(ustekinumab) injection, for subcutaneous or intravenous use
Ustekinumab is a human IgG1κ monoclonal antibody against the p40 subunit of the IL-12 and IL-23 cytokines. Using DNA recombinant technology, ustekinumab is produced in a well characterized recombinant cell line and is purified using standard bio-processing technology. The manufacturing process contains steps for the clearance of viruses. Ustekinumab is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons.
STELARA® (ustekinumab) Injection is a sterile, preservative-free, colorless to light yellow solution and may contain a few small translucent or white particles with pH of 5.7- 6.3.
STELARA® For Subcutaneous Use
Available as 45 mg of ustekinumab in 0.5 mL and 90 mg of ustekinumab in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 27 gauge fixed ½ inch needle and as 45 mg of ustekinumab in 0.5 mL in a single-dose 2 mL Type I glass vial with a coated stopper. The syringe is fitted with a passive needle guard and a needle cover that contains dry natural rubber (a derivative of latex).
Each 0.5 mL prefilled syringe or vial delivers 45 mg ustekinumab, L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg).
Each 1 mL prefilled syringe delivers 90 mg ustekinumab, L-histidine and L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg).
STELARA® For Intravenous Infusion
Available as 130 mg of ustekinumab in 26 mL, supplied as a single-dose 30 mL Type I glass vial with a coated stopper.
Each 26 mL vial delivers 130 mg ustekinumab, EDTA disodium salt dihydrate (0.52 mg), L-histidine (20 mg), L-histidine hydrochloride monohydrate (27 mg), L-methionine (10.4 mg), Polysorbate 80 (10.4 mg) and sucrose (2210 mg).
STELARA® is indicated for the treatment of patients 12 years or older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
Psoriatic Arthritis (PsA)
STELARA® is indicated for the treatment of adult patients with active psoriatic arthritis. STELARA® can be used alone or in combination with methotrexate (MTX).
Crohn’s Disease (CD)
STELARA® is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease who have:
- failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with a tumor necrosis factor (TNF) blocker or
- failed or were intolerant to treatment with one or more TNF blockers.
DOSAGE AND ADMINISTRATION
Subcutaneous Adult Dosage Regimen
- For patients weighing 100 kg or less, the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
- For patients weighing more than 100 kg, the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.
In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these subjects [see Clinical Studies].
Subcutaneous Adolescent Dosage Regimen
Administer STELARA® subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.
The recommended dose of STELARA® for adolescents (12-17 years old) based on body weight is shown below (Table 1).
Table 1: Recommended Dose of STELARA® for Subcutaneous Injection in Adolescent Patients with Psoriasis
|Body Weight of Patient at the Time of Dosing||Recommended Dose|
|less than 60 kg||0.75 mg/kg|
|60 kg to100 kg||45 mg|
|more than 100 kg||90 mg|
For adolescent 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.
Table 2: Injection volumes of STELARA®
45 mg/0.5mL single-dose vials for
adolescent psoriasis patients less than
|Body Weight (kg) at the time of dosing||Dose (mg)||Volume of injection (mL)|
Subcutaneous Adult Dosage Regimen
- The recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
- For patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.
Intravenous Induction Adult Dosage Regimen
A single intravenous infusion dose of STELARA® using the weight-based dosage regimen specified in Table 3 [see Instructions for dilution of STELARA® 130 mg vial for intravenous infusion].
Table 3: Initial Intravenous Dosage of STELARA®
|Body Weight of Patient at the time of dosing||Dose||Number of 130 mg/26 mL (5 mg/mL) STELARA® vials|
|55 kgor less||260 mg||2|
|more than55kg to 85kg||390 mg||3|
|more than 85 kg||520 mg||4|
Subcutaneous Maintenance Adult Dosage Regimen
The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the initial intravenous dose, then every 8 weeks thereafter.
General Considerations For Administration
- STELARA® is intended for use under the guidance and supervision of a physician. STELARA® should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician. The appropriate dose should be determined by a healthcare provider using the patient’s current weight at the time of dosing. In adolescent patients, it is recommended that STELARA® be administered by a health care provider. If a physician determines that it is appropriate, a patient may self-inject or a caregiver may inject STELARA® after proper training in subcutaneous injection technique. Patients should be instructed to follow the directions provided in the Medication Guide [see PATIENT INFORMATION].
- The needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex). The needle cover should not be handled by persons sensitive to latex.
- It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, or indurated. When using the single-dose vial, a 1 mL syringe with a 27 gauge, ½ inch needle is recommended.
- Prior to administration, visually inspect STELARA® for particulate matter and discoloration. STELARA® is a colorless to light yellow solution and may contain a few small translucent or white particles. Do not use STELARA® if it is discolored or cloudy, or if other particulate matter is present. STELARA® does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe.
Instructions For Administration Of STELARA® Prefilled Syringes Equipped With Needle Safety Guard
Refer to the diagram below for the provided instructions.
To prevent premature activation of the needle safety guard, do not touch the NEEDLE GUARD ACTIVATION CLIPS at any time during use.
- Hold the BODY and remove the NEEDLE COVER. Do not hold the PLUNGER or PLUNGER HEAD while removing the NEEDLE COVER or the PLUNGER may move. Do not use the prefilled syringe if it is dropped without the NEEDLE COVER in place.
- Inject STELARA® subcutaneously as recommended [see Psoriasis, Psoriatic Arthritis, Crohn’s Disease].
- Inject all of the medication by pushing in the PLUNGER until the PLUNGER HEAD is completely between the needle guard wings. Injection of the entire prefilled syringe contents is necessary to activate the needle guard.
- After injection, maintain the pressure on the PLUNGER HEAD and remove the needle from the skin. Slowly take your thumb off the PLUNGER HEAD to allow the empty syringe to move up until the entire needle is covered by the needle guard, as shown by the illustration below:
- Used syringes should be placed in a puncture-resistant container.
Preparation And Administration Of STELARA® 130 mg/26 mL (5 mg/mL) Vial For Intravenous Infusion (Crohn’s Disease)
STELARA® solution for intravenous infusion must be diluted, prepared and infused by a healthcare professional using aseptic technique.
- Calculate the dose and the number of STELARA® vials needed based on patient weight (Table 3). Each 26 mL vial of STELARA® contains 130 mg of ustekinumab.
- Withdraw, and then discard a volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal to the volume of STELARA® to be added (discard 26 mL sodium chloride for each vial of STELARA® needed, for 2 vials- discard 52 mL, for 3 vials- discard 78 mL, 4 vials- discard 104 mL).
- Withdraw 26 mL of STELARA® from each vial needed and add it to the 250 mL infusion bag. The final volume in the infusion bag should be 250 mL. Gently mix.
- Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
- Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion solution may be stored for up to four hours prior to infusion.
- Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer).
- Do not infuse STELARA® concomitantly in the same intravenous line with other agents.
- STELARA® does not contain preservatives. Each vial is for single use only. Discard any remaining solution. Dispose any unused medicinal product in accordance with local requirements.
If necessary, the diluted infusion solution may be stored for up to 4 hours at room temperature up to 25°C (77°F). Do not freeze. Discard any unused portion of the infusion solution.
Dosage Forms And Strengths
STELARA® (ustekinumab) is a colorless to light yellow solution and may contain a few small translucent or white particles.
- 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
- Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
Storage And Handling
STELARA® (ustekinumab) Injection is a sterile, preservative-free, colorless to light yellow solution and may contain a few small translucent or white particles. It is supplied as individually packaged, single-dose prefilled syringes or single-dose vials.
For Subcutaneous Use
- 45 mg/0.5 mL (NDC 57894-060-03)
- 90 mg/mL (NDC 57894-061-03)
Each prefilled syringe is equipped with a 27 gauge fixed ½ inch needle, a needle safety guard, and a needle cover that contains dry natural rubber.
- 45 mg/0.5 mL (NDC 57894-060-02)
For Intravenous Infusion
- 130 mg/26 mL (5 mg/mL) (NDC 57894-054-27)
Storage And Stability
STELARA® vials and prefilled syringes must be refrigerated at 2°C to 8°C (36°F to 46°F). Store STELARA® vials upright. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake.
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 (19732007) - 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.
Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, US. Revised: June 2018
The following serious adverse reactions are discussed elsewhere in the label:
- Infections [see WARNINGS AND PRECAUTIONS]
- Malignancies [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
- Reversible Posterior Leukoencephalopathy Syndrome [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adult Subjects With Plaque Psoriasis
The safety data reflect exposure to STELARA® in 3117 adult psoriasis subjects, 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% and at a higher rate in the STELARA® groups than the placebo group during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies].
Table 4: Adverse Reactions Reported by ≥1% of Subjects through Week 12 in Ps STUDY 1 and Ps STUDY 2
|Placebo||45 mg||90 mg|
|Nasopharyngitis||51 (8%)||56 (8%)||49 (7%)|
|Upper respiratory tract infection||30 (5%)||36 (5%)||28 (4%)|
|Headache||23 (3%)||33 (5%)||32 (5%)|
|Fatigue||14 (2%)||18 (3%)||17 (3%)|
|Diarrhea||12 (2%)||13 (2%)||13 (2%)|
|Back pain||8 (1%)||9 (1%)||14 (2%)|
|Dizziness||8 (1%)||8 (1%)||14 (2%)|
|Pharyngolaryngeal pain||7 (1%)||9 (1%)||12 (2%)|
|Pruritus||9 (1%)||10 (2%)||9 (1%)|
|Injection site erythema||3 (<1%)||6 (1%)||13 (2%)|
|Myalgia||4 (1%)||7 (1%)||8 (1%)|
|Depression||3 (<1%)||8 (1%)||4 (1%)|
Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation).
One case of RPLS occurred during clinical studies [see WARNINGS AND PRECAUTIONS].
In the placebo-controlled period of clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA®-treated subjects), 27% of STELARA®-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 STELARA®-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].
In the controlled and non-controlled portions of psoriasis clinical studies (median follow-up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of STELARA®-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).
In the controlled and non-controlled portions of psoriasis clinical studies (median follow-up of 3.2 years, representing 8998 subject-years of exposure), 1.7% of STELARA®-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 STELARA®-treated subjects (0.52 per hundred subject-years of follow-up) [see WARNINGS AND PRECAUTIONS]. The most frequently observed malignancies other than non-melanoma skin cancer during the clinical studies were: prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in STELARA®-treated patients during the controlled and uncontrolled portions of studies 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
Adolescent Subjects With Plaque Psoriasis
The safety of STELARA® was assessed in a study of 110 subjects 12 to 17 years of age with moderate to severe plaque psoriasis. The safety profile in these subjects through Week 60 was similar to the safety profile from studies in adults with plaque psoriasis.
The safety of STELARA® was assessed in 927 patients in two randomized, double-blind, placebo-controlled studies in adult patients with active psoriatic arthritis (PsA). The overall safety profile of STELARA® in patients with PsA was consistent with the safety profile seen in adult psoriasis clinical studies. A higher incidence of arthralgia, nausea, and dental infections was observed in STELARA®-treated patients when compared with placebo-treated patients (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 studies.
The safety of STELARA® was assessed in 1407 patients 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 studies. These 1407 patients included 40 patients who received a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In Studies CD-1 and CD-2 there were 470 patients who received STELARA® 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo [see DOSAGE AND ADMINISTRATION]. Patients who were responders in either Study CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA® every 8 weeks, or placebo for 44 weeks in Study CD-3. Patients in these 3 studies 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].
The overall safety profile of STELARA® was consistent with the safety profile seen in the adult psoriasis and psoriatic arthritis clinical studies. Common adverse reactions in Studies CD-1 and CD-2 and in Study CD-3 are listed in Tables 5 and 6, respectively.
Table 5: Common adverse reactions through Week 8 in Studies CD-1 and CD-2 occurring in ≥3% of STELARA®-treated patients and higher than placebo
6 mg/kg single intravenous induction dose
Other less common adverse reactions reported in patients in Studies 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 Study CD-3 occurring in ≥3% of STELARA®-treated patients and higher than placebo
90 mg subcutaneous maintenance dose every 8 weeks
|Injection site erythema||0||5%|
|Vulvovaginal candidiasis/mycotic infection||1%||5%|
|Urinary tract infection||2%||4%|
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 were reported in one patient each.
With up to one year of treatment in the Crohn’s disease clinical studies, 0.2% of STELARA®-treated patients (0.36 events per hundred patient-years) and 0.2% of placebo-treated patients (0.58 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.2% of STELARA®-treated patients (0.27 events per hundred patient-years) and in none of the placebo-treated patients.
Hypersensitivity Reactions Including Anaphylaxis
In CD studies, two patients reported hypersensitivity reactions following STELARA® 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 STELARA®). 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 STELARA® dose (0.08% of patients receiving intravenous STELARA®). These patients were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour.
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab in the studies described below with the incidence of antibodies to other products may be misleading.
Approximately 6-12.4% of subjects treated with STELARA® in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. In Crohn’s disease clinical studies, less than 3% of patients treated with STELARA® developed antibodies to ustekinumab. In psoriasis clinical studies, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies.
The following adverse reactions have been reported during post-approval of STELARA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to STELARA® exposure.
In psoriasis studies the safety of STELARA® in combination with immunosuppressive agents or phototherapy has not been evaluated [see WARNINGS AND PRECAUTIONS]. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of STELARA®. In Crohn’s disease studies, immunomodulators (6-mercaptopurine, azathioprine, methotrexate) were used concomitantly in approximately 30% of patients and corticosteroids were used concomitantly in approximately 40% of patients. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of STELARA®.
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, STELARA®, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation of STELARA® in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) should be considered and the individual dose of the drug adjusted as needed [see CLINICAL PHARMACOLOGY].
STELARA® has not been evaluated in patients who have undergone allergy immunotherapy. STELARA® may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis.
Included as part of the "PRECAUTIONS" Section
STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA® [see ADVERSE REACTIONS].
Serious infections requiring hospitalization occurred in patients with psoriasis, psoriatic arthritis and Crohn’s disease in clinical studies. In patients with psoriasis, serious infections included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections. In patients with psoriatic arthritis, serious infections included cholecystitis. In patients with Crohn’s disease, serious or other clinically significant infections included anal abscess, gastroenteritis, ophthalmic herpes, pneumonia, and listeria meningitis.
Treatment with STELARA® should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of STELARA® in patients with a chronic infection or a history of recurrent infection.
Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with STELARA® and consider discontinuing STELARA® for serious or clinically significant infections until the infection resolves or is adequately treated.
Theoretical Risk For Vulnerability To Particular Infections
Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients.
It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® may be susceptible to these types of infections. Appropriate diagnostic testing should be considered, e.g., tissue culture, stool culture, as dictated by clinical circumstances.
Pre-Treatment Evaluation For Tuberculosis
Evaluate patients for tuberculosis infection prior to initiating treatment with STELARA®.
Do not administer STELARA® to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis prior to administering STELARA®. Consider anti-tuberculosis therapy prior to initiation of STELARA® in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving STELARA® for signs and symptoms of active tuberculosis during and after treatment.
STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received STELARA® in clinical studies [see ADVERSE REACTIONS]. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology].
The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy.
There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving STELARA® who had pre-existing risk factors for developing non-melanoma skin cancer. All patients receiving STELARA® should be monitored for the appearance of non-melanoma skin cancer. Patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment should be followed closely [see ADVERSE REACTIONS].
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with STELARA® [see ADVERSE REACTIONS]. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STELARA®.
Reversible Posterior Leukoencephalopathy Syndrome
One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed in clinical studies of psoriasis and psoriatic arthritis. The subject, who had received 12 doses of STELARA® over approximately two years, presented with headache, seizures and confusion. No additional STELARA® injections were administered and the subject fully recovered with appropriate treatment. No cases of RPLS were observed in clinical studies of Crohn’s disease.
RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy. Fatal outcomes have been reported.
If RPLS is suspected, administer appropriate treatment and discontinue STELARA®.
Prior to initiating therapy with STELARA®, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment with STELARA® or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STELARA® because of the potential risk for shedding from the household contact and transmission to patient.
Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease.
In clinical studies of psoriasis the safety of STELARA® in combination with other immunosuppressive agents or phototherapy was not evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL12 and IL-23 or IL-12 alone [see Nonclinical Toxicology].
Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval use of STELARA®. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue STELARA® and institute appropriate treatment [see Postmarketing Experience].
Patient Counseling Information
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before the patient starts using STELARA®, and each time the prescription is renewed, as there may be new information they need to know.
Inform patients that STELARA® 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].
Inform patients of the risk of developing malignancies while receiving STELARA® [see WARNINGS AND PRECAUTIONS].
- Advise patients to seek immediate medical attention if they experience any signs or symptoms of serious hypersensitivity reactions and discontinue STELARA® [see WARNINGS AND PRECAUTIONS].
- Inform patients the needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex [see DOSAGE AND ADMINISTRATION]
Inform patients that STELARA® can interfere with the usual response to immunizations and that they should avoid live vaccines [see WARNINGS AND PRECAUTIONS].
Inform patients that there is a pregnancy registry to monitor fetal outcomes of pregnant women exposed to STELARA® [see Use In Specific Populations].
Instruct patients to follow sharps disposal recommendations, as described in the Instructions for Use.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of STELARA®. Published literature showed that administration of murine IL-12 caused an anti-tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV-induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in mouse models for malignancy risk in humans is unknown.
No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated females.
No effects on fertility were observed in female mice that were administered an analogous IL12/ IL-23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy.
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to STELARA® during pregnancy. Patients should be encouraged to enroll by calling 1-877-3118972.
Limited data on the use of STELARA® in pregnant women are insufficient to inform a drug associated risk [see Data]. In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the human exposure at the maximum recommended human subcutaneous dose (MRHD).
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. 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.
Limited data on use of STELARA® in pregnant women from observational studies, published case reports, and postmarketing surveillance are insufficient to inform a drug associated risk.
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 human subcutaneous exposure 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.
There are no data on the presence of ustekinumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ustekinumab was present in the milk of lactating monkeys administered ustekinumab. Due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. Maternal IgG is known to be present in human milk. Published data suggest that the systemic exposure to a breastfed infant is expected to be low because ustekinumab is a large molecule and is degraded in the gastrointestinal tract. However, if ustekinumab is transferred into human milk the effects of local exposure in the gastrointestinal tract are unknown.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for STELARA® and any potential adverse effects on the breastfed child from STELARA® or from the underlying maternal condition.
The safety and effectiveness of STELARA® have been established in pediatric subjects 12 to 17 years old with moderate to severe plaque psoriasis. Use of STELARA® in this age group is supported by evidence from a multicenter, randomized, 60-week trial that included a 12-week, double-blind, placebo-controlled, parallel-group portion, in 110 pediatric subjects 12 years and older [see ADVERSE REACTIONS and Clinical Studies]. The safety and effectiveness of STELARA® for pediatric patients less than 12 years of age have not been established.
Of the 5884 subjects exposed to STELARA®, a total of 306 were 65 years or older (183 patients with psoriasis, 65 patients with psoriatic arthritis and 58 with Crohn’s disease), and 34 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.
Single doses up to 6 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately.
STELARA® is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or to any of the excipients [see WARNINGS AND PRECAUTIONS].
Mechanism Of Action
Ustekinumab is a human IgG1κ monoclonal antibody that binds with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab was shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn’s disease. In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab, was shown to be protective.
In a small exploratory study, 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 psoriasis.
In adult subjects with 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 psoriasis.
Following multiple subcutaneous doses of STELARA® in adult subjects with 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.
In patients with Crohn’s disease, following the recommended intravenous induction dose, mean ±SD peak serum ustekinumab concentration was 125.2 ± 33.6 mcg/mL. 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 2.51 ± 2.06 mcg/mL for 90 mg ustekinumab administered every 8 weeks.
In a population pharmacokinetic analysis of ustekinumab, the volume of distribution of the central compartment was 2.74 L (95% CI: 2.69, 2.78), and the total volume of distribution at steady-state was 4.62 L in patients with Crohn’s disease.
The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all psoriasis studies following subcutaneous administration. In a population pharmacokinetic analysis of ustekinumab, the clearance was 0.19 L/day (95% CI: 0.185, 0.197) with an estimated median terminal half-life of approximately 19 days in patients with Crohn’s disease.
The metabolic pathway of ustekinumab has not been characterized. As a human IgG1κ monoclonal antibody, ustekinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
When given the same dose, subjects with 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.
A population pharmacokinetic analysis (N=106/1937 patients with 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.
Following multiple recommended doses of STELARA® in adolescent subjects 12 to 17 years of age with psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. At Week 28, the mean ±SD steady-state trough serum ustekinumab concentration was 0.54 ± 0.43 mcg/mL.
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].
No in vivo drug interaction studies have been conducted with STELARA®.
Population pharmacokinetic data 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.
Animal Toxicology And/Or Pharmacology
In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection.
Two multicenter, randomized, double-blind, placebo-controlled studies (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 studies.
Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The studies had the same design through Week 28. In both studies, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of STELARA®. Subjects randomized to STELARA® received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks 0 and 4 crossed over to receive STELARA® (either 45 mg or 90 mg) at Weeks 12 and 16.
In both studies, 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.
In both studies, 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.
The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 7 below.
Table 7: Clinical Outcomes Ps STUDY 1 and Ps STUDY 2
|Week 12||Ps STUDY 1||Ps STUDY 2|
|Placebo||45 mg||90 mg||Placebo||45 mg||90 mg|
|PASI 75 response||8 (3%)||171 (67%)||170 (66%)||15 (4%)||273 (67%)||311 (76%)|
|PGA of Cleared or Minimal||10 (4%)||151 (59%)||156 (61%)||18 (4%)||277 (68%)||300 (73%)|
Examination of age, gender, and race subgroups did not identify differences in response to STELARA® among these subgroups.
In subjects who weighed 100 kg or less, response rates were similar 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
|Ps STUDY 1||Ps STUDY 2|
|Placebo||45 mg||90 mg||Placebo||45 mg||90 mg|
|PASI 75 response at Week 12*|
|≤100 kg||4% 6/166||74%124/ 168||65% 107/164||4% 12/290||73% 218/297||78% 225/289|
|>100 kg||2% 2/89||54% 47/87||68% 63/92||3% 3/120||49% 55/112||71% 86/121|
|PGA of Cleared or Minimal at Week 12*|
|≤100 kg||4% 7/166||64% 108/168||63% 103/164||5% 14/290||74% 220/297||75% 216/289|
|>100 kg||3% 3/89||49% 43/87||58% 53/92||3% 4/120||51% 57/112||69% 84/121|
|* Patients were dosed with study medication at Weeks 0 and 4.|
Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at Week 40 to either continued dosing of STELARA® (STELARA® at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomized to STELARA® treatment were PASI 75 responders compared with 63% (100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks.
Adolescent Subjects With Plaque Psoriasis
A multicenter, randomized, double blind, placebo controlled study (Ps STUDY 3) enrolled 110 adolescent 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 STELARA® (n = 36), or one-half the recommended dose of STELARA® (n = 37) by subcutaneous injection at Weeks 0 and 4 followed by dosing every 12 weeks (q12w). The recommended dose of STELARA® was 0.75 mg/kg for subjects weighing less than 60 kg, 45 mg for subjects weighing 60 kg to 100 kg, and 90 mg for subjects weighing greater than 100 kg. At Week 12, subjects who received placebo were crossed over to receive STELARA® at the recommended dose or one-half the recommended dose.
Of the adolescent 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 patients 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 study agent.
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
|Ps STUDY 3|
|PGA of cleared (0) or minimal (1)||2 (5.4%)||25 (69.4%)|
|PASI 75 responders||4 (10.8%)||29 (80.6%)|
|PASI 90 responders||2 (5.4%)||22 (61.1%)|
|* Using the weight-based dosage regimen specified in Table 1 and Table 2.|
The safety and efficacy of STELARA® was assessed in 927 patients (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled studies in adult patients 18 years of age and older with active PsA (≥5 swollen joints and ≥5 tender joints) despite non-steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Patients in these studies 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 STELARA® 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.
In both studies, a greater proportion of patients achieved ACR 20, ACR 50 and PASI 75 response in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 10). ACR 70 responses were also higher in the STELARA® 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in STUDY 2. Responses were 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
|PsA STUDY 1||PsA STUDY 2|
|Placebo||45 mg||90 mg||Placebo||45 mg||90 mg|
|Number of patients randomized||206||205||204||104||103||105|
|ACR 20 response, N (%)||47 (23%)||87 (42%)||101 (50%)||21 (20%)||45 (44%)||46 (44%)|
|ACR 50 response, N (%)||18 (9%)||51 (25%)||57 (28%)||7 (7%)||18 (17%)||24 (23%)|
|ACR 70 response, N (%)||5 (2%)||25 (12%)||29 (14%)||3 (3%)||7 (7%)||9 (9%)|
|Number of patients with ≥ 3% BSAa||146||145||149||80||80||81|
|PASI 75 response, N (%)||16 (11%)||83 (57%)||93 (62%)||4 (5%)||41 (51%)||45 (56%)|
|a Number of patients with ≥ 3% BSA psoriasis skin involvement at baseline|
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
|PsA STUDY 1|
|Number of swollen jointsa|
|Mean Change at Week 24||-3||-5||-6|
|Number of tender jointsb|
|Mean Change at Week 24||-4||-8||-9|
|Patient’s assessment of painc|
|Mean Change at Week 24||-0.5||-2.0||-2.6|
|Patient global assessmentc|
|Mean Change at Week 24||-0.5||-2.0||-2.5|
|Physician global assessmentc|
|Mean Change at Week 24||-1.4||-2.6||-3.1|
|Disability index (HAQ)d|
|Mean Change at Week 24||-0.1||-0.3||-0.4|
|Mean Change at Week 24||0.01||-0.5||-0.8|
a Number of swollen joints counted (0-66)
b Number of tender joints counted (0-68)
c Visual analogue scale; 0= best, 10=worst.
d 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.
e CRP: (Normal Range 0.0-1.0 mg/dL)
An improvement in enthesitis and dactylitis scores was observed in each STELARA® group compared with placebo at Week 24.
STELARA® treated patients showed improvement in physical function compared to patients treated with placebo as assessed by HAQ-DI at Week 24. In both studies, the proportion of HAQ-DI responders (≥0.3 improvement in HAQ-DI score) was greater in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24.
STELARA® was evaluated in three randomized, double-blind, placebo-controlled clinical studies 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 studies (CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal maintenance study (CD-3) representing 52 weeks of therapy.
Studies CD-1 And CD-2
In studies 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 studies, patients were randomized to receive a single intravenous administration of STELARA® at either approximately 6 mg/kg, placebo (see Table 3), or 130 mg (a lower dose than recommended).
In Study 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 study, approximately 46% of the patients were receiving corticosteroids and 31% of the patients were receiving immunomodulators (azathioprine, 6-mercaptopurine, methotrexate). The median baseline CDAI score was 319 in the STELARA® approximately 6 mg/kg group and 313 in the placebo group.
In Study CD-2, patients had failed or were intolerant to prior treatment with corticosteroids (81% of patients), at least one immunomodulator (6-mercaptopurine, azathioprine, methotrexate; 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 study, approximately 39% of the patients were receiving corticosteroids and 35% of the patients were receiving immunomodulators (azathioprine, 6-mercaptopurine, methotrexate). The median baseline CDAI score was 286 in the STELARA® and 290 in the placebo group.
In these induction studies, a greater proportion of patients treated with STELARA® 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 STELARA®-treated patients and continued to improve through Week 8.
Table 12: Induction of Clinical Response and Remission in CD-1* and CD-2**
|Treatment difference and 95% CI||Placebo
|Treatment difference and 95% CI|
|Clinical Response (100 point), Week 6||53 (21%)||84 (34%)a||12% (4%, 20%)||60 (29%)||116 (56%)b||27% (18%, 36%)|
|Clinical Remission, Week 8||18 (7%)||a52 (21%)b||14% (8%, 20%)||41 (20%)||84 (40%)b||21% (12%, 29%)|
|Clinical Response (100 point), Week 8||50 (20%)||94 (38%)b||18% (10%, 25%)||67 (32%)||121 (58%)b||26% (17%, 35%)|
|70 Point Response, Week 6||75 (30%)||109 (44%)a||13% (5%, 22%)||81 (39%)||135 (65%)b||26% (17%, 35%)|
|70 Point Response, Week 3||67 (27%)||101 (41%)a||13% (5%, 22%)||66 (32%)||106 (51%)b||19% (10%, 28%)|
Clinical remission is defined as CDAI score < 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
* Patient population consisted of patients who failed or were intolerant to TNF blocker therapy
** Patient population consisted of patients who failed or were intolerant to corticosteroids or immunomodulators (e.g., 6-mercaptopurine, azathioprine, methotrexate) and previously received but not failed a TNF blocker or were never treated with a TNF blocker.
† Infusion dose of STELARA® using the weight-based dosage regimen specified in Table 3.
a 0.001≤ p < 0.01
b p < 0.001
The maintenance study (CD-3), evaluated 388 patients who achieved clinical response (≥100 point reduction in CDAI score) at Week 8 of induction with STELARA® in studies CD-1 or CD-2. Patients were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA® 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)
|90 mg STELARA® every 8 weeks
|Treatment difference and 95% CI|
|Clinical Remission||47 (36%)||68 (53%)a||17% (5%, 29%)|
|Clinical Response||58 (44%)||76 (59%)b||15% (3%, 27%)|
|Clinical Remission in patients in remission at the start of maintenance therapy**||36/79 (46%)||52/78 (67%)a||21% (6%, 36%)|
Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of at least 100 points or being in clinical remission
* The placebo group consisted of patients who were in response to STELARA® and were randomized to receive placebo at the start of maintenance therapy.
** 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.
† Patients who achieved clinical response to STELARA® at the end of the induction study.
a p < 0.01
b 0.01≤ p < 0.05
At Week 44, 47% of patients who received STELARA® were corticosteroid-free and in clinical remission, compared to 30% of patients in the placebo group.
At Week 0 of Study CD-3, 34/56 (61%) STELARA® 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 Study CD-3, 46/72 (64%) STELARA® 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 STELARA® 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 STELARA® induction were not included in the primary efficacy analyses for Study CD-3; however, these patients were eligible to receive a 90 mg subcutaneous injection of STELARA® upon entry into Study CD-3. Of these patients, 102/219 (47%) achieved clinical response eight weeks later and were followed for the duration of the study.
(stel ar’ a)
(ustekinumab) injection, for subcutaneous or intravenous use
What is the most important information I should know about STELARA?
STELARA is a medicine that affects your immune system. STELARA can increase your risk of having serious side effects, including:
Serious infections. STELARA 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 STELARA, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their infection.
- Your doctor should check you for TB before starting STELARA.
- If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with STELARA and during treatment with STELARA.
- Your doctor should watch you closely for signs and symptoms of TB while you are being treated with STELARA.
You should not start taking STELARA if you have any kind of infection unless your doctor says it is okay.
Before starting STELARA, tell your doctor if you:
- think you have an infection or have symptoms of an infection such as:
- fever, sweat, or chills
- warm, red, or painful skin or sores on your body
- muscle aches
- diarrhea or stomach pain
- shortness of breath
- blood in phlegm
- weight loss
- burning when you urinate or urinate more often than normal
- feel very tired
- are being treated for an infection.
- get a lot of infections or have infections that keep coming back.
- have TB, or have been in close contact with someone with TB.
After starting STELARA, call your doctor right away if you have any symptoms of an infection (see above). STELARA can make you more likely to get infections or make an infection that you have worse. People who have a genetic problem where the body does not make any of the proteins interleukin 12 (IL12) 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 STELARA may also be more likely to get these infections.
Cancers. STELARA 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 STELARA and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with STELARA, tell your doctor if you develop any new skin growths.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS). RPLS is a rare condition that affects the brain and can cause death. The cause of RPLS is not known. If RPLS is found early and treated, most people recover. Tell your doctor right away if you have any new or worsening medical problems including:
- vision problems
What is STELARA?
STELARA is a prescription medicine used to treat:
- adults and children 12 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).
- adults 18 years and older with active psoriatic arthritis. STELARA can be used alone or with the medicine methotrexate.
- adults 18 years and older with moderately to severely active Crohn’s disease who have already taken other medicines that did not work well enough or they could not tolerate it.
It is not known if STELARA is safe and effective in children less than 12 years of age.
Do not take STELARA if you are allergic to ustekinumab or any of the ingredients in STELARA. See the end of this Medication Guide for a complete list of ingredients in STELARA.
Before you receive STELARA, tell your doctor about all of your medical conditions, including if you:
- have any of the conditions or symptoms listed in the section “What is the most important information I should know about STELARA?”
- ever had an allergic reaction to STELARA. Ask your doctor if you are not sure.
- are allergic to latex. The needle cover on the prefilled syringe contains latex.
- have recently received or are scheduled to receive an immunization (vaccine). People who take STELARA 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 STELARA or one year after you stop receiving STELARA.
- have any new or changing lesions within psoriasis areas or on normal skin.
- are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as well for you during treatment with STELARA. STELARA may also increase your risk of having an allergic reaction to an allergy shot.
- receive or have received phototherapy for your psoriasis.
- are pregnant or planning to become pregnant. It is not known if STELARA can harm your unborn baby. You and your doctor should decide if you will receive STELARA. There is a pregnancy registry for women who are treated with STELARA during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. If you are pregnant or become pregnant while receiving STELARA, talk to your doctor about how you can join this pregnancy registry or you may contact the registry at 1-877-311-8972 to enroll.
- are breastfeeding or plan to breastfeed. It is thought that STELARA passes into your breast milk in small amounts.
- Talk to your doctor about the best way to feed your baby if you receive STELARA.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I use STELARA?
- Use STELARA exactly as your doctor tells you to.
- The needle cover on the STELARA prefilled syringe contains latex. Do not handle the needle cover if you are sensitive to latex.
- Adults with Crohn’s disease will receive the first dose of STELARA 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 STELARA as an injection under the skin (subcutaneous injection) 8 weeks after the first dose of STELARA, as described below.
- Adults with psoriasis or psoriatic arthritis and children 12 years and older with psoriasis will receive STELARA as an injection under the skin (subcutaneous injection) as described below.
- Injecting STELARA under your skin
- STELARA is intended for use under the guidance and supervision of your doctor. In children 12 years and older, it is recommended that STELARA be administered by a healthcare provider. If your doctor decides that you or a caregiver may give your injections of STELARA at home, you should receive training on the right way to prepare and inject STELARA. Your doctor will determine the right dose of STELARA for you, the amount for each injection, and how often you should receive it. Do not try to inject STELARA yourself until you or your caregiver have been shown how to inject STELARA by your doctor or nurse.
- Inject STELARA under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs (thighs) or stomach area (abdomen).
- Do not give an injection in an area of the skin that is tender, bruised, red or hard.
- Use a different injection site each time you use STELARA.
- If you inject more STELARA than prescribed, call your doctor right away.
- Be sure to keep all of your scheduled follow-up appointments.
Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to prepare and inject a dose of STELARA, and how to properly throw away (dispose of) used needles and syringes. The syringe, needle and vial must never be re-used. After the cap is punctured, STELARA can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused portion of STELARA.
What should I avoid while using STELARA?
You should not receive a live vaccine while taking STELARA. See “Before you receive STELARA, tell your doctor about all of your medical conditions, including if you:”
What are the possible side effects of STELARA?
STELARA may cause serious side effects, including:
- See “What is the most important information I should know about STELARA?”
- Serious allergic reactions. Serious allergic reactions can occur with STELARA. Stop using STELARA and get medical help right away if you have any of the following symptoms of a serious allergic reaction:
- feeling faint
- swelling of your face, eyelids, tongue, or throat
- chest tightness
- skin rash
- Lung inflammation. Cases of lung inflammation hasve happened in some people who receive STELARA, 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 STELARA.
Common side effects of STELARA include:
- upper respiratory infections
- vaginal yeast infections
- urinary tract infections
- redness at the injection site
These are not all of the possible side effects of STELARA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to Janssen Biotech, Inc. at 1-800 JANSSEN (1-800-526-7736).
How should I store STELARA?
- Store STELARA prefilled syringes in a refrigerator between 36°F to 46°F (2°C to 8°C).
- Store STELARA vials standing up straight.
- Store STELARA in the original carton to protect it from light until time to use it.
- Do not freeze STELARA.
- Do not shake STELARA.
Keep STELARA and all medicines out of the reach of children.
General information about the safe and effective use of STELARA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use STELARA for a condition for which it was not prescribed. Do not give STELARA 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 STELARA that was written for health professionals.
What are the ingredients in STELARA?
Active ingredient: ustekinumab
Inactive ingredients: Single-dose prefilled syringe for subcutaneous use contains L-histidine, L- histidine monohydrochloride monohydrate, Polysorbate 80, and sucrose. Single-dose vial for subcutaneous use contains L-histidine, L-histidine hydrochloride monohydrate, Polysorbate 80 and sucrose. Single-dose vial for intravenous infusion contains EDTA disodium salt dihydrate, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, Polysorbate 80, and sucrose.
This Medication Guide has been approved by the U.S. Food and Drug Administration
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.