Pharmacological properties of the drug Stelara
Pharmacodynamics. Mechanism of action. Ustekinumab is a fully human IgG1k monoclonal antibody with high affinity and specificity for the p40 subunit of human interleukins (IL)-12 and IL-23. The drug blocks the biological activity of IL-12 and IL-23, preventing their binding to the IL-12Rβ1 protein receptor, which is expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 and IL-23, which are already bound to the receptor. Therefore, the drug cannot influence the formation of complement- or antibody-dependent cytotoxicity of cells bearing these receptors. IL-12 and IL-23 are heterodimeric cytokines that are secreted by activated antigen-presenting cells, particularly macrophages and dendritic cells. IL-12 and IL-23 take part in immune reactions, promote the activation of NK cells and the differentiation and activation of CD4+ T cells. However, in diseases associated with dysfunction of the immune system, dysregulation of the secretion of IL-12 and IL-23 is observed. Ustekinumab eliminates the effect of IL-12 and IL-23 on immune cell activation, in particular intracellular signal transduction and cytokine secretion caused by these ILs. Thus, it is assumed that ustekinumab interrupts the cascade of signal transduction reactions and cytokine secretion, which are critical in the development of psoriasis. Pharmacokinetics . Suction . The average time to reach Cmax in serum after a single subcutaneous administration of 90 mg ustekinumab to healthy volunteers was 8.5 days. In patients with psoriasis, this value at drug doses of 45 and 90 mg was the same as in healthy volunteers. Absolute bioavailability after a single subcutaneous administration to patients with psoriasis is 57.2%. Distribution . The median volume of distribution of ustekinumab in the terminal phase of elimination after a single intravenous administration to patients with psoriasis ranged from 57 to 83 ml/kg. Metabolism . The metabolic pathways of ustekinumab are not precisely known. Removal . The median systemic clearance of ustekinumab after a single intravenous administration to patients with psoriasis ranged from 1.99 to 2.34 ml/day/kg. The mean half-life of ustekinumab in patients with psoriasis is approximately 3 weeks and ranged from 15 to 32 days in different studies. In a population pharmacokinetic analysis, apparent clearance (CL/F) and volume of distribution (V/F) were 0.465/day and 15.71, respectively, in patients with psoriasis. Gender did not influence the apparent clearance of ustekinumab. Population pharmacokinetic analysis showed a trend towards increased ustekinumab clearance in patients in whom antibodies to ustekinumab were detected. Dose linearity . The level of systemic action (Cmax and AUC) of ustekinumab increased in a dose-dependent manner after a single intravenous administration to patients with psoriasis in a dose range of 0.09–4.5 mg/kg or after a single subcutaneous administration in a dose range of 24–240 mg. Single and multiple administration . Following single and multiple subcutaneous administration of ustekinumab, serum AUC is generally predictable. After subcutaneous administration of Stelara at the 0th week and 4th week of treatment and then every 12 weeks, the equilibrium concentration in the blood serum is achieved before the 28th week and is 0.21–0.26 mcg/ml (45 mg) or 0.47–0.49 μg/ml (90 mg). With subcutaneous administration every 12 weeks, no accumulation of ustekinumab in the blood serum was detected. Effect of body weight on pharmacokinetics . Population pharmacokinetic analysis showed the influence of patient body weight on ustekinumab serum concentrations. In patients weighing 100 kg, the median serum drug concentration was almost 55% higher compared to patients weighing ≤100 kg. The median volume of distribution in patients weighing 100 kg was almost 37% higher compared with patients weighing ≤100 kg. The median ustekinumab serum concentration after a 90 mg dose in patients weighing 100 kg was comparable to that after a 45 mg dose in patients weighing ≤100 kg. Special populations of patients. The pharmacokinetics of ustekinumab in patients with renal or hepatic impairment have not been studied. No studies have been conducted in elderly patients. Population pharmacokinetic analysis showed no effect of smoking and alcohol intake on the pharmacokinetics of ustekinumab.
Ustekinumab in the treatment of ulcerative colitis
Currently, new methods of treating inflammatory bowel diseases, including biological drugs, are being actively developed. The drug ustekinumab, recently registered for the treatment of ulcerative colitis (UC) and Crohn's disease, is an antagonist of interleukins 12 and 23. This review is devoted to the analysis of the effectiveness and safety of this drug in patients with UC based on data from a phase III clinical trial and data from cohort studies in real clinical practice. In studies, ustekinumab showed high efficacy in both induction and maintenance therapy of UC and was superior to placebo in most parameters assessed (clinical, endoscopic and histological remission). In addition, the drug demonstrated a good safety profile.
Introduction
Drug therapy for inflammatory bowel diseases (IBD) is actively developing. IBD, including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, relapsing inflammation affecting the gastrointestinal (GI) tract. Due to the progressive nature of these diseases, patients often require lifelong drug therapy [1, 2].
Over the past two decades, the first and main biological therapy for moderate to severe forms of IBD has been tumor necrosis factor (TNF) alpha antagonists. However, up to 1/3 of patients do not respond to initial anti-TNF therapy (primary non-responders), and up to 40% of responders eventually lose response (secondary non-responders) [3]. Moreover, anti-TNF therapy is associated with rare but severe side effects, including paradoxical autoimmune reactions, serious infections and malignancies [4–6].
Thus, there is clearly an increasing need for new drug treatments that are safe and effective for IBD.
With a better understanding of the pathophysiology of IBD, new therapeutic targets have emerged in recent years. One of them is interleukins (IL) 12 and 23. IL-12 and IL-23 induce T-lymphocyte differentiation, which leads to upregulation of inflammatory cytokines.
IL-23 is a proinflammatory heterodimeric cytokine composed of p40 and p35 subunits. Before the discovery of IL-23, IL-12, which consists of the common p40 subunit, was considered a major mediator of inflammation [7]. An early clinical trial evaluating anti-IL-12 monoclonal antibodies showed some promise in patients with active CD [8]. Later it became obvious that the p40 subunit, common to IL-12 and IL-23, plays an important role in the pathogenesis of inflammatory diseases [9, 10]. IL-12 and IL-23 induce inflammation of the gastrointestinal mucosa by promoting the differentiation of naive CD4+ T lymphocytes into T helper 1 and T helper 17 cells, which subsequently leads to upregulation of inflammatory cytokines [11–13].
Ustekinumab is a fully human IgG1 monoclonal antibody that targets the common p40 subunit of IL-12 and IL-23. As a result, the receptors of these pro-inflammatory cytokines on cells are blocked [14]. Ustekinumab was first approved for the treatment of moderate to severe psoriasis in 2009, and in 2016 for the treatment of moderate to severe CD [15]. In 2022, the drug was also approved for the treatment of UC. Currently, ustekinumab is registered in Russia for the treatment of moderate and severe CD and UC. The drug is included in international and Russian recommendations for the management of patients with moderate and severe CD and UC.
Efficacy of ustekinumab: clinical trial data
The efficacy and safety of ustekinumab in patients with moderate to severe UC was assessed in a phase III study (UNIFI) using doses identical to those in the phase III study in patients with CD [16].
The study included adult patients (≥ 18 years) with a diagnosis of UC at least three months before screening, moderate to severe activity, defined as a total Mayo score of 6 to 12, and an endoscopic Mayo score of 2 or 3 [ 17, 18] and scores for each of the four parameters of the Mayo scale from 0 to 3. Eligible patients were required to have an inadequate response or side effects to anti-TNF drugs, vedolizumab, or disease-modifying (nonbiologic) therapy. Patients took stable doses of aminosalicylates and immunosuppressants from the time of inclusion until the 44th week of maintenance therapy. Those receiving oral corticosteroids (OCS) at enrollment continued at a stable dose during induction and tapered when maintenance treatment began.
Previous treatment with IL-12 or IL-23 antagonists was prohibited. Previous anti-TNF therapy was discontinued at least eight weeks before study entry, and vedolizumab therapy was discontinued at least four months before study entry. Other background therapy was discontinued at least 2–4 weeks before inclusion in the study. Exclusion criteria included indications for colectomy, gastrointestinal diseases that could lead to surgery or complicate assessment of disease activity, cancer, and active infections (including tuberculosis). Thus, in this clinical study, for the first time, the effectiveness of genetically engineered biological drugs (GEBD) was studied in the most severe category of patients with an inadequate response or side effects not only to anti-TNF therapy, but also to vedolizumab (multiple “non-responders”).
At week 0 of induction therapy, patients were randomly assigned to three groups in a 1:1:1 ratio. Patients in the first group received a single intravenous infusion of ustekinumab 130 mg, patients in the second received ustekinumab at a body weight dose of approximately 6 mg/day. kg, patients of the third - placebo. Randomization was based on previous biologic treatment failure and geographic region (Eastern Europe, Asia, or rest of the world).
The maintenance study included patients with a clinical response to intravenous ustekinumab at week eight and those who did not respond to intravenous placebo and then received an induction dose of intravenous ustekinumab (6 mg/kg) at week eight and had a response at week 16. th week. Response to therapy was defined as a ≥ 30% reduction in Mayo total score and ≥ 3 points from baseline, with a corresponding ≥ 1 point reduction in Mayo rectal bleeding score and a rectal bleeding score of 0 or 1. At week 0 of maintenance therapy, patients were randomly assigned to three groups in a 1:1:1 ratio. The first group received subcutaneous injections of ustekinumab 90 mg every 12 weeks, the second every eight weeks, and the third placebo until the 40th week. Randomization was carried out taking into account intravenous induction therapy, the presence of clinical remission at the initial level of maintenance therapy and oral corticosteroids.
Patients who did not respond to intravenous ustekinumab at week eight received ustekinumab 90 mg subcutaneously and were reevaluated at week 16. Those who responded entered a maintenance study and received ustekinumab 90 mg subcutaneously every eight weeks. Such patients were considered delayed responders to ustekinumab. Those who responded to intravenous placebo at week eight then received subcutaneous placebo.
The primary endpoint for the induction therapy study was clinical remission (defined as a Mayo total score ≤ 2 and any parameter ≤ 1) at week eight. The primary secondary endpoints at week eight were endoscopic remission (defined as a Mayo endoscopic score of 0 or 1), clinical response, and change from baseline in IBDQ score. The secondary endpoint at week 8 was histoendoscopic mucosal healing, which required both histological remission (defined as neutrophil infiltration in less than 5% of crypts, absence of crypt destruction and absence of erosions, ulcerations or granulation tissue) [19, 20] and endoscopic remission. In the maintenance study, the primary endpoint was clinical remission at week 44. Primary secondary endpoints were maintenance of clinical response to week 44, endoscopic remission at week 44, steroid-free clinical remission at week 44, and maintenance of clinical remission to week 44 in patients with clinical remission at baseline during maintenance therapy.
Separately, histologic remission, histoendoscopic mucosal healing, and changes in partial Mayo scores, IBDQ scores, serum C-reactive protein (CRP) concentrations, and fecal biomarker concentrations were assessed separately in both arms of the study. Follow-up safety assessments were conducted during induction therapy until week eight or 16 when patients entered the maintenance study, or 20 weeks after the final induction dose for those who discontinued the study, and during maintenance therapy until week 44. weeks (i.e. 52 weeks of treatment).
Induction of remission
The induction therapy study included 961 patients. After randomization, 319 patients received placebo, 320 patients received ustekinumab 130 mg, and 322 patients received ustekinumab 6 mg/kg.
Among the 51.1% of randomized patients who failed prior biologic treatment (491 of 961), a total of 98.8% (485 of 491) failed treatment with at least one TNF antagonist. In 32.6% (160 of 491), treatment with both a TNF antagonist and vedolizumab was ineffective, and in 1.2% (6 of 491) treatment with vedolizumab alone was ineffective.
At week eight, the percentage of patients in clinical remission in the groups receiving ustekinumab 130 mg (15.6% (50 of 320 patients)) or 6 mg/kg (15.5% (50 of 322 patients)) was higher than in placebo group (5.3% (17 of 319)) (p
Among patients who did not have a clinical response to intravenous ustekinumab and who received 90 mg subcutaneous ustekinumab at week eight, a total of 59.7% (139 of 233) had a delayed clinical response at week 16. Among all patients in the induction trial, 77.6% of patients (498 of 642) initially prescribed ustekinumab experienced a clinical response at 16 weeks. Additionally, among patients who did not have a clinical response to IV placebo and then received IV ustekinumab 6 mg/kg, 67.9% (125 of 184) had a clinical response at week 16.
Results from pre-study treatment-by-treatment analyzes suggest benefits of ustekinumab in different patient subgroups.
The proportion of patients achieving key secondary endpoints or having histoendoscopic mucosal healing was significantly higher in both ustekinumab groups compared with the placebo group. At week eight, mean changes in IBDQ scores from baseline were greater in both ustekinumab groups compared with the placebo group. The proportion of patients with histological improvement at week 8 was higher in both ustekinumab groups than in the placebo group. Significant versus placebo improvements in fecal calprotectin and lactoferrin and serum CRP concentrations compared with baseline levels support the clinical results obtained.
In conclusion, ustekinumab is more effective than placebo in inducing clinical remission after eight weeks. This effect was observed in all patients regardless of the failure of previous biologic therapy, including patients who had not previously received biologics. The results of the evaluation of the effectiveness of ustekinumab therapy at week 16 showed that 87% of patients who had not previously received GEBP and 80% of patients in the combination group achieved a clinical response [21].
The effect of ustekinumab occurred soon after induction: according to BE Sands et al. [22], symptom improvement (patient-rated stool frequency and presence of rectal bleeding) was recorded daily for seven days before each visit. Partial Mayo scores were performed at baseline and week 2 using the average of stool frequency and rectal bleeding scores for the most recent period of three consecutive days before the visit. During the visit, values on the Physician's General Assessment Scale were recorded. Reductions in systemic inflammation (CRP and fecal biomarkers assays performed at baseline and day 14) were observed as early as the first assessments on days seven and day 14, respectively.
Maintenance therapy
The maintenance therapy study included 783 patients [16]. Among patients who demonstrated a clinical response to ustekinumab induction therapy, the proportion who were in clinical remission at week 44 (52 weeks after intravenous induction) in the ustekinumab 90 mg every 12 groups (38.4% (66 of 172 patients) )) or eight weeks (43.8% (77 of 176)) was significantly higher than the placebo group (24.0% (42 of 175)) (p = 0.002 and p
The proportion of patients with sustained clinical response to week 44, endoscopic remission at week 44, or clinical remission without corticosteroids (by any definition of clinical remission) at week 44 was significantly higher in both ustekinumab groups than in the placebo group. Among patients receiving corticosteroids at baseline, the proportion who discontinued corticosteroids at least 90 days before week 44 in the ustekinumab 90 mg every 12 (67% (55 of 82 patients)) or eight weeks (77) groups % (71 of 92)) was higher than in the placebo group (44% (40 of 91)). Patients receiving ustekinumab (median seven weeks in each group) stopped taking corticosteroids earlier than patients receiving placebo (median 16 weeks).
The proportion of patients who experienced both histological remission and histoendoscopic mucosal healing was higher in both ustekinumab groups than in the placebo group. At week 44, mean IBDQ scores improved or remained unchanged from baseline with ustekinumab every 12 and eight weeks, but worsened with placebo. Improvements in partial Mayo scores and concentrations of CRP, lactoferrin, and calprotectin observed at the time of entry into the maintenance study were maintained in both ustekinumab groups, whereas these values worsened in the placebo group.
Among patients who demonstrated a delayed response to ustekinumab and received 90 mg every eight weeks, 62.4% (98 of 157) had a clinical response at week 44. There were fewer patients who met this endpoint or other efficacy measures at week 44 than patients who responded to intravenous ustekinumab and who received 90 mg of ustekinumab subcutaneously every eight weeks during maintenance therapy.
In conclusion, among patients who responded to induction therapy with intravenous ustekinumab and underwent a second randomization, the likelihood of clinical remission at 44 weeks was higher in the subcutaneous ustekinumab groups compared with the placebo group. For all prespecified primary secondary endpoints in the induction and maintenance studies, the percentages of patients were significantly higher in the ustekinumab groups compared with the placebo group.
All patients who completed week 44 of the maintenance study and met inclusion criteria for long-term follow-up continued to receive ustekinumab 90 mg every 12 or eight weeks. Ustekinumab dose adjustments (from every 12 to eight weeks or a dummy dose adjustment from every eight weeks to eight weeks) were provided from week 56. Patients who continued to take placebo were excluded from this part of the study. During the maintenance therapy study, all patients receiving corticosteroids at baseline were recommended to gradually reduce the dose of these drugs. Of the 284 patients in the randomized population receiving ustekinumab maintenance, 139 received corticosteroids at baseline maintenance. At week 92 of the long-term follow-up period, the rate of symptomatic remission without and with the use of corticosteroids was calculated using ITT analysis (intention-to-treat). Findings were similar for maintenance doses of ustekinumab 90 mg every eight and 12 weeks. Among those who received ustekinumab and were in symptomatic remission at week 92, 98.4% (182/185) were not taking corticosteroids.
Safety of ustekinumab in the treatment of UC
In the induction therapy study, 41.4% of patients in the ustekinumab 130 mg group, 50.6% of patients in the ustekinumab 6 mg/kg group, and 48.0% of patients in the placebo group experienced at least one adverse event (AE). The proportion of patients in these groups with at least one serious AE was 3.7, 3.4 and 6.9%, respectively. At week 44 of the maintenance study, at least one AE was reported in 69.2% of patients receiving ustekinumab 90 mg every 12 weeks, 77.3% of patients receiving 90 mg every eight weeks, and 78.9% of patients receiving ustekinumab 90 mg every 8 weeks. who received placebo. The proportion of patients in these groups with at least one serious AE was 7.6, 8.5 and 9.7%, respectively, and with a serious infection 3.5, 1.7 and 2.3%, respectively. Among patients receiving ustekinumab, there were two deaths before week 44 (sudden death associated with bleeding due to esophageal varices and death due to acute respiratory distress syndrome (ARDS)) and one death after week 44 (a patient with a disorder of normal development suffered cardiac arrest). Cancer developed in seven of 825 patients treated with ustekinumab (one case each of prostate, colon, renal papillary and rectal cancer and three cases of nonmelanoma skin cancer) and one of 319 patients treated with placebo (testicular cancer). Potential opportunistic infections were identified in four patients receiving ustekinumab: cytomegalovirus colitis (in two patients during maintenance therapy), Legionella pneumonia (in one patient during induction), and concomitant ophthalmic and oral herpetic infections (in one patient during treatment ). Cardiovascular events: nonfatal cardiac arrest (in a patient who received ustekinumab during induction and placebo during maintenance), acute myocardial infarction (in a patient who received ustekinumab and died from complications of ARDS), and nonfatal stroke (in a patient who received placebo during induction).
Thus, during treatment with ustekinumab, there was no increase in the risk of developing any AEs compared to placebo, which, according to experts, allows the drug to be used in patients with comorbid conditions or an increased individual risk of AEs on biological therapy [23].
Despite the recent approval of ustekinumab for CD and UC, there is extensive evidence for its use in dermatology and rheumatology.
The incidence of AEs with ustekinumab in the UNIFI study was comparable to that with placebo (AEs, serious AEs, infections, serious infections). This correlates with pooled data on the safety of the drug (phase II/III clinical studies of ustekinumab in patients with psoriasis, psoriatic arthritis, CD).
Analyzed data from 6,280 study patients (3,117 psoriasis, 1,018 psoriatic arthritis, 1,749 CD), based on one year of therapy (i.e., per patient-year), included 4,521 observations versus 674 in the placebo group (829 and 385 patient-years over eight to 16 weeks of follow-up). The combined event rate per 100 patient-years for ustekinumab versus placebo (95% confidence interval) is:
infections 125.4 (122.2–128.7) versus 129.4 (120.9–138.3) at one year follow-up with no increase in infection rates with combination therapy with methotrexate (92.5 (84.2) –101.5) vs 115.3 (109.9–121.0)) with an increase in the incidence of infections when combined with GCS compared with ustekinumab monotherapy (116.3 (107.3–125.9) vs 107.3 ( 102.0–112.8));
rare incidence of major cardiovascular pathologies (0.5 (0.3–0.7) vs 0.3 (0.0–1.1)), oncology (0.4 (0.2–0.6) vs 0.2 (0.0–0.8)) and deaths (0.1 (0.0–0.3) vs 0.0 (0.0–0.4)) [24].
Meta-analysis VS Rolston et al. to assess the incidence of AEs in randomized clinical trials (RCTs) of ustekinumab and placebo in the treatment of immunoinflammatory diseases [25] included 30 RCTs involving 16,068 patients. The authors concluded that in the short term (16 weeks), the risk of serious or mild/moderate AEs was not increased with ustekinumab compared with placebo. In addition, there are no differences in the incidence of AEs when comparing high (for IBD) and low doses (for psoriasis/psoriatic arthritis) ustekinumab in the treatment of immunoinflammatory diseases.
The use of ustekinumab for the treatment of UC in real clinical practice
To date, little experience has been accumulated with the use of ustekinumab in real clinical practice. Nevertheless, the results of the first publications are optimistic. The French GETAID study [26] retrospectively included 103 patients with UC. Of these, 70% had previously taken two or more biological drugs, 85% had taken vedolizumab. The majority of patients (90.3%) were given an intravenous induction dose of 6 mg/kg, the rest received 90 mg subcutaneously. All patients received a subcutaneous injection of ustekinumab 90 mg at the eighth week after induction. The primary endpoint was steroid-free clinical remission (assessed by partial Mayo index ≤ 2) at weeks 12–16 of ustekinumab therapy. Clinical response was obtained in 55.4% of patients. 35% of patients achieved the primary endpoint. The absence of rectal bleeding with normal stool frequency was observed in 19.4% of patients. Two patients stopped ustekinumab before the 12–16 week visit and underwent surgery. In multivariate analysis, partial Mayo score >6 at enrollment (18.6 vs 46.7%; p = 0.003) and history of both anti-TNF therapy and vedolizumab use (27.3 vs 80.0%; p = 0.001) were negatively associated with steroid-free clinical remission at weeks 12–16. AEs were registered in 7.8% of patients, serious AEs – in 3.9% of patients.
A German study [27] conducted a retrospective analysis of data from 19 patients with UC who were intolerant or resistant to corticosteroids, purine analogues, anti-TNF therapy, and vedolizumab. All patients received ustekinumab as rescue treatment (6 mg/kg intravenously followed by 90 mg subcutaneously every eight weeks). The primary endpoint was the achievement of clinical remission after one year, defined as ≥ 3 points on the Lichtiger scale (UC activity index) [28].
In five patients, therapy was discontinued due to resistance or side effects. In the remaining 14 patients, the mean UC activity index decreased from 8.5 points (range, 1–12) at baseline to 2 points at one year (range, 0–5.5). The Mayo endoscopic activity score decreased from a median of 2 points (range 1–3, mean 2.3) at baseline to a median of 1 point (range 1–3, mean 1.4) over the course of the year. Clinical remission was achieved in 53% of patients after one year (including five dropouts).
Study results show that in a cohort of patients with UC with prior therapy with multiple biological agents, the use of ustekinumab leads to the achievement of steroid-free clinical remission in 1/3 of patients by 12-16 weeks and in half of patients after a year. Clinical severity and previous use of anti-TNF therapy and vedolizumab are associated with a high risk of ustekinumab failure.
Conclusion
In a phase III study of an IL-12 and IL-23 antagonist in patients with moderate to severe UC [16], ustekinumab was more effective than placebo in achieving clinical remission after eight weeks. This effect was observed both in bionaïve patients and in patients with previous treatment failure with biological agents. The effectiveness of induction therapy has also been demonstrated in a small cohort of patients in real clinical practice [26].
In the UNIFI trial [16], among patients who responded to induction therapy with intravenous ustekinumab and underwent a second randomization, patients assigned to either subcutaneous ustekinumab regimen were more likely to have clinical remission at 44 weeks than patients receiving placebo. For all prespecified primary secondary endpoints in both induction and maintenance therapy, the proportion of patients in the ustekinumab groups was significantly higher than in the placebo group. In real clinical practice, the effectiveness of long-term therapy with ustekinumab for a year has also been shown [27].
The therapeutic goal in patients with UC is to achieve and maintain long-term remission, since the disease is often relapsing [29, 30]. Endoscopic mucosal improvement is associated with better subsequent long-term outcomes [31, 32]. Histological improvement is also associated with better long-term outcomes, including reduction in GCS use and relapse rates [33, 34]. Histoendoscopic mucosal healing, an endpoint assessed in the induction therapy study, was induced by both intravenous doses of ustekinumab and maintained by both subcutaneous doses.
Currently, the safety of the drug can be judged by data on the treatment of patients with other diseases (dermatological, rheumatological and CD) [35–37]. Nevertheless, based on these data and the data obtained in the UNIFI study [16], we can talk about the good tolerability and safety of this drug in most patients.
Currently, ustekinumab is the only drug for the treatment of CD and UC that targets IL-12/23-mediated inflammatory pathways. This type of treatment with a new mechanism of action is intended for patients who are ineffective or intolerant of basic therapy or therapy with anti-TNF drugs and vedolizumab. Clinical trials have shown that ustekinumab can be used effectively and safely in the treatment of UC both in “bionaive” patients and after the failure of biological therapy with other drugs or their withdrawal due to the development of AEs. A drug with a new mechanism of action can be the first line of therapy to achieve long-term effectiveness and sustainable results in patients with a high risk of infectious complications, significant comorbid diseases (class III-IV heart failure, diabetes, demyelinating diseases), in patients with a combination of IBD and skin ( psoriasis) or joint manifestations. Ustekinumab is effective in patients with psoriasiform lesions treated with anti-TNF drugs. Ustekinumab has a favorable safety profile. To date, reactivation of tuberculosis has not been described. In addition, the drug has a convenient administration regimen: a single intravenous induction dose of 6 mg/kg followed by subcutaneous administration of 90 mg once every 12 or eight weeks [23, 38].
To date, there have been no direct comparative clinical trials of ustekinumab and other drugs approved for the treatment of UC (infliximab, adalimumab, golimumab, vedolizumab). A systematic review and network meta-analysis of the comparative effectiveness of 1-year therapy with ustekinumab and other pharmacological agents in patients with moderate-to-severe UC [39] showed that in the absence of a history of failure of biological therapy, ustekinumab for a year is associated with a higher likelihood of clinical response, remission and endoscopic healing of the mucous membrane. compared to other study drugs. However, further additional studies, longer observations, and expansion of the base of real clinical data of patients with UC are needed.
Use of the drug Stelara
Stelara should be used by a physician experienced in the treatment of psoriasis. Dosing . Recommended dosing regimen: initial dose of 45 mg subcutaneously at week 0 and week 4 of treatment, then every 12 weeks. Interruption of treatment should be promptly considered in patients who do not achieve response before 28 weeks of treatment. Patients weighing 100 kg. For patients weighing 100 kg, a dose of 90 mg is administered subcutaneously at week 0, then 90 mg at week 4, and then every 12 weeks. In patients weighing 100 kg, a dose of 45 mg is also effective, but a dose of 90 mg provides greater effectiveness. Elderly patients (65 years and older) . No dose adjustment is required for elderly patients. Children and adolescents (under 18 years old) . Stelara is not recommended for use in children under 18 years of age due to the lack of data on safety and effectiveness. Impaired kidney and liver function . No studies of Stelara have been conducted in this category of patients and no recommendations regarding the dosage regimen can be made. Mode of application . The drug should be used subcutaneously. If possible, do not inject into areas of skin with psoriatic lesions. At the discretion of the doctor, after appropriate training, the patient can administer subcutaneous injections of the drug to himself.
Indications of the active substances of the drug Stelara®
For subcutaneous administration
Adults and children from 12 to 18 years of age: moderate to severe plaque psoriasis in the absence of response to treatment or in the presence of contraindications, or intolerance to other methods of systemic therapy or phototherapy.
Adults: active psoriatic arthritis (as monotherapy or in combination with methotrexate); Crohn's disease; ulcerative colitis.
For IV infusions
Adults: Moderate to severe Crohn's disease.
Side effects of the drug Stelara
The most common adverse reactions (10%) in controlled and uncontrolled clinical trials of Stelara for psoriasis were nasopharyngitis and upper respiratory tract infections. Most of these events were moderate and did not require discontinuation of treatment. Adverse reactions are classified by organ system and frequency: very often (≥1/10), often (≥1/100, ≤1/10), infrequently (≥1/1000, ≤1/100), rarely (≥1/10 000, ≤1/1000), very rare (1/10,000), unknown (cannot be estimated from available data). Within each frequency group, adverse reactions are presented in order of decreasing severity. Infections and infestations : very often - upper respiratory tract infections, nasopharyngitis; often - cellulitis, viral infections of the upper respiratory tract. Mental disorders : often - depression. From the side of the central nervous system : often - dizziness, headache. From the respiratory system : often - sore throat/pharynx, nasal congestion. From the gastrointestinal tract : often - diarrhea. From the skin and subcutaneous tissue : often - itching. From the musculoskeletal system : often - back pain, myalgia. General condition and local reactions : often - weakness, redness at the injection site; Uncommon: injection site reactions, including pain, swelling, itching, induration, bleeding, hematoma and irritation. Infections . In controlled trials of psoriasis, the incidence of infections and serious infections was similar with Stelara and placebo (infection rates 1.39 and 1.21 per year of treatment, respectively; serious infection rates 0.01 (5/407) and 0.01 (5/407), respectively. 02 (3/177) cases per person-year of treatment). In the controlled and uncontrolled portions of the clinical studies, the infection rate was 1.24 patient/year and the serious infection rate was 0.01 patient/year for patients treated with ustekinumab (24 serious infections in 2251 patients/year); Serious infections reported included cellulitis, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia, and urinary tract infections. When the drug Stelara was used in combination with isoniazid in patients with latent tuberculosis, no progression of tuberculosis was recorded in clinical studies. Malignant tumors . In placebo-controlled clinical trials of psoriasis, the incidence of malignancy (including melanoma, but not other forms of skin cancer) in patients receiving Stelara and placebo was 0.25 (1/406) and 0.57 (1/406), respectively. 177) cases per 100 person/years of treatment. The incidence of other (excluding melanoma) forms of cancer with the use of these drugs was 0.74 (3/406) and 0.57 (1/177) cases per 100 person-years of treatment, respectively. In the controlled and uncontrolled portions of clinical studies, the incidence of malignant tumors (including melanoma, but not including other forms of skin cancer) in patients receiving Stelara was 0.36 (8/2249) cases per 100 person-years of treatment; malignancies that were observed included breast, colon, head and neck, kidney, prostate and thyroid cancers. The incidence of malignancy in patients receiving Stelara was the same as in the general population (standardized rate ratio 0.68; 95% confidence interval: 0.29, 1.34). The incidence of other forms of cancer (excluding melanoma) with Stelara was 0.80 (18/2245) cases per 100 person-years of treatment. Hypersensitivity reactions. In clinical studies of Stelara, rash and urticaria were observed in less than 2% of patients. Immunogenicity. Approximately 5% of patients using ustekinumab developed antibodies to ustekinumab, usually at low titres. There was no clear correlation between the formation of antibodies and the presence of reactions at the injection site. In the presence of antibodies to the drug, a decrease in the effect was observed in patients, although the formation of antibodies does not exclude the achievement of a clinical effect.
Contraindications for use
Clinically significant increased sensitivity to ustekinumab; infectious diseases in the acute phase (including tuberculosis), malignant neoplasms, pregnancy, breastfeeding; for subcutaneous administration: - children under 12 years of age (according to indications for plaque psoriasis), up to 18 years of age (according to indications for psoriatic arthritis, Crohn's disease, ulcerative colitis); for IV infusions – children under 18 years of age.
Carefully
Chronic or recurrent parasitic and infectious diseases of viral, fungal or bacterial etiology; history of malignant tumors; elderly age.
Special instructions for the use of Stelara
Infections . Stelara is a selective immunosuppressant and may increase the risk of developing infections and reactivation of latent infections. In clinical studies, serious bacterial, fungal and viral infections were observed in patients using Stelara. The drug should be used with caution in patients with chronic infections or a history of recurrent infections. Before starting to use the drug Stelara, it is necessary to examine the patient for the presence of tuberculosis. The drug should not be used in patients with active tuberculosis. If you have latent tuberculosis, treatment should begin before using Stelara. It is also necessary to begin treatment for tuberculosis before using Stelara in patients with a history of latent or active tuberculosis and in whom the sufficient effect of previous treatment has not been confirmed. During and after treatment with the drug, patients should be carefully examined in order to promptly identify signs and symptoms of active tuberculosis. Patients should be instructed to seek medical attention if they develop signs and symptoms that suggest the development of an infection. If a serious infection develops, patients should be closely monitored; Stelara should not be used until the infection is cured. Malignant tumors . The drug Stelara is a selective immunosuppressant. Drugs in this group may increase the risk of developing malignant tumors. Some patients treated with this drug in clinical studies developed skin and other types of malignant tumors. No studies on the use of Stelara have been conducted in patients with a history of malignant tumors. Caution should be used when using the drug in patients who have a history of malignant tumors or when considering continuing treatment after the development of such a tumor. Hypersensitivity reactions . If anaphylactic or other serious allergic reactions develop, the use of Stelara should be stopped immediately and appropriate treatment should be prescribed. Vaccination . During treatment with Stelara, it is not recommended to use live viral and bacterial vaccines (such as the BCG vaccine). No specific studies have been conducted in patients who have recently been vaccinated with live viral or live bacterial vaccines. Before using live viral and bacterial vaccines, treatment with Stelara should be delayed for less than 15 weeks after the last dose and can be resumed 2 weeks after vaccination. The doctor should know about the peculiarities of using the drug and specific vaccines and immunosuppressants before and after vaccination. Inactivated vaccines and vaccines from killed microorganisms can be used simultaneously with Stelara. Concomitant immunosuppressive therapy . The safety and effectiveness of Stelara in combination with immunosuppressants and phototherapy have not been studied. If it is necessary to use the drug Stelara, it is necessary to weigh the advantages of its simultaneous use with immunosuppressants. Special categories of patients Use in pediatric practice (up to 18 years of age) . No specific studies have been conducted on the use of Stelara in children. Application in geriatric practice (65 years and older) . The effectiveness and safety of the drug in patients over 65 years of age and in younger patients did not differ significantly. Since the incidence of infections in elderly patients is generally higher, caution should be exercised when treating patients in this age group. Liver and kidney failure . No special studies have been conducted on the use of Stelara in patients with liver and kidney failure. Special safety precautions . The solution of the drug Stelara in the bottle should not be shaken. Before subcutaneous administration, the solution in the bottle should be visually checked for the presence of mechanical inclusions or color changes. It should be clear or slightly opalescent, colorless or slightly yellowish and may contain trace amounts of small clear or white protein particles. This appearance is not unusual for protein solutions. If there is a change in color, cloudiness or the presence of solid particles, the solution cannot be used. Before using the drug, the solution must reach a comfortable temperature for injection (approximately within 30 minutes). Stelara does not contain preservatives, so any unused remainder of the drug in the vial and syringe cannot be reused. Unused drug and waste must be destroyed in accordance with generally accepted requirements. During pregnancy and breastfeeding . There is insufficient data regarding the use of Stelara during pregnancy. Animal studies have shown no direct or indirect negative effects on pregnancy, embryonic development, childbirth or postnatal development. As a preventative measure, it is recommended to avoid the use of Stelara during pregnancy. Women of reproductive age must use adequate contraception throughout the course of treatment and for 15 weeks after its completion. It is not known whether ustekinumab passes into breast milk. Animal studies have shown low levels of penetration into breast milk. It is not known whether the drug is absorbed systemically after absorption. Since Stelara may cause adverse reactions in infants, a decision must be made to stop breastfeeding while taking the drug and for 15 weeks after treatment, or to discontinue therapy. The benefit/risk ratio should be carefully weighed before deciding whether a woman needs treatment or continues breastfeeding. Children . The safety and effectiveness of the drug in this age category have not been studied. Therefore, the drug is not recommended for use in children under 18 years of age. The ability to influence reaction speed when driving vehicles or working with other mechanisms. Studies of the effect of the drug on the reaction rate when driving vehicles or working with other mechanisms have not been conducted.
Dosage regimen
The method of administration and dosage regimen of a particular drug depend on its release form and other factors. The optimal dosage regimen is determined by the doctor. The compliance of the dosage form of a particular drug with the indications for use and dosage regimen should be strictly observed.
Administered subcutaneously and intravenously as infusions in appropriate dosage forms.
For subcutaneous administration, a single dose is 45-90 mg, depending on the patient’s body weight. For children over 12 years of age weighing less than 60 kg, a single dose is 0.75 mg/kg.
When administered as an intravenous infusion, a single dose is 260-520 mg, depending on the patient’s body weight.
The treatment regimen is established individually, depending on the indications and clinical situation.
Drug interactions Stelara
No drug interaction studies have been conducted. A phase III population pharmacokinetic analysis examined the effect of concomitant use of drugs in patients with psoriasis (including paracetamol, ibuprofen, acetylsalicylic acid, metformin, atorvastatin, levothyroxine) on the pharmacokinetics of ustekinumab. No data have been obtained regarding interactions with these drugs when used concomitantly with Stelara. These studies were conducted in at least 100 patients (5% of the study population) who were simultaneously receiving concomitant therapy with these drugs for almost the entire study period (90%). Live vaccines cannot be used simultaneously with Stelara. The safety and effectiveness of Stelara in combination with immunosuppressants and phototherapy have not been studied, so this combination should be used with caution.
Release form, packaging and composition of the drug Stelara®
Solution for subcutaneous administration is colorless to light yellow, transparent or slightly opalescent; the solution may contain single transparent particles of protein.
| 1 syringe (1 ml) | |
| ustekinumab | 90 mg |
Excipients: sucrose - 76 mg, L-histidine (including L-histidine hydrochloride monohydrate) - 1.0 mg, polysorbate 80 - 0.04 mg, water for injection - up to 1.0 ml.
1.0 ml – syringes (1) made of borosilicate glass (type I) with UltraSafe Passive® device – cardboard packs.
Clinical and pharmacological group: Immunosuppressive drug. Interleukin receptor antagonist
Pharmacotherapeutic group: Immunosuppressors, interleukin inhibitors
