Rrule"> <ul class="Circle"> <li>warm, red, or painful skin or sores on your body</li> <li>diarrhea or stomach pain</li> <li>burning when you urinate or urinate more often than normal</li> <li>feel very tired</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3"> <br/> <ul class="Disk"> <li>are being treated for an infection or have any open cuts.</li> <li>get a lot of infections or have infections that keep coming back.</li> <li>have TB, or have been in close contact with someone with TB.</li> </ul> <p class="First"> <span class="Bold">After starting SELARSDI, </span>call your doctor right away if you have any symptoms of an infection (see above). These may be signs of infections such as chest infections, or skin infections or shingles that could have serious complications. SELARSDI can make you more likely to get infections or make an infection that you have worse.</p> <p>People who have a genetic problem where the body does not make any of the proteins interleukin 12 (IL-12) and interleukin 23 (IL-23) are at a higher risk for certain serious infections. These infections can spread throughout the body and cause death. People who take SELARSDI may also be more likely to get these infections.</p> <p> <span class="Bold">Cancers. </span>SELARSDI may decrease the activity of your immune system and increase your risk for certain types of cancers. Tell your doctor if you have ever had any type of cancer. Some people who are receiving ustekinumab products and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with SELARSDI, tell your doctor if you develop any new skin growths.</p> <p> <span class="Bold">Posterior Reversible Encephalopathy Syndrome (PRES). </span>PRES is a rare condition that affects the brain and can cause death. The cause of PRES is not known. If PRES is found early and treated, most people recover. Tell your doctor right away if you have any new or worsening medical problems including:</p> </td> </tr> <tr> <td class="Lrule" colspan="2"> <br/> <ul class="Circle"> <li>headache </li> <li>confusion</li> </ul> </td><td class="Rrule"> <ul class="Circle"> <li>seizures </li> <li>vision problems</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <br/> <p class="First"> <span class="Bold">What is SELARSDI?<br/> </span>SELARSDI is a prescription medicine used to treat:</p> <ul class="Disk"> <li>adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).</li> <li>adults and children 6 years and older with active psoriatic arthritis.</li> <li>adults 18 years and older with moderately to severely active Crohn’s disease.</li> <li>adults 18 years and older with moderately to severely active ulcerative colitis.</li> </ul> <p>It is not known if SELARSDI is safe and effective in children less than 6 years of age.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <br/> <span class="Bold">Do not take SELARSDI if you are</span> allergic to ustekinumab products or any of the ingredients in SELARSDI. See the end of this Medication Guide for a complete list of ingredients in SELARSDI.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <br/> <p class="First"> <span class="Bold">Before you receive SELARSDI, tell your doctor about all of your medical conditions, including if you:</span> </p> <ul class="Disk"> <li>have any of the conditions or symptoms listed in the section "<span class="Bold">What is the most important information I should know about SELARSDI?</span>"</li> <li>ever had an allergic reaction to ustekinumab products. Ask your doctor if you are not sure.</li> <li>have recently received or are scheduled to receive an immunization (vaccine). People who take SELARSDI should not receive live vaccines. Tell your doctor if anyone in your house needs a live vaccine. The viruses used in some types of live vaccines can spread to people with a weakened immune system, and can cause serious problems. <span class="Bold">You should not receive the BCG vaccine during the one year before receiving SELARSDI or one year after<br/> you stop receiving SELARSDI.</span> </li> <li>have any new or changing lesions within psoriasis areas or on normal skin.</li> <li>are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as well for you during treatment with SELARSDI. SELARSDI may also increase your risk of having an allergic reaction to an allergy shot.</li> <li>receive or have received phototherapy for your psoriasis.</li> <li>are pregnant or plan to become pregnant. It is not known if SELARSDI can harm your unborn baby. You and your doctor should decide if you will receive SELARSDI. See "What should I avoid while using SELARSDI?"</li> <li>received SELARSDI while you were pregnant. It is important that you tell your baby's healthcare provider before any vaccinations are given to your baby.</li> <li>are breastfeeding or plan to breastfeed. SELARSDI can pass into your breast milk.</li> <li>Talk to your doctor about the best way to feed your baby if you receive SELARSDI.</li> </ul> <p> <span class="Bold">Tell your doctor about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p> <p>Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <br/> <p class="First"> <span class="Bold">How should I use SELARSDI?</span> </p> <ul class="Disk"> <li>Use SELARSDI exactly as your doctor tells you to.</li> <li>Adults with Crohn’s disease and ulcerative colitis will receive the first dose of SELARSDI through a vein in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour to receive the full dose of medicine. You will then receive SELARSDI as an injection under the skin (subcutaneous injection) 8 weeks after the first dose of SELARSDI, as described below. </li> <li>Adults with psoriasis or psoriatic arthritis, and children 6 years and older with psoriasis or psoriatic arthritis will receive SELARSDI as an injection under the skin (subcutaneous injection) as described below.</li> <li> <span class="Bold">Injecting SELARSDI under your skin</span> <ul class="Circle"> <li>SELARSDI is intended for use under the guidance and supervision of your doctor. In children 6 years and older, it is recommended that SELARSDI be administered by a healthcare provider. If your doctor decides that you or a caregiver may give your injections of SELARSDI at home, you should receive training on the right way to prepare and inject SELARSDI. Your doctor will determine the right dose of SELARSDI for you, the amount<br/> for each injection, and how often you should receive it. Do not try to inject SELARSDI yourself until you or your caregiver have been shown how to inject SELARSDI by your doctor or nurse.</li> <li>Inject SELARSDI under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs (thighs) or stomach area (abdomen).</li> <li>Do not give an injection in an area of the skin that is tender, bruised, red or hard.</li> <li>Use a different injection site each time you use SELARSDI.</li> <li>If you inject more SELARSDI than prescribed, call your doctor right away.</li> <li>Be sure to keep all of your scheduled follow-up appointments.</li> </ul> </li> </ul> <p> <span class="Bold">Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to prepare and inject a dose of SELARSDI, and how to properly throw away (dispose of) used needles and syringes. The syringe, needle and vial must never be re-used.  After the rubber stopper is punctured, SELARSDI can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused portion of SELARSDI. </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <br/> <p class="First"> <span class="Bold">What should I avoid while using SELARSDI?<br/> </span>You should not receive a live vaccine while taking SELARSDI. See <span class="Bold">"Before you receive SELARSDI, tell your doctor about all of your medical conditions, including if you:</span><span class="Bold">"</span> </p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="3"> <br/> <p class="First"> <span class="Bold">What are the possible side effects of SELARSDI?<br/> </span>SELARSDI may cause serious side effects, including:</p> <ul class="Disk"> <li>See <span class="Bold">"What is the most important information I should know about SELARSDI?"</span> </li> <li> <span class="Bold">Serious allergic reactions. </span>Serious allergic reactions can occur with SELARSDI. Stop using SELARSDI and get medical help right away if you have any of the following symptoms of a serious allergic reaction:</li> </ul> </td> </tr> <tr> <td class="Lrule" colspan="2"> <br/> <ul class="Circle"> <li>feeling faint</li> <li>swelling of your face, eyelids, tongue, or throat</li> </ul> </td><td class="Rrule"> <ul class="Circle"> <li>chest tightness</li> <li>skin rash</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3"> <br/> <ul class="Disk"> <li> <span class="Bold">Lung inflammation. </span>Cases of lung inflammation have happened in some people who receive ustekinumab products and may be serious. These lung problems may need to be treated in a hospital. Tell your doctor right away if you develop shortness of breath or a cough that doesn't go away during treatment with SELARSDI.</li> </ul> <p class="First"> <span class="Bold">Common side effects of SELARSDI include:</span> </p> </td> </tr> <tr> <td class="Lrule" colspan="2"> <br/> <ul class="Disk"> <li>nasal congestion, sore throat, and runny nose</li> <li>upper respiratory infections</li> <li>fever</li> <li>headache</li> <li>tiredness</li> <li>itching</li> <li>nausea and vomiting</li> </ul> </td><td class="Rrule"> <ul class="Disk"> <li>redness at the injection site</li> <li>vaginal yeast infections</li> <li>urinary tract infections</li> <li>sinus infection</li> <li>bronchitis</li> <li>diarrhea</li> <li>stomach pain</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3"> <br/> <p class="First">These are not all of the possible side effects of SELARSDI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.<br/> You may also report side effects to Teva Pharmaceuticals at 1-888-483-8279.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <br/> <p class="First"> <span class="Bold">How should I store SELARSDI?</span> </p> <ul class="Disk"> <li>Store SELARSDI vials and prefilled syringes in a refrigerator between 36°F to 46°F (2°C to 8°C).</li> <li>Store SELARSDI vials standing up straight.</li> <li>Store SELARSDI in the original carton to protect it from light until time to use it.</li> <li>Do not freeze SELARSDI.</li> <li>Do not shake SELARSDI.</li> </ul> <p>If needed, individual SELARSDI prefilled syringes may also be stored at room temperature up to 86°F (30°C) for a maximum single period of up to 30 days in the original carton to protect from light. Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided. Once a syringe has been stored at room temperature, it should not be returned to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage. Do not use SELARSDI after the expiration date on the carton or on the prefilled syringe.</p> <p> <span class="Bold">Keep SELARSDI and all medicines out of the reach of children.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <br/> <p class="First"> <span class="Bold">General information about the safe and effective use of SELARSDI.<br/> </span>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SELARSDI for a condition for which it was not prescribed. Do not give SELARSDI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about SELARSDI that was written for health professionals.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <br/> <p class="First"> <span class="Bold">What are the ingredients in SELARSDI?<br/> Active ingredient: </span>ustekinumab-aekn<span class="Bold"> <br/> </span> </p> <p> <span class="Bold">Inactive ingredients: Single-dose prefilled syringe <span class="Bold">and single-dose vial</span> for subcutaneous use contains </span>histidine, L-histidine monohydrochloride monohydrate, polysorbate 80, sucrose and water for injection. <span class="Bold">Single-dose vial for intravenous infusion contains </span>edetate disodium, histidine, L-histidine monohydrochloride monohydrate, methionine, polysorbate 80, sucrose and water for injection.</p> <p>Manufactured By: <span class="Bold">Alvotech USA Inc.,</span> Leesburg, VA 20175<br/> U.S. License No. 2225<br/> Product of Iceland<br/> Marketed By: <span class="Bold">Teva Pharmaceuticals,</span> Parsippany, NJ 07054<br/> For more information, go to www.SELARSDI.com or call 1-888-483-8279.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col/>\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"> <br/>\n<p class=\"First\">\n<span class=\"Bold\">MEDICATION GUIDE<br/>\n</span><span class=\"Bold\">SELARSDI™ (seh-LARS-dee)<br/>\n</span><span class=\"Bold\">(ustekinumab-aekn)<br/>\n</span><span class=\"Bold\">injection, for subcutaneous or intravenous use</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\"> <br/>\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about SELARSDI?<br/>\n</span>SELARSDI is a medicine that affects your immune system. SELARSDI can increase your risk of having serious side<br/>\n effects, including:</p>\n<p>\n<span class=\"Bold\">Serious infections. </span>SELARSDI may lower the ability of your immune system to fight infections and may increase your risk of infections. Some people have serious infections while taking ustekinumab products, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their infection.</p>\n<ul class=\"Disk\">\n<li>Your doctor should check you for TB before starting SELARSDI.</li>\n<li>If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with SELARSDI and during treatment with SELARSDI.</li>\n<li>Your doctor should watch you closely for signs and symptoms of TB while you are being treated with SELARSDI.</li>\n</ul>\n<p>You should not start taking SELARSDI if you have any kind of infection unless your doctor says it is okay.</p>\n<p>\n<span class=\"Bold\">Before starting SELARSDI, tell your doctor if you:</span>\n</p>\n<ul class=\"Disk\">\n<li>think you have an infection or have symptoms of an infection such as:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\"> <br/>\n<ul class=\"Circle\">\n<li>fever, sweat, or chills</li>\n<li>muscle aches</li>\n<li>cough</li>\n<li>shortness of breath</li>\n<li>blood in phlegm</li>\n<li>weight loss</li>\n</ul>\n</td><td class=\"Rrule\">\n<ul class=\"Circle\">\n<li>warm, red, or painful skin or sores on your body</li>\n<li>diarrhea or stomach pain</li>\n<li>burning when you urinate or urinate more often than normal</li>\n<li>feel very tired</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\"> <br/>\n<ul class=\"Disk\">\n<li>are being treated for an infection or have any open cuts.</li>\n<li>get a lot of infections or have infections that keep coming back.</li>\n<li>have TB, or have been in close contact with someone with TB.</li>\n</ul>\n<p class=\"First\">\n<span class=\"Bold\">After starting SELARSDI, </span>call your doctor right away if you have any symptoms of an infection (see above). These may be signs of infections such as chest infections, or skin infections or shingles that could have serious complications. SELARSDI can make you more likely to get infections or make an infection that you have worse.</p>\n<p>People who have a genetic problem where the body does not make any of the proteins interleukin 12 (IL-12) and interleukin 23 (IL-23) are at a higher risk for certain serious infections. These infections can spread throughout the body and cause death. People who take SELARSDI may also be more likely to get these infections.</p>\n<p>\n<span class=\"Bold\">Cancers. </span>SELARSDI may decrease the activity of your immune system and increase your risk for certain types of cancers. Tell your doctor if you have ever had any type of cancer. Some people who are receiving ustekinumab products and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with SELARSDI, tell your doctor if you develop any new skin growths.</p>\n<p>\n<span class=\"Bold\">Posterior Reversible Encephalopathy Syndrome (PRES). </span>PRES is a rare condition that affects the brain and can cause death. The cause of PRES is not known. If PRES is found early and treated, most people recover. Tell your doctor right away if you have any new or worsening medical problems including:</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\"> <br/>\n<ul class=\"Circle\">\n<li>headache </li>\n<li>confusion</li>\n</ul>\n</td><td class=\"Rrule\">\n<ul class=\"Circle\">\n<li>seizures </li>\n<li>vision problems</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"> <br/>\n<p class=\"First\">\n<span class=\"Bold\">What is SELARSDI?<br/>\n</span>SELARSDI is a prescription medicine used to treat:</p>\n<ul class=\"Disk\">\n<li>adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).</li>\n<li>adults and children 6 years and older with active psoriatic arthritis.</li>\n<li>adults 18 years and older with moderately to severely active Crohn’s disease.</li>\n<li>adults 18 years and older with moderately to severely active ulcerative colitis.</li>\n</ul>\n<p>It is not known if SELARSDI is safe and effective in children less than 6 years of age.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"> <br/>\n<span class=\"Bold\">Do not take SELARSDI if you are</span> allergic to ustekinumab products or any of the ingredients in SELARSDI. See the end of this Medication Guide for a complete list of ingredients in SELARSDI.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"> <br/>\n<p class=\"First\">\n<span class=\"Bold\">Before you receive SELARSDI, tell your doctor about all of your medical conditions, including if you:</span>\n</p>\n<ul class=\"Disk\">\n<li>have any of the conditions or symptoms listed in the section \"<span class=\"Bold\">What is the most important information I should know about SELARSDI?</span>\"</li>\n<li>ever had an allergic reaction to ustekinumab products. Ask your doctor if you are not sure.</li>\n<li>have recently received or are scheduled to receive an immunization (vaccine). People who take SELARSDI should not receive live vaccines. Tell your doctor if anyone in your house needs a live vaccine. The viruses used in some types of live vaccines can spread to people with a weakened immune system, and can cause serious problems. <span class=\"Bold\">You should not receive the BCG vaccine during the one year before receiving SELARSDI or one year after<br/>\n you stop receiving SELARSDI.</span>\n</li>\n<li>have any new or changing lesions within psoriasis areas or on normal skin.</li>\n<li>are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as well for you during treatment with SELARSDI. SELARSDI may also increase your risk of having an allergic reaction to an allergy shot.</li>\n<li>receive or have received phototherapy for your psoriasis.</li>\n<li>are pregnant or plan to become pregnant. It is not known if SELARSDI can harm your unborn baby. You and your doctor should decide if you will receive SELARSDI. See \"What should I avoid while using SELARSDI?\"</li>\n<li>received SELARSDI while you were pregnant. It is important that you tell your baby's healthcare provider before any vaccinations are given to your baby.</li>\n<li>are breastfeeding or plan to breastfeed. SELARSDI can pass into your breast milk.</li>\n<li>Talk to your doctor about the best way to feed your baby if you receive SELARSDI.</li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your doctor about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p>\n<p>Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"> <br/>\n<p class=\"First\">\n<span class=\"Bold\">How should I use SELARSDI?</span>\n</p>\n<ul class=\"Disk\">\n<li>Use SELARSDI exactly as your doctor tells you to.</li>\n<li>Adults with Crohn’s disease and ulcerative colitis will receive the first dose of SELARSDI through a vein in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour to receive the full dose of medicine. You will then receive SELARSDI as an injection under the skin (subcutaneous injection) 8 weeks after the first dose of SELARSDI, as described below. </li>\n<li>Adults with psoriasis or psoriatic arthritis, and children 6 years and older with psoriasis or psoriatic arthritis will receive SELARSDI as an injection under the skin (subcutaneous injection) as described below.</li>\n<li>\n<span class=\"Bold\">Injecting SELARSDI under your skin</span>\n<ul class=\"Circle\">\n<li>SELARSDI is intended for use under the guidance and supervision of your doctor. In children 6 years and older, it is recommended that SELARSDI be administered by a healthcare provider. If your doctor decides that you or a caregiver may give your injections of SELARSDI at home, you should receive training on the right way to prepare and inject SELARSDI. Your doctor will determine the right dose of SELARSDI for you, the amount<br/>\n for each injection, and how often you should receive it. Do not try to inject SELARSDI yourself until you or your caregiver have been shown how to inject SELARSDI by your doctor or nurse.</li>\n<li>Inject SELARSDI under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs (thighs) or stomach area (abdomen).</li>\n<li>Do not give an injection in an area of the skin that is tender, bruised, red or hard.</li>\n<li>Use a different injection site each time you use SELARSDI.</li>\n<li>If you inject more SELARSDI than prescribed, call your doctor right away.</li>\n<li>Be sure to keep all of your scheduled follow-up appointments.</li>\n</ul>\n</li>\n</ul>\n<p>\n<span class=\"Bold\">Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to prepare and inject a dose of SELARSDI, and how to properly throw away (dispose of) used needles and syringes. The syringe, needle and vial must never be re-used.  After the rubber stopper is punctured, SELARSDI can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused portion of SELARSDI. </span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"> <br/>\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while using SELARSDI?<br/>\n</span>You should not receive a live vaccine while taking SELARSDI. See <span class=\"Bold\">\"Before you receive SELARSDI, tell your doctor about all of your medical conditions, including if you:</span><span class=\"Bold\">\"</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"3\"> <br/>\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of SELARSDI?<br/>\n</span>SELARSDI may cause serious side effects, including:</p>\n<ul class=\"Disk\">\n<li>See <span class=\"Bold\">\"What is the most important information I should know about SELARSDI?\"</span>\n</li>\n<li>\n<span class=\"Bold\">Serious allergic reactions. </span>Serious allergic reactions can occur with SELARSDI. Stop using SELARSDI and get medical help right away if you have any of the following symptoms of a serious allergic reaction:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\"> <br/>\n<ul class=\"Circle\">\n<li>feeling faint</li>\n<li>swelling of your face, eyelids, tongue, or throat</li>\n</ul>\n</td><td class=\"Rrule\">\n<ul class=\"Circle\">\n<li>chest tightness</li>\n<li>skin rash</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\"> <br/>\n<ul class=\"Disk\">\n<li>\n<span class=\"Bold\">Lung inflammation. </span>Cases of lung inflammation have happened in some people who receive ustekinumab products and may be serious. These lung problems may need to be treated in a hospital. Tell your doctor right away if you develop shortness of breath or a cough that doesn't go away during treatment with SELARSDI.</li>\n</ul>\n<p class=\"First\">\n<span class=\"Bold\">Common side effects of SELARSDI include:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\"> <br/>\n<ul class=\"Disk\">\n<li>nasal congestion, sore throat, and runny nose</li>\n<li>upper respiratory infections</li>\n<li>fever</li>\n<li>headache</li>\n<li>tiredness</li>\n<li>itching</li>\n<li>nausea and vomiting</li>\n</ul>\n</td><td class=\"Rrule\">\n<ul class=\"Disk\">\n<li>redness at the injection site</li>\n<li>vaginal yeast infections</li>\n<li>urinary tract infections</li>\n<li>sinus infection</li>\n<li>bronchitis</li>\n<li>diarrhea</li>\n<li>stomach pain</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\"> <br/>\n<p class=\"First\">These are not all of the possible side effects of SELARSDI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.<br/>\n You may also report side effects to Teva Pharmaceuticals at 1-888-483-8279.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"> <br/>\n<p class=\"First\">\n<span class=\"Bold\">How should I store SELARSDI?</span>\n</p>\n<ul class=\"Disk\">\n<li>Store SELARSDI vials and prefilled syringes in a refrigerator between 36°F to 46°F (2°C to 8°C).</li>\n<li>Store SELARSDI vials standing up straight.</li>\n<li>Store SELARSDI in the original carton to protect it from light until time to use it.</li>\n<li>Do not freeze SELARSDI.</li>\n<li>Do not shake SELARSDI.</li>\n</ul>\n<p>If needed, individual SELARSDI prefilled syringes may also be stored at room temperature up to 86°F (30°C) for a maximum single period of up to 30 days in the original carton to protect from light. Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided. Once a syringe has been stored at room temperature, it should not be returned to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage. Do not use SELARSDI after the expiration date on the carton or on the prefilled syringe.</p>\n<p>\n<span class=\"Bold\">Keep SELARSDI and all medicines out of the reach of children.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"> <br/>\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of SELARSDI.<br/>\n</span>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SELARSDI for a condition for which it was not prescribed. Do not give SELARSDI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about SELARSDI that was written for health professionals.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"> <br/>\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in SELARSDI?<br/>\n Active ingredient: </span>ustekinumab-aekn<span class=\"Bold\">\n<br/>\n</span>\n</p>\n<p>\n<span class=\"Bold\">Inactive ingredients: Single-dose prefilled syringe <span class=\"Bold\">and single-dose vial</span> for subcutaneous use contains </span>histidine, L-histidine monohydrochloride monohydrate, polysorbate 80, sucrose and water for injection. <span class=\"Bold\">Single-dose vial for intravenous infusion contains </span>edetate disodium, histidine, L-histidine monohydrochloride monohydrate, methionine, polysorbate 80, sucrose and water for injection.</p>\n<p>Manufactured By: <span class=\"Bold\">Alvotech USA Inc.,</span> Leesburg, VA 20175<br/>\n U.S. License No. 2225<br/>\n Product of Iceland<br/>\n Marketed By: <span class=\"Bold\">Teva Pharmaceuticals,</span> Parsippany, NJ 07054<br/>\n For more information, go to www.SELARSDI.com or call 1-888-483-8279.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Medication Guide has been approved by the U.S. Food and Drug Administration                                     Revised: 02/2025

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration                                     Revised: 02/2025" }

INSTRUCTIONS FOR USE SELARSDI™ [seh-LARS-dee] (ustekinumab-aekn) injection, for subcutaneous use

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USE\nSELARSDI™ [seh-LARS-dee]\n(ustekinumab-aekn)\ninjection, for subcutaneous use\n" }

This Instructions for Use contains information on how to inject SELARSDI. Read this Instructions for Use before you start using SELARSDI. Your doctor or nurse should show you how to prepare and give your injection of SELARSDI the right way.

{ "type": "p", "children": [], "text": "\nThis Instructions for Use contains information on how to inject SELARSDI.\nRead this Instructions for Use before you start using SELARSDI. Your doctor or nurse should show you how\nto prepare and give your injection of SELARSDI the right way.\n\n" }

If you cannot give yourself the injection:

{ "type": "p", "children": [], "text": "If you cannot give yourself the injection:\n\n\n" }

{ "type": "ul", "children": [ "ask your doctor or nurse to help you, or", "ask someone who has been trained by a doctor or nurse to give your injections." ], "text": "" }

Do not try to inject SELARSDI yourself until you have been shown how to inject SELARSDI by your doctor, nurse or health professional.

{ "type": "p", "children": [], "text": "Do not try to inject SELARSDI yourself until you have been shown how to inject SELARSDI by your doctor, nurse or\nhealth professional." }

Important Information You Need to Know Before Injecting SELARSDI

{ "type": "p", "children": [], "text": "\nImportant Information You Need to Know Before Injecting SELARSDI\n\n" }

{ "type": "ul", "children": [ "\nFor subcutaneous injection only (inject directly under the skin).\n", "Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as\n prescribed by your doctor.\n \nIf your dose is 45 mg, you will receive one 45 mg prefilled syringe.\nIf your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If\n you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself two injections, one right after the other.\n\n", "Children 12 years of age and older with psoriasis who weigh 132 pounds or more may use a prefilled syringe.", "Check the expiration date on the prefilled syringe and carton. If the expiration date has passed or if the prefilled syringe has been kept at room temperature up to 30°C (86°F) for longer than a maximum single period of 30 days or if the prefilled syringe has been stored above 30°C (86°F), do not use it. If the expiration date has passed or if the prefilled syringe has been stored above 30°C (86°F), call your doctor or pharmacist, or call 1-888-483-8279 for help.", "Make sure the prefilled syringe is not damaged.", "Check your prefilled syringe for any particles or discoloration. Your prefilled syringe should look clear and colorless to slightly yellow solution and should not have any particles.", "\nDo not use if it is frozen, discolored, cloudy, or has particles. Get a new prefilled syringe.", "\nDo not shake the prefilled syringe at any time. Shaking your prefilled syringe may damage your SELARSDI medicine. If your prefilled syringe has been shaken, do not use it. Get a new prefilled syringe.", "To reduce the risk of accidental needle sticks, each prefilled syringe has a needle guard that is automatically activated to cover the needle after you have given your injection. Do not pull back on the plunger at any time." ], "text": "" }

Storing SELARSDI

{ "type": "p", "children": [], "text": "\nStoring SELARSDI\n" }

{ "type": "ul", "children": [ "Store SELARSDI in a refrigerator between 36°F to 46°F (2°C to 8°C).", "Store SELARSDI in the original carton to protect it from light until time to use it.", "Do not freeze SELARSDI.", "Do not shake SELARSDI." ], "text": "" }

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, it should not be returned to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage.

{ "type": "p", "children": [], "text": "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, it should not be returned to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage." }

Do not use SELARSDI after the expiration date on the carton or on the prefilled syringe.

{ "type": "p", "children": [], "text": "Do not use SELARSDI after the expiration date on the carton or on the prefilled syringe." }

Keep SELARSDI and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep SELARSDI and all medicines out of the reach of children.\n" }

Preparing to inject SELARSDI

{ "type": "p", "children": [], "text": "\nPreparing to inject SELARSDI\n" }

STEP 1: Gather Supplies

{ "type": "p", "children": [], "text": "\nSTEP 1: Gather Supplies \n" }

Gather the supplies you will need to prepare and to give your injection. (See Figure B)

{ "type": "p", "children": [], "text": "\nGather the supplies you will need to prepare and to give your injection. (See Figure B) \n" }

{ "type": "ul", "children": [ "You will need:\n \nantiseptic wipes\ncotton balls or gauze pads\nadhesive bandage\nyour prescribed dose of SELARSDI (See Figure A)\n\nFDA-cleared sharps disposal container. See\"STEP 9: Dispose of the used prefilled syringe.\"\n\n\n" ], "text": "" }

STEP 2: Prepare Your Injection Site

{ "type": "p", "children": [], "text": "\nSTEP 2: Prepare Your Injection Site \n" }

{ "type": "ul", "children": [ "Choose a well-lit, clean, flat work surface.", "Wash your hands well with soap and warm water.", "Choose an injection site around your stomach area (abdomen), buttocks, or upper legs (thighs). If a caregiver is giving you the injection, the outer area of the upper arms may also be used. (See Figure C)\n", "\nUse a different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard.", "Clean the skin with an antiseptic wipe where you plan to give your injection.", "\nDo not touch this area again before giving the injection. Let your skin dry before injecting.", "\nDo not fan or blow on the clean area.", "\nDo not inject through clothes." ], "text": "" }

 Injecting SELARSDI

{ "type": "p", "children": [], "text": "\n Injecting SELARSDI\n" }

STEP 3: Remove Needle Cover

{ "type": "p", "children": [], "text": "\nSTEP 3: Remove Needle Cover \n" }

{ "type": "ul", "children": [ "Remove the needle cover when you are ready to inject your SELARSDI.", "\nDo not touch the plunger or plunger head while removing the needle cover.", "Hold the body of the prefilled syringe with one hand, and pull the needle cover straight off. (See Figure D)\n", "Put the needle cover in the trash. Do not recap.", "You may also see a drop of liquid at the end of the needle. This is normal.", "\nDo not touch the needle or let it touch anything.", "\nDo not use the prefilled syringe if it is dropped without the needle cover in place. Call your doctor, nurse or health professional for instructions." ], "text": "" }

STEP 4: Grasp the Syringe

{ "type": "p", "children": [], "text": "\nSTEP 4: Grasp the Syringe \n" }

{ "type": "ul", "children": [ "Hold the body of the prefilled syringe in one hand between the thumb and index fingers. (See Figure E)\n", "\nDo not pull back on the plunger at any time." ], "text": "" }

STEP 5: Pinch the Skin and Insert Needle

{ "type": "p", "children": [], "text": "\nSTEP 5: Pinch the Skin and Insert Needle \n" }

{ "type": "ul", "children": [ "Use the other hand to gently pinch the cleaned area of skin. Hold firmly.", "Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree angle. (See Figure F)\n" ], "text": "" }

STEP 6: Inject the Drug

{ "type": "p", "children": [], "text": "\nSTEP 6: Inject the Drug \n" }

{ "type": "ul", "children": [ "Inject all of the liquid by using your thumb to push in the plunger head all the way in until the plunger head is completely between the needle guard activation clips. (See Figure G)\n" ], "text": "" }

STEP 7: Allow Needle to Retract

{ "type": "p", "children": [], "text": "\nSTEP 7: Allow Needle to Retract \n" }

{ "type": "ul", "children": [ "When the plunger is pushed as far as it will go, keep pressure on the plunger head. Take the needle out of the skin and let go of the skin.", "Slowly take your thumb off the plunger head. This will let the empty syringe move up until the entire needle is covered by the needle guard. (See Figure H)\n" ], "text": "" }

STEP 8: Treat Injection Site

{ "type": "p", "children": [], "text": "\nSTEP 8: Treat Injection Site \n" }

{ "type": "ul", "children": [ "When the needle is pulled out of your skin, there may be a little bleeding at the injection site. This is normal.", "You can press a cotton ball or gauze pad on the skin of the injection site, if needed (See Figure I). Do not rub the injection site.", "Cover the injection site with a small adhesive bandage, if necessary." ], "text": "" }

If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself a second injection right after the first. Repeat Steps 1 to 8 for the second injection using a new syringe.

{ "type": "p", "children": [], "text": "If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself a second injection right after the first. Repeat Steps 1 to 8 for the second injection using a new syringe. " }

Choose a different site for the second injection.

{ "type": "p", "children": [], "text": "\nChoose a different site for the second injection.\n" }

Disposing of SELARSDI

{ "type": "p", "children": [], "text": "\nDisposing of SELARSDI\n" }

STEP 9: Dispose of the used prefilled syringe

{ "type": "p", "children": [], "text": "\nSTEP 9: Dispose of the used prefilled syringe \n" }

{ "type": "ul", "children": [ "Put the syringe in a FDA-cleared sharps disposal container right away after use (See Figure J). Do not throw away (dispose of) loose syringes in your household trash.\n" ], "text": "" }

{ "type": "ul", "children": [ "If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:\n \nmade of heavy-duty plastic,\ncan be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,\nupright and stable during use,\nleak-resistant, and\nproperly labeled to warn of hazardous waste inside the container.\nWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.\nDo not dispose of your sharps disposal container in your household trash unless your community guidelines permit this.\nDo not recycle your sharps disposal container.\nIf you have any questions, talk to your doctor or pharmacist.\n\n" ], "text": "" }

Keep SELARSDI and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep SELARSDI and all medicines out of the reach of children.\n" }

Manufactured By: Alvotech USA Inc. Leesburg, VA 20175

{ "type": "p", "children": [], "text": "Manufactured By:\nAlvotech USA Inc.\nLeesburg, VA 20175" }

U.S. License No. 2225

{ "type": "p", "children": [], "text": "U.S. License No. 2225" }

Product of Iceland

{ "type": "p", "children": [], "text": "Product of Iceland" }

Marketed By: Teva Pharmaceuticals Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Marketed By:\nTeva Pharmaceuticals\nParsippany, NJ 07054" }

For additional information, call Teva Pharmaceuticals at 1-888-483-8279.

{ "type": "p", "children": [], "text": "\nFor additional information, call Teva Pharmaceuticals at 1-888-483-8279.\n" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

Approved: 04/2024

{ "type": "p", "children": [], "text": "Approved: 04/2024" }

INSTRUCTIONS FOR USE

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USE\n" }

SELARSDI™[seh-LARS-dee]

{ "type": "p", "children": [], "text": "\nSELARSDI™[seh-LARS-dee]\n" }

(ustekinumab-aekn)

{ "type": "p", "children": [], "text": "\n(ustekinumab-aekn)\n" }

injection, for subcutaneous use

{ "type": "p", "children": [], "text": "\ninjection, for subcutaneous use\n" }

Instructions for injecting SELARSDI from a vial.

{ "type": "p", "children": [], "text": "\nInstructions for injecting SELARSDI from a vial. \n" }

Read this Instructions for Use before you start using SELARSDI. Your doctor or nurse should show you how to prepare, measure your dose and give your injection of SELARSDI the right way.

{ "type": "p", "children": [], "text": "\nRead this Instructions for Use before you start using SELARSDI. Your doctor or nurse should show you how to prepare, measure your dose and give your injection of SELARSDI the right way. \n" }

If you cannot give yourself the injection:

{ "type": "p", "children": [], "text": "If you cannot give yourself the injection: " }

{ "type": "ul", "children": [ "ask your doctor or nurse to help you, or ", "ask someone who has been trained by a doctor or nurse to give your injections. " ], "text": "" }

Do not try to inject SELARSDI yourself until you have been shown how to inject SELARSDI by your doctor, nurse or health professional.

{ "type": "p", "children": [], "text": "Do not try to inject SELARSDI yourself until you have been shown how to inject SELARSDI by your doctor, nurse or health professional." }

Important Information:

{ "type": "p", "children": [], "text": "\nImportant Information:\n" }

{ "type": "ul", "children": [ "Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by your doctor.\n \nIf your dose is 45 mg or less you will receive one 45 mg vial. \nIf your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself two injections, one right after the other. \n\n", "Children 12 years of age and older weighing less than 132 pounds require a dose lower than 45 mg. ", "Check the expiration date on the vial and carton. If the expiration date has passed, do not use it. If the expiration date has passed, call your doctor or pharmacist, or call Teva Pharmaceuticals at 1-888-483-8279 for help. ", "Check the vial for any particles or discoloration. The liquid in your vial should look clear and colorless to slightly yellow and without visible particles. ", "Do not use if it is frozen, discolored, cloudy or has large particles. Get a new vial. ", "\nDo not shake the vial at any time. Shaking your vial may damage your SELARSDI medicine. If your vial has been shaken, do not use it. Get a new vial.", "Do not use a SELARSDI vial more than one time, even if there is medicine left in the vial. After the rubber stopper is punctured, SELARSDI can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused SELARSDI after you give your injection.", "Safely throw away (dispose of) SELARSDI vials after use.", "Do not re-use syringes or needles. See “Step 6: Dispose of needles and syringes.”", "To avoid needle-stick injuries, do not recap needles. " ], "text": "" }

Storing SELARSDI

{ "type": "p", "children": [], "text": "\nStoring SELARSDI\n" }

{ "type": "ul", "children": [ "Store SELARSDI in a refrigerator between 36°F to 46°F (2°C to 8°C).", "Store SELARSDI standing up straight.", "Store SELARSDI in the original carton to protect it from light until time to use it.", "Do not freeze SELARSDI.", "Do not shake SELARSDI." ], "text": "" }

Keep SELARSDI and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep SELARSDI and all medicines out of the reach of children. \n" }

Gather the supplies you will need to prepare SELARSDI and to give your injection. (See Figure A)

{ "type": "p", "children": [], "text": "\nGather the supplies you will need to prepare SELARSDI and to give your injection. (See Figure A) \n" }

{ "type": "ul", "children": [ "You will need: " ], "text": "" }

{ "type": "ul", "children": [ "a syringe with the needle attached, you will need a prescription from your healthcare provider to get syringes with the needles attached from your pharmacy.", "antiseptic wipes ", "cotton balls or gauze pads ", "adhesive bandage ", "your prescribed dose of SELARSDI ", "FDA-cleared sharps disposal container. See “Step 6: Dispose of the needles and syringes.”\n" ], "text": "" }

Step 1: Prepare the injection.

{ "type": "p", "children": [], "text": "\nStep 1: Prepare the injection. \n" }

{ "type": "ul", "children": [ "Choose a well-lit, clean, flat work surface.", "Wash your hands well with soap and warm water. " ], "text": "" }

Step 2: Prepare your injection site.

{ "type": "p", "children": [], "text": "\nStep 2: Prepare your injection site. \n" }

{ "type": "ul", "children": [ "Choose an injection site around your stomach area (abdomen), buttocks, and upper legs (thighs). If a caregiver is giving you the injection, the outer area of the upper arms may also be used. (See Figure B)\n", "\nUse a different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard.", "Clean the skin with an antiseptic wipe where you plan to give your injection. ", "\nDo not touch this area again before giving the injection. Let your skin dry before injecting.", "\nDo not fan or blow on the clean area." ], "text": "" }

*Areas in yellow are recommended injection sites

{ "type": "p", "children": [], "text": "*Areas in yellow are recommended injection sites" }

Step 3: Prepare the vial.

{ "type": "p", "children": [], "text": "\nStep 3: Prepare the vial.\n" }

{ "type": "ul", "children": [ "Remove the cap from the top of the vial. Throw away the cap but do not remove the rubber stopper. (See Figure C)\n" ], "text": "" }

{ "type": "ul", "children": [ "Clean the rubber stopper with an antiseptic swab. (See Figure D)\n" ], "text": "" }

{ "type": "ul", "children": [ "Do not touch the rubber stopper after you clean it.", "Put the vial on a flat surface." ], "text": "" }

Step 4: Prepare the Needle.

{ "type": "p", "children": [], "text": "\nStep 4: Prepare the Needle.\n" }

{ "type": "ul", "children": [ "Pick up the syringe with the needle attached.", "Remove the cap that covers the needle. (See Figure E)\n", "Throw the needle cap away. Do not touch the needle or allow the needle to touch anything." ], "text": "" }

{ "type": "ul", "children": [ "Carefully pull back on the plunger to the line that matches the dose prescribed by your doctor.", "Hold the vial between your thumb and index (pointer) finger.", "Use your other hand to push the syringe needle through the center of the rubber stopper. (See Figure F)\n" ], "text": "" }

{ "type": "ul", "children": [ "Push down on the plunger until all of the air has gone from the syringe into the vial.", "Turn the vial and the syringe upside down. (See Figure G)\n", "Hold the SELARSDI vial with one hand.", "It is important that the needle is always in the liquid in order to prevent air bubbles forming in the syringe.", "Pull back on the syringe plunger with your other hand.", "Fill the syringe until the black tip of the plunger lines up with the mark that matches your prescribed dose." ], "text": "" }

{ "type": "ul", "children": [ "\nDo not remove the needle from the vial. Hold the syringe with the needle pointing up to see if it has any air bubbles inside.", "If there are air bubbles, gently tap the side of the syringe until the air bubbles rise to the top. (See Figure H)\n", "Slowly press the plunger up until all of the air bubbles are out of the syringe (but none of the liquid is out).", "Remove the syringe from the vial. Do not lay the syringe down or allow the needle to touch anything." ], "text": "" }

Step 5: Inject SELARSDI.

{ "type": "p", "children": [], "text": "\nStep 5: Inject SELARSDI. \n" }

{ "type": "ul", "children": [ "Hold the barrel of the syringe in one hand, between the thumb and index fingers. ", "\nDo not pull back on the plunger at any time.", "Use the other hand to gently pinch the cleaned area of skin. Hold firmly.", "Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree angle. (See Figure I) \n" ], "text": "" }

{ "type": "ul", "children": [ "Push the plunger with your thumb as far as it will go to inject all of the liquid. Push it slowly and evenly, keeping the skin gently pinched.", "When the syringe is empty, pull the needle out of your skin and let go of the skin. (See Figure J)\n" ], "text": "" }

{ "type": "ul", "children": [ "When the needle is pulled out of your skin, there may be a little bleeding at the injection site. This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary.\n \nIf your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself a second injection right after the first. Repeat Steps 1 to 5 for using a new syringe. Choose a different site for the second injection.\n\nStep 6: Dispose of the needles and syringes.\n\n", "\nDo not re-use a syringe or needle.", "To avoid needle-stick injuries, do not recap a needle.", "Put your needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. \n", "If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:\n \nmade of heavy-duty plastic \ncan be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out \nupright and stable during use \nleak-resistant, \nand properly labeled to warn of hazardous waste inside the container. \n\n", "When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. ", "Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container.", "Throw away the vial into the container where you put the syringes and needles. ", "If you have any questions, talk to your doctor or pharmacist. " ], "text": "" }

For additional information, go to www.SELARSDI.com or call Teva Pharmaceuticals at 1-888-483-8279.

{ "type": "p", "children": [], "text": "\nFor additional information, go to www.SELARSDI.com or call Teva Pharmaceuticals at 1-888-483-8279.\n" }

Manufactured By: Alvotech USA Inc., Leesburg, VA 20175

{ "type": "p", "children": [], "text": "Manufactured By: Alvotech USA Inc., Leesburg, VA 20175" }

U.S. License No. 2225

{ "type": "p", "children": [], "text": "U.S. License No. 2225" }

Product of Iceland

{ "type": "p", "children": [], "text": "Product of Iceland" }

Marketed By: Teva Pharmaceuticals, Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Marketed By: Teva Pharmaceuticals, Parsippany, NJ 07054" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.                  Approved: 02/2025

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NDC 51759-505-32

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Selarsdi™

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(ustekinumab-aekn)

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Injection

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45 mg/0.5 mL

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For Subcutaneous Use

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ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide.

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Single-Dose Prefilled Syringe Discard Unused Portion

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Contains one 45 mg/0.5 mL syringe

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NDC 51759-607-32

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Selarsdi™

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(ustekinumab-aekn)

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Injection

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90 mg/mL

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For Subcutaneous Use

{ "type": "p", "children": [], "text": "For Subcutaneous Use" }

ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide.

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Single-Dose Prefilled Syringe Discard Unused Portion

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Contains one 90 mg/mL syringe

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NDC 51759-708-13

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Selarsdi™

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(ustekinumab-aekn)

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Injection

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130 mg/26 mL

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(5 mg/mL)

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For Intravenous Infusion Only

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Must be diluted 

{ "type": "p", "children": [], "text": "Must be diluted " }

ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide.

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Contains One Single-Dose Vial Discard Unused Portion

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NDC 51759-505-13

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Selarsdi™

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(ustekinumab-aekn)

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Injection

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45 mg/0.5 mL

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(5 mg/mL)

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For Subcutaneous Use

{ "type": "p", "children": [], "text": "For Subcutaneous Use" }

ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide.

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Contains One Single-Dose Vial Discard Unused Portion

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