Source: FDA, National Drug Code (US) Revision Year: 2022
STELARA is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or to any of the excipients [see Warnings and Precautions (5.5)].
STELARA may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving STELARA [see Adverse Reactions (6.1, 6.3)].
Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical studies included the following:
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.
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.
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 (6.1)]. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology (13)].
The safety of STELARA has not been evaluated in patients who have a history of malignancy or who have a known malignancy.
There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving STELARA who had pre-existing risk factors for developing non-melanoma skin cancer. 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 (6.1)].
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with STELARA [see Adverse Reactions (6.1, 6.3)]. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STELARA.
Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis, psoriatic arthritis and Crohn’s disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab.
Monitor all patients treated with STELARA for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue STELARA.
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 biologic 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 IL-12 and IL-23 or IL-12 alone [see Concomitant Therapies (7.1), Nonclinical Toxicology (13.1)].
Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval use of STELARA. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue STELARA and institute appropriate treatment [see Postmarketing Experience (6.3)].
The following serious adverse reactions are discussed elsewhere in the label:
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.
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 5 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 (14)].
Table 5. Adverse Reactions Reported by ≥1% of Subjects through Week 12 in Ps STUDY 1 and Ps STUDY 2:
| STELARA | |||
|---|---|---|---|
| Placebo | 45 mg | 90 mg | |
| Subjects treated | 665 | 664 | 666 |
| Nasopharyngitis | 51 (8%) | 56 (8%) | 49 (7%) |
| Upper respiratory tract infection | 30 (5%) | 36 (5%) | 28 (4%) |
| Headache | 23 (3%) | 33 (5%) | 32 (5%) |
| Fatigue | 14 (2%) | 18 (3%) | 17 (3%) |
| 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 PRES occurred during adult plaque psoriasis clinical studies [see Warnings and Precautions (5.6)].
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 (5.1)].
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 (5.4)]. 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
The safety of STELARA was assessed in two studies of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 adolescents (12 to 17 years old). Ps STUDY 4 evaluated safety for up to 56 weeks in 44 children (6 to 11 years old). The safety profile in pediatric subjects was similar to the safety profile from studies in adults with plaque psoriasis.
The safety of STELARA was assessed in 927 subjects in two randomized, double-blind, placebo-controlled studies in adults with active psoriatic arthritis (PsA). The overall safety profile of STELARA in subjects with PsA was consistent with the safety profile seen in adult psoriasis clinical studies. A higher incidence of arthralgia, nausea, and dental infections was observed in STELARA-treated subjects when compared with placebo-treated subjects (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical studies.
The safety of STELARA was assessed in 1407 subjects with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] greater than or equal to 220 and less than or equal to 450) in three randomized, double-blind, placebo-controlled, parallel-group, multicenter studies. These 1407 subjects included 40 subjects 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 subjects who received STELARA 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo [see Dosage and Administration (2.3)]. Subjects who were responders in either 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. Subjects 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 (14.4)].
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 6 and 7, respectively.
Table 6. Common adverse reactions through Week 8 in Studies CD-1 and CD-2 occurring in ≥3% of STELARA-treated subjects and higher than placebo:
| Placebo | STELARA 6 mg/kg single intravenous induction dose | |
|---|---|---|
| N=466 | N=470 | |
| Vomiting | 3% | 4% |
Other less common adverse reactions reported in subjects in Studies CD-1 and CD-2 included asthenia (1% vs 0.4%), acne (1% vs 0.4%), and pruritus (2% vs 0.4%).
Table 7. Common adverse reactions through Week 44 in Study CD-3 occurring in ≥3% of STELARA-treated subjects and higher than placebo:
| Placebo | STELARA 90 mg subcutaneous maintenance dose every 8 weeks | |
|---|---|---|
| N=133 | N=131 | |
| Nasopharyngitis | 8% | 11% |
| Injection site erythema | 0 | 5% |
| Vulvovaginal candidiasis/mycotic infection | 1% | 5% |
| Bronchitis | 3% | 5% |
| Pruritus | 2% | 4% |
| Urinary tract infection | 2% | 4% |
| Sinusitis | 2% | 3% |
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)].
With up to one year of treatment in the Crohn’s disease clinical studies, 0.2% of STELARA-treated subjects (0.36 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.2% of STELARA-treated subjects (0.27 events per hundred patient-years) and in none of the placebo-treated subjects.
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.
The safety of STELARA was evaluated in two randomized, double-blind, placebo-controlled clinical studies (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to severely active ulcerative colitis [see Clinical Studies (14.5)]. The overall safety profile of STELARA in patients with ulcerative colitis was consistent with the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of STELARA-treated subjects and at a higher rate than placebo were:
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)].
With up to one year of treatment in the ulcerative colitis clinical studies, 0.4% of STELARA-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 STELARA-treated subjects (0.64 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.40 events per hundred patient-years).
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 to 12.4% of subjects treated with STELARA in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. In psoriasis clinical studies, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In psoriasis studies, the majority of subjects who were positive for antibodies to ustekinumab had neutralizing antibodies.
In Crohn’s disease and ulcerative colitis clinical studies, 2.9% and 4.6% of subjects, respectively, developed antibodies to ustekinumab when treated with STELARA for approximately one year. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen.
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.
Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria) [see Warnings and Precautions (5.5)].
Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections and tuberculosis) [see Warnings and Precautions (5.1)].
Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)].
Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia [see Warnings and Precautions (5.9)].
Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis.
In psoriasis studies the safety of STELARA in combination with immunosuppressive agents or phototherapy has not been evaluated [see Warnings and Precautions (5.8)]. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of STELARA. In Crohn’s disease and ulcerative colitis induction studies, immunomodulators (6-MP, AZA, MTX) were used concomitantly in approximately 30% of subjects and corticosteroids were used concomitantly in approximately 40% and 50% of Crohn’s disease and ulcerative colitis subjects, respectively. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of STELARA.
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 (12.3)].
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.
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).
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.
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 for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 to 17 years old. Use of STELARA in patients 12 to less than 17 years old is supported by evidence from a multicenter, randomized, 60-week trial (Ps STUDY 3) that included a 12-week, double-blind, placebo-controlled, parallel-group portion, in 110 pediatric subjects 12 years and older [see Adverse Reactions (6.1), Clinical Studies (14.2)].
Use of STELARA in patients 6 to 11 years old is supported by evidence from an open-label, single-arm, efficacy, safety and pharmacokinetics study (Ps STUDY 4) in 44 subjects [see Adverse Reactions (6.1), Pharmacokinetics (12.3)].
The safety and effectiveness of STELARA have not been established in pediatric patients less than 6 years of age with psoriasis.
The safety and effectiveness of STELARA have been established for treatment of psoriatic arthritis in pediatric patients 6 to 17 years old.
Use of STELARA in these age groups is supported by evidence from adequate and well controlled studies of STELARA 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 from two clinical studies 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), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2, 14.3)].
The safety and effectiveness of STELARA have not been established in pediatric patients less than 6 years old with psoriatic arthritis.
The safety and effectiveness of STELARA have not been established in pediatric patients with Crohn’s disease or ulcerative colitis.
Of the 6709 patients exposed to STELARA , a total of 340 were 65 years or older (183 patients with psoriasis, 65 patients with psoriatic arthritis, 58 patients with Crohn’s disease and 34 patients with ulcerative colitis), and 40 patients were 75 years or older. Although no overall differences in safety or efficacy were observed between older and younger patients, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.
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