Source: FDA, National Drug Code (US) Revision Year: 2024
SELARSDI is contraindicated in patients with clinically significant hypersensitivity to ustekinumab products or to any of the excipients in SELARSDI [see Warnings and Precautions (5.5)].
Ustekinumab products may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab products [see Adverse Reactions (6.1, 6.3)].
Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical trials included the following:
Avoid initiating treatment with SELARSDI in patients with any clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of SELARSDI in patients with a chronic infection or a history of recurrent infection.
Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with SELARSDI and discontinue SELARSDI for serious or clinically significant infections until the infection resolves or is adequately treated.
Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including non typhi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients.
It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with ustekinumab products may be susceptible to these types of infections. Consider appropriate diagnostic testing, (e.g., tissue culture, stool culture, as dictated by clinical circumstances).
Evaluate patients for tuberculosis infection prior to initiating treatment with SELARSDI.
Avoid administering SELARSDI to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis prior to administering SELARSDI. Consider anti-tuberculosis therapy prior to initiation of SELARSDI in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving SELARSDI for signs and symptoms of active tuberculosis during and after treatment.
Ustekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies were reported among subjects who received ustekinumab in clinical trials [see Adverse Reactions (6.1)]. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology (13)].
The safety of ustekinumab products has not been evaluated in patients who have a history of malignancy or who have a known malignancy.
There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving ustekinumab products who had pre-existing risk factors for developing nonmelanoma skin cancer. Monitor all patients receiving SELARSDI should be monitored for the appearance of non-melanoma skin cancer. Closely follow patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment [see Adverse Reactions (6.1)].
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with ustekinumab products [see Adverse Reactions (6.1, 6.3)]. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue SELARSDI.
Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis and psoriatic arthritis. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab product initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab products.
Monitor all patients treated with SELARSDI for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue SELARSDI.
Prior to initiating therapy with SELARSDI, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with SELARSDI should avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with SELARSDI or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving SELARSDI because of the potential risk for shedding from the household contact and transmission to patient.
Non-live vaccinations received during a course of SELARSDI may not elicit an immune response sufficient to prevent disease.
Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue SELARSDI and institute appropriate treatment [see Postmarketing Experience (6.3)].
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 ustekinumab in 3117 adult subjects with plaque psoriasis, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years.
Table 3 summarizes the adverse reactions that occurred at a rate of at least 1% with higher rates in the ustekinumab groups during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies (14)].
Table 3. Adverse Reactions Reported by ≥1% of Subjects with Plaque Psoriasis and at Higher Rates in the ustekinumab groups through Week 12 in Ps STUDY 1 and Ps STUDY 2:
| Placebo | Ustekinumab 45 mg | 90 mg | |
|---|---|---|---|
| Subjects treated | 665 | 664 | 666 |
| Nasopharyngitis | 51 (8%) | 56 (8%) | 49 (7%) |
| Upper respiratory tract infection | 30 (5%) | 36 (5%) | 28 (4%) |
| Headache | 23 (3%) | 33 (5%) | 32 (5%) |
| Fatigue | 14 (2%) | 18 (3%) | 17 (3%) |
| Back pain | 8 (1%) | 9 (1%) | 14 (2%) |
| Dizziness | 8 (1%) | 8 (1%) | 14 (2%) |
| Pharyngolaryngeal pain | 7 (1%) | 9 (1%) | 12 (2%) |
| Pruritus | 9 (1%) | 10 (2%) | 9 (1%) |
| Injection site erythema | 3 (<1%) | 6 (1%) | 13 (2%) |
| Myalgia | 4 (1%) | 7 (1%) | 8 (1%) |
| Depression | 3 (<1%) | 8 (1%) | 4 (1%) |
Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis, and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation).
One case of PRES occurred during adult plaque psoriasis clinical trials [see Warnings and Precautions (5.6)].
In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow-up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for ustekinumab-treated subjects), 27% of ustekinumabtreated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in 0.3% of ustekinumab-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) [see Warnings and Precautions (5.1)].
In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of ustekinumab-treated subjects reported infections (0.87 per subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up).
In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years, representing 8998 subject-years of exposure), 1.7% of ustekinumab-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of ustekinumab-treated subjects (0.52 per hundred subject-years of follow-up) [see Warnings and Precautions (5.4)]. The most frequently observed malignancies other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast. Malignancies other than nonmelanoma skin cancer in ustekinumab-treated patients during the controlled and uncontrolled portions of trials were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).1
The safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects 12 to 17 years old. Ps STUDY 4 evaluated safety for up to 56 weeks in 44 pediatric subjects 6 to 11 years old. The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque psoriasis.
The safety of ustekinumab was assessed in 927 subjects in two randomized, double-blind, placebo-controlled trials in adults with active psoriatic arthritis (PsA). The overall safety profile of ustekinumab in subjects with PsA was consistent with the safety profile seen in adult psoriasis clinical trials. A higher incidence of arthralgia, nausea, and dental infections was observed in ustekinumab-treated subjects when compared with placebotreated subjects (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical trials.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ustekinumab or of other ustekinumab products.
Approximately 6 to 12.4% of subjects treated with ustekinumab in plaque psoriasis and psoriatic arthritis clinical trials developed antibodies to ustekinumab, which were generally low-titer. In plaque psoriasis clinical trials, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In plaque psoriasis trials, the majority of subjects who were positive for antibodies to ustekinumab had neutralizing antibodies.
The following adverse reactions have been reported during post-approval of ustekinumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ustekinumab products exposure.
Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria).
Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections and tuberculosis).
Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES).
Respiratory, thoracic, and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia.
Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis.
In plaque psoriasis trials the safety of ustekinumab products in combination with immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis trials, concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of ustekinumab.
The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL10, TNFα, IFN) during chronic inflammation. Thus, ustekinumab products, antagonists of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation of SELARSDI in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and adjust the individual dose of the drug as needed [see Clinical Pharmacology (12.3)].
Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab products may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis.
Limited data from observational studies, published case reports, and postmarketing surveillance on the use of ustekinumab products during pregnancy are insufficient to inform a drug associated risk of major birth defects, miscarriage, and other adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore, SELARSDI may be transferred to the developing fetus (see Clinical Considerations). In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the maximum recommended human dose (MRHD).
The background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Because ustekinumab products may theoretically interfere with immune response to infections, consider risks and benefits prior to administering live vaccines to infants exposed to SELARSDI in utero. There are insufficient data regarding exposed infant serum levels of ustekinumab products at birth and the duration of persistence of ustekinumab products in infant serum after birth. Although a specific timeframe to delay administration of live attenuated vaccines in infants exposed in utero is unknown, consider the risks and benefits of delaying a minimum of 6 months after birth because of the clearance of the product.
Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No teratogenic or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab subcutaneously twice weekly or intravenously weekly during the period of organogenesis. Serum concentrations of ustekinumab in pregnant monkeys were greater than 100 times the serum concentration in patients treated subcutaneously with 90 mg of ustekinumab weekly for 4 weeks.
In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures greater than 100 times the MRHD from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related-effects on functional, morphological, or immunological development were observed in the neonates from birth through six months of age.
Limited data from published literature suggests that ustekinumab products are present in human breast milk. There are no available data on the effects of ustekinumab products on milk production. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ustekinumab products are unknown. No adverse effects on the breastfed infant causally related to ustekinumab products have been identified in the published literature or postmarketing experience.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SELARSDI and any potential adverse effects on the breastfed child from SELARSDI or from the underlying maternal condition.
The safety and effectiveness of SELARSDI have been established for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 to 17 years of age who are candidates for phototherapy or systemic therapy.
Use of SELARSDI in pediatric patients 12 to less than 17 years of age is supported by evidence from a multicenter, randomized, 60week trial (Ps STUDY 3) of ustekinumab that included a 12week, double-blind, placebo-controlled, parallel group portion, in 110 pediatric subjects 12 years of age and older [see Adverse Reactions (6.1), Clinical Studies (14.2)].
Use of SELARSDI in pediatric patients 6 to 11 years of age is supported by evidence from an open-label, single-arm, efficacy, safety, and pharmacokinetics trial (Ps STUDY 4) of ustekinumab in 44 subjects [see Adverse Reactions (6.1), Pharmacokinetics (12.3)].
The safety and effectiveness of SELARSDI have not been established in pediatric patients less than 6 years of age with plaque psoriasis.
The safety and effectiveness of SELARSDI have been established for treatment of psoriatic arthritis in pediatric patients 6 to 17 years old.
Use of SELARSDI in these age groups is supported by evidence from adequate and well controlled trials of ustekinumab in adults with psoriasis and PsA, pharmacokinetic data from adult patients with psoriasis, adult patients with PsA and pediatric patients with psoriasis, and safety data of ustekinumab from two clinical trials in 44 pediatric patients 6 to 11 years old with psoriasis and 110 pediatric patients 12 to 17 years old with psoriasis. The observed pre-dose (trough) concentrations are generally comparable between adult patients with psoriasis, adult patients with PsA and pediatric patients with psoriasis, and the PK exposure is expected to be comparable between adult and pediatric patients with PsA [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2, 14.3)].
The safety and effectiveness of SELARSDI have not been established in pediatric patients less than 6 years old with psoriatic arthritis.
Of the 6709 patients exposed to ustekinumab, a total of 340 were 65 years of age or older (183 patients with plaque psoriasis, 65 patients with psoriatic arthritis, 58 patients with one indication, and 34 patients with another indication), and 40 patients were 75 years of age or older. Clinical trials of ustekinumab did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.
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