Imraldi

Overdose

No dose-limiting toxicity was observed during clinical trials. The highest dose level evaluated has been multiple intravenous doses of 10 mg/kg, which is approximately 15 times the recommended dose.

Contraindications

Active tuberculosis or other severe infections such as sepsis and opportunistic infections.

Moderate to severe heart failure (NYHA class III/IV).

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Pharmaceutical form

Undesirable effects

Summary of the safety profile

Imraldi was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months or more. These trials included rheumatoid arthritis patients with short term and long standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS), psoriatic arthritis, Crohn's disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving Imraldi and 3,801 patients receiving placebo or active comparator during the controlled period.

The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies was 5.9% for patients taking Imraldi and 5.4% for control treated patients.

The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.

Serious adverse reactions have been reported for Imraldi. TNF-antagonists, such as Imraldi affect the immune system and their use may affect the body's defence against infection and cancer.

Fatal and life-threatening infections (including sepsis, opportunistic infections and TB), HBV reactivation and various malignancies (including leukaemia, lymphoma and HSTCL) have also been reported with use of Imraldi.

Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome.

Paediatric population

In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.

Tabulated list of adverse reactions

The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency in Table 6 below: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); and not known (cannot be estimated from the available data).4 and 4.8.

Table 6

Undesirable Effects

** including open label extension studies

1) including spontaneous reporting data

Uveitis

The safety profile for patients with uveitis treated with Imraldi every other week was consistent with the known safety profile of Imraldi.

Description of selected adverse reactions

Injection site reactions

In the pivotal controlled trials in adults and children, 12.9% of patients treated with Imraldi developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.2% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.

Infections

In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the Imraldi treated patients and 1.46 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on Imraldi after the infection resolved.

The incidence of serious infections was 0.04 per patient year in Imraldi treated patients and 0.03 per patient year in placebo and active control − treated patients.

In controlled and open label adult and paediatric studies with Imraldi, serious infections (including fatal infections, which occurred rarely) have been reported, which include reports of tuberculosis (including miliary and extra-pulmonary locations) and invasive opportunistic infections (e.g. disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, pneumocystis, candidiasis, aspergillosis and listeriosis). Most of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease.

Malignancies and lymphoproliferative disorders

No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years during Imraldi trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric patients with an exposure of 498.1 patient years during Imraldi trials in paediatric patients with Crohn's disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during a Imraldi trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during a Imraldi trial in paediatric patients with uveitis.

During the controlled portions of pivotal Imraldi trials in adults of at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn's disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291 Imraldi treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for Imraldi and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among Imraldi-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among Imraldi-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among Imraldi-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients.

When combining controlled portions of these trials and ongoing and completed open label extension studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1,000 patient years.

In post-marketing experience from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient treatment years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 0.3 per 1,000 patient treatment years, respectively.

Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab.

Autoantibodies

Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis studies I − V. In these trials, 11.9% of patients treated with Imraldi and 8.1% of placebo and active control − treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at Week 24. Two patients out of 3,441 treated with Imraldi in all rheumatoid arthritis and psoriatic arthritis studies developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms.

Hepato-biliary events

In controlled Phase 3 trials of Imraldi in patients with rheumatoid arthritis and psoriatic arthritis with a control period duration ranging from 4 to 104 weeks, ALT elevations > 3 x ULN occurred in 3.7% of Imraldi-treated patients and 1.6% of control-treated patients.

In controlled Phase 3 trials of Imraldi in patients with polyarticular juvenile idiopathic arthritis who were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations > 3 x ULN occurred in 6.1% of Imraldi-treated patients and 1.3% of control-treated patients. Most ALT elevations occurred with concomitant methotrexate use. No ALT elevations > 3 x ULN occurred in the Phase 3 trial of Imraldi in patients with polyarticular juvenile idiopathic arthritis who were 2 to < 4 years.

In controlled Phase 3 trials of Imraldi in patients with Crohn's disease and ulcerative colitis with a control period ranging from 4 to 52 weeks. ALT elevations > 3 x ULN occurred in 0.9% of Imraldi-treated patients and 0.9% of controlled-treated patients.

In the Phase 3 trial of Imraldi in patients with paediatric Crohn's disease which evaluated efficacy and safety of two body weight adjusted maintenance dose regimens following body weight adjusted induction therapy up to 52 weeks of treatment, ALT elevations > 3 x ULN occurred in 2.6% (5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline.

In controlled Phase 3 trials of Imraldi in patients with plaque psoriasis with a control period duration ranging from 12 to 24 weeks, ALT elevations > 3 x ULN occurred in 1.8% of Imraldi-treated patients and 1.8% of control-treated patients.

No ALT elevations > 3 x ULN occurred in the Phase 3 trial of Imraldi in paediatric patients with plaque psoriasis.

In controlled trials of Imraldi (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 days and 105.0 days in Imraldi-treated and control-treated patients, respectively, ALT elevations > 3 x ULN occurred in 2.4% of Imraldi-treated patients and 2.4% of control-treated patients.

Across all indications in clinical trials patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved on continued treatment. However, there have also been post-marketing reports of liver failure as well as less severe liver disorders that may precede liver failure, such as hepatitis including autoimmune hepatitis in patients receiving adalimumab.

Concurrent treatment with azathioprine/6-mercaptopurine

In adult Crohn's disease studies, higher incidences of malignant and serious infection-related adverse events were seen with the combination of Imraldi and azathioprine/6-mercaptopurine compared with Imraldi alone.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme:

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on studies of single dose toxicity, repeated dose toxicity, and genotoxicity.

An embryo-foetal developmental toxicity/perinatal developmental study has been performed in cynomologous monkeys at 0, 30 and 100 mg/kg (9-17 monkeys/group) and has revealed no evidence of harm to the foetuses due to adalimumab. Neither carcinogenicity studies, nor a standard assessment of fertility and postnatal toxicity, were performed with adalimumab due to the lack of appropriate models for an antibody with limited cross-reactivity to rodent TNF and to the development of neutralising antibodies in rodents.

Therapeutic indications

Juvenile idiopathic arthritis

Polyarticular juvenile idiopathic arthritis

Imraldi in combination with methotrexate is indicated for the treatment of active polyarticular juvenile idiopathic arthritis, in patients from the age of 2 years who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). Imraldi can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. Imraldi has not been studied in patients aged less than 2 years.

Enthesitis-related arthritis

Imraldi is indicated for the treatment of active enthesitis-related arthritis in patients, 6 years of age and older, who have had an inadequate response to, or who are intolerant of, conventional therapy.

Paediatric plaque psoriasis

Imraldi is indicated for the treatment of severe chronic plaque psoriasis in children and adolescents from 4 years of age who have had an inadequate response to or are inappropriate candidates for topical therapy and phototherapies.

Paediatric Crohn's disease

Imraldi is indicated for the treatment of moderately to severely active Crohn's disease in paediatric patients (from 6 years of age) who have had an inadequate response to conventional therapy including primary nutrition therapy and a corticosteroid and/or an immunomodulator, or who are intolerant to or have contraindications for such therapies.

Paediatric Uveitis

Imraldi is indicated for the treatment of paediatric chronic non-infectious anterior uveitis in patients from 2 years of age who have had an inadequate response to or are intolerant to conventional therapy, or in whom conventional therapy is inappropriate.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNF-α) inhibitors.

ATC code: L04AB04

Mechanism of action

Adalimumab binds specifically to TNF and neutralises the biological function of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors.

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of0.1-0.2 nM).

Pharmacodynamic effects

After treatment with Imraldi, a rapid decrease in levels of acute phase reactants of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL-6) was observed, compared to baseline in patients with rheumatoid arthritis. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodelling responsible for cartilage destruction were also decreased after Imraldi administration. Patients treated with Imraldi usually experienced improvement in haematological signs of chronic inflammation.

A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis and hidradenitis suppurativa after treatment with Imraldi. In patients with Crohn's disease, a reduction of the number of cells expressing inflammatory markers in the colon including a significant reduction of expression of TNFα was seen. Endoscopic studies in intestinal mucosa have shown evidence of mucosal healing in adalimumab treated patients.

Clinical efficacy and safety

Juvenile idiopathic arthritis (JIA)

Polyarticular juvenile idiopathic arthritis (pJIA)

The safety and efficacy of Imraldi was assessed in two studies (pJIA I and II) in children with active polyarticular or polyarticular course juvenile idiopathic arthritis, who had a variety of JIA onset types (most frequently rheumatoid-factor negative or positive polyarthritis and extended oligoarthritis).

pJIA I

The safety and efficacy of Imraldi were assessed in a multicentre, randomised, double-blind, parallel − group study in 171 children (4-17 years old) with polyarticular JIA. In the open-label lead in phase (OL LI) patients were stratified into two groups, MTX (methotrexate)-treated or non-MTX-treated. Patients who were in the non-MTX stratum were either naïve to or had been withdrawn from MTX at least two weeks prior to study drug administration. Patients remained on stable doses of NSAIDs and or prednisone (≤ 0.2 mg/kg/day or 10 mg/day maximum). In the OL LI phase all patients received 24 mg/m2 up to a maximum of 40 mg Imraldi every other week for 16 weeks. The distribution of patients by age and minimum, median and maximum dose received during the OL LI phase is presented in Table 7.

Table 7

Distribution of patients by age and adalimumab dose received during the OL LI phase

Patients demonstrating a Pediatric ACR 30 response at Week 16 were eligible to be randomised into the double blind (DB) phase and received either Imraldi 24 mg/m2 up to a maximum of 40 mg, or placebo every other week for an additional 32 weeks or until disease flare. Disease flare criteria were defined as a worsening of > 30% from baseline in > 3 of 6 Pediatric ACR core criteria, > 2 active joints, and improvement of > 30% in no more than 1 of the 6 criteria. After 32 weeks or at disease flare, patients were eligible to enrol into the open label extension phase.

Table 8

Ped ACR 30 Responses in the JIA study

a Ped ACR 30/50/70 responses Week 48 significantly greater than those of placebo treated patients

b p = 0.015

c p = 0.031

Amongst those who responded at Week 16 (n=144), the Pediatric ACR 30/50/70/90 responses were maintained for up to six years in the OLE phase in patients who received Imraldi throughout the study. Over all 19 subjects, of which 11 of the baseline age group 4 to 12 and 8 of the baseline age group 13 to 17 years were treated 6 years or longer.

Overall responses were generally better and, fewer patients developed antibodies when treated with the combination of Imraldi and MTX compared to Imraldi alone. Taking these results into consideration, Imraldi is recommended for use in combination with MTX and for use as monotherapy in patients for whom MTX use is not appropriate.

pJIA II

The safety and efficacy of Imraldi was assessed in an open-label, multicentre study in 32 children (2 - < 4 years old or aged 4 and above weighing < 15 kg) with moderately to severely active polyarticular JIA. The patients received 24 mg/m2 body surface area (BSA) of Imraldi up to a maximum of 20 mg every other week as a single dose via SC injection for at least 24 weeks. During the study, most subjects used concomitant MTX, with fewer reporting use of corticosteroids or NSAIDs.

At Week 12 and Week 24, PedACR30 response was 93.5% and 90.0%, respectively, using the observed data approach. The proportions of subjects with PedACR50/70/90 at Week 12 and Week 24 were 90.3%/61.3%/38.7% and 83.3%/73.3%/36.7%, respectively. Amongst those who responded (Pediatric ACR 30) at Week 24 (n=27 out of 30 patients), the Pediatric ACR 30 responses were maintained for up to 60 weeks in the OLE phase in patients who received Imraldi throughout this time period. Overall, 20 subjects were treated for 60 weeks or longer.

Enthesitis-related arthritis

The safety and efficacy of Imraldi were assessed in a multicentre, randomised, double-blind study in 46 paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients were randomised to receive either 24 mg/m2 body surface area (BSA) of Imraldi up to a maximum of 40 mg, or placebo every other week for 12 weeks. The double-blind period is followed by an open-label (OL) period during which patients received 24 mg/m2 BSA of Imraldi up to a maximum of 40 mg every other week subcutaneously for up to an additional 192 weeks. The primary endpoint was the percent change from Baseline to Week 12 in the number of active joints with arthritis (swelling not due to deformity or joints with loss of motion plus pain and/or tenderness), which was achieved with mean percent decrease of -62.6% (median percent change -88.9%) in patients in the Imraldi group compared to -11.6% (median percent change -50.0%) in patients in the placebo group. Improvement in number of active joints with arthritis was maintained during the OL period through Week 156 for the 26 of 31 (84%) patients in the Imraldi group who remained in the study. Although not statistically significant, the majority of patients demonstrated clinical improvement in secondary endpoints such as number of sites of enthesitis, tender joint count (TJC), swollen joint count (SJC), Pediatric ACR 50 response, and Pediatric ACR 70 response.

Adults with rheumatoid arthritis

Imraldi was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. The efficacy and safety of Imraldi were assessed in five randomised, double-blind and well-controlled studies. Some patients were treated for up to 120 months duration.

RA study I evaluated 271 patients with moderately to severely active rheumatoid arthritis who were > 18 years old, had failed therapy with at least one disease-modifying, anti rheumatic drug and had insufficient efficacy with methotrexate at doses of 12.5 to 25 mg (10 mg if methotrexate-intolerant) every week and whose methotrexate dose remained constant at 10 to 25 mg every week. Doses of 20, 40 or 80 mg of Imraldi or placebo were given every other week for 24 weeks.

RA study II evaluated 544 patients with moderately to severely active rheumatoid arthritis who were > 18 years old and had failed therapy with at least one disease-modifying, anti-rheumatic drugs. Doses of 20 or 40 mg of Imraldi were given by subcutaneous injection every other week with placebo on alternative weeks or every week for 26 weeks; placebo was given every week for the same duration. No other disease-modifying anti-rheumatic drugs were allowed.

RA study III evaluated 619 patients with moderately to severely active rheumatoid arthritis who were > 18 years old, and who had an ineffective response to methotrexate at doses of 12.5 to 25 mg or have been intolerant to 10 mg of methotrexate every week. There were three groups in this study. The first received placebo injections every week for 52 weeks. The second received 20 mg of Imraldi every week for 52 weeks. The third group received 40 mg of Imraldi every other week with placebo injections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of Imraldi/MTX was administered every other week up to 10 years.

RA study IV primarily assessed safety in 636 patients with moderately to severely active rheumatoid arthritis who were > 18 years old. Patients were permitted to be either disease-modifying, anti-rheumatic drug-naïve or to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. These therapies include methotrexate, leflunomide, hydroxychloroquine, sulfasalazine and/or gold salts. Patients were randomised to 40 mg of Imraldi or placebo every other week for 24 weeks.

RA study V evaluated 799 methotrexate-naïve, adult patients with moderate to severely active early rheumatoid arthritis (mean disease duration less than 9 months). This study evaluated the efficacy of Imraldi 40 mg every other week/methotrexate combination therapy, Imraldi 40 mg every other week monotherapy and methotrexate monotherapy in reducing the signs and symptoms and rate of progression of joint damage in rheumatoid arthritis for 104 weeks. Upon completion of the first 104 weeks, 497 patients enrolled in an open-label extension phase in which 40 mg of Imraldi was administered every other week up to 10 years.

The primary end point in RA studies I, II and III and the secondary endpoint in RA study IV was the percent of patients who achieved an ACR 20 response at Week 24 or 26. The primary endpoint in RA study V was the percent of patients who achieved an ACR 50 response at Week 52. RA studies III and V had an additional primary endpoint at 52 weeks of retardation of disease progression (as detected by X-ray results). RA study III also had a primary endpoint of changes in quality of life.

ACR response

The percent of Imraldi-treated patients achieving ACR 20, 50 and 70 responses was consistent across RA studies I, II and III. The results for the 40 mg every other week dose are summarised in Table 9.

In RA studies I-IV, all individual components of the ACR response criteria (number of tender and swollen joints, physician and patient assessment of disease activity and pain, disability index (HAQ) scores and CRP (mg/dl) values) improved at 24 or 26 weeks compared to placebo. In RA study III, these improvements were maintained throughout 52 weeks.

In the open-label extension for RA study III, most patients who were ACR responders maintained response when followed for up to 10 years. Of 207 patients who were randomised to Imraldi 40 mg every other week, 114 patients continued on Imraldi 40 mg every other week for 5 years. Among those, 86 patients (75.4%) had ACR 20 responses; 72 patients (63.2%) had ACR 50 responses; and 41 patients (36%) had ACR 70 responses. Of 207 patients, 81 patients continued on Imraldi 40 mg every other week for 10 years. Among those, 64 patients (79.0%) had ACR 20 responses; 56 patients (69.1%) had ACR 50 responses; and 43 patients (53.1%) had ACR 70 responses.

In RA study IV, the ACR 20 response of patients treated with Imraldi plus standard of care was statistically significantly better than patients treated with placebo plus standard of care (p < 0.001).

In RA studies I-IV, Imraldi-treated patients achieved statistically significant ACR 20 and 50 responses compared to placebo as early as one to two weeks after initiation of treatment.

In RA study V with early rheumatoid arthritis patients who were methotrexate naïve, combination therapy with Imraldi and methotrexate led to faster and significantly greater ACR responses than methotrexate monotherapy and Imraldi monotherapy at Week 52 and responses were sustained at Week 104 (see Table 10).

In the open-label extension for RA study V, ACR response rates were maintained when followed for up to 10 years. Of 542 patients who were randomised to Imraldi 40 mg every other week, 170 patients continued on Imraldi 40 mg every other week for 10 years. Among those, 154 patients (90.6%) had ACR 20 responses; 127 patients (74.7%) had ACR 50 responses; and 102 patients (60.0%) had ACR 70 responses.

At Week 52, 42.9% of patients who received Imraldi/methotrexate combination therapy achieved clinical remission (DAS28 (CRP) < 2.6) compared to 20.6% of patients receiving methotrexate monotherapy and 23.4% of patients receiving Imraldi monotherapy. Imraldi/methotrexate combination therapy was clinically and statistically superior to methotrexate (p < 0.001) and Imraldi monotherapy (p < 0.001) in achieving a low disease state in patients with recently diagnosed moderate to severe rheumatoid arthritis. The response for the two monotherapy arms was similar (p = 0.447). Of 342 subjects originally randomized to Imraldi monotherapy or Imraldi/methotrexate combination therapy who entered the open-label extension study, 171 subjects completed 10 years of Imraldi treatment. Among those, 109 subjects (63.7%) were reported to be in remission at 10 years.

Radiographic response

In RA study III, where Imraldi treated patients had a mean duration of rheumatoid arthritis of approximately 11 years, structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (TSS) and its components, the erosion score and joint space narrowing score. Imraldi/methotrexate patients demonstrated significantly less radiographic progression than patients receiving methotrexate alone at 6 and 12 months (see Table 11).

In the open-label extension of RA Study III, the reduction in rate of progression of structural damage is maintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated with 40 mg Imraldi every other week were evaluated radiographically. Among those, 48 patients showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less. At 10 years, 79 of 207 patients originally treated with 40 mg Imraldi every other week were evaluated radiographically. Among those, 40 patients showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less.

amethotrexate

b95% confidence intervals for the differences in change scores between methotrexate and Imraldi.

cBased on rank analysis

dJoint Space Narrowing

In RA study V, structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (see Table 12).

Following 52 weeks and 104 weeks of treatment, the percentage of patients without progression (change from baseline in modified Total Sharp Score ≤ 0.5) was significantly higher with Imraldi/methotrexate combination therapy (63.8% and 61.2% respectively) compared to methotrexate monotherapy (37.4% and 33.5% respectively, p < 0.001) and Imraldi monotherapy (50.7%, p < 0.002 and 44.5%, p < 0.001 respectively).

In the open-label extension of RA study V, the mean change from baseline at Year 10 in the modified Total Sharp Score was 10.8, 9.2 and 3.9 in patients originally randomized to methotrexate monotherapy, Imraldi monotherapy and Imraldi/methotrexate combination therapy, respectively. The corresponding proportions of patients with no radiographic progression were 31.3%, 23.7% and 36.7% respectively.

Quality of life and physical function

Health-related quality of life and physical function were assessed using the disability index of the Health Assessment Questionnaire (HAQ) in the four original adequate and well-controlled trials, which was a pre-specified primary endpoint at Week 52 in RA study III. All doses/schedules of Imraldi in all four studies showed statistically significantly greater improvement in the disability index of the HAQ from baseline to Month 6 compared to placebo and in RA study III the same was seen at Week 52. Results from the Short Form Health Survey (SF 36) for all doses/schedules of Imraldi in all four studies support these findings, with statistically significant physical component summary (PCS) scores, as well as statistically significant pain and vitality domain scores for the 40 mg every other week dose. A statistically significant decrease in fatigue as measured by functional assessment of chronic illness therapy (FACIT) scores was seen in all three studies in which it was ass

Pharmacokinetic properties

Absorption and distribution

Following the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously every other week to patients with polyarticular juvenile idiopathic arthritis (JIA) who were 4 to 17 years the mean trough steady-state (values measured from Week 20 to 48) serum adalimumab concentration was 5.6 ± 5.6 µg/ml (102% CV) for adalimumab without concomitant methotrexate and 10.9 ± 5.2 µg/ml (47.7% CV) with concomitant methotrexate.

In patients with polyarticular JIA who were 2 to < 4 years old or aged 4 and above weighing < 15 kg dosed with adalimumab 24 mg/m2 , the mean trough steady-state serum adalimumab concentrations was 6.0 ± 6.1 µg/ml (101% CV) for adalimumab without concomitant methotrexate and 7.9 ± 5.6 µg/ml (71.2% CV) with concomitant methotrexate.

Following the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously every other week to patients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state (values measured at Week 24) serum adalimumab concentrations were 8.8 ± 6.6 μg/ml for adalimumab without concomitant methotrexate and 11.8 ± 4.3 μg/ml with concomitant methotrexate.

Following the administration of 0.8 mg/kg (up to a maximum of 40 mg) subcutaneously every other week to paediatric patients with chronic plaque psoriasis, the mean ± SD steady-state adalimumab trough concentration was approximately 7.4 ± 5.8 µg/ml (79% CV).

In paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was 160/80 mg or 80/40 mg at Weeks 0 and 2, respectively, dependent on a body weight cut-off of 40 kg. At Week 4, patients were randomised 1:1 to either the Standard Dose (40/20 mg eow) or Low Dose (20/10 mg eow) maintenance treatment groups based on their body weight. The mean (±SD) serum adalimumab trough concentrations achieved at Week 4 were 15.7 ± 6.6 μg/ml for patients > 40 kg (160/80 mg) and 10.6 ± 6.1 μg/ml for patients < 40 kg (80/40 mg).

For patients who stayed on their randomised therapy, the mean (±SD) adalimumab trough concentrations at Week 52 were 9.5 ± 5.6 μg/ml for the Standard Dose group and 3.5 ± 2.2 μg/ml for the Low Dose group. The mean trough concentrations were maintained in patients who continued to receive adalimumab treatment eow for 52 weeks. For patients who dose escalated from eow to weekly regimen, the mean (±SD) serum concentrations of adalimumab at Week 52 were 15.3 ± 11.4 μg/ml (40/20 mg, weekly) and 6.7 ± 3.5 μg/ml (20/10 mg, weekly).

Adalimumab exposure in paediatric uveitis patients was predicted using population pharmacokinetic modelling and simulation based on cross-indication pharmacokinetics in other paediatric patients (paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn's disease, and enthesitis-related arthritis). No clinical exposure data are available on the use of a loading dose in children < 6 years. The predicted exposures indicate that in the absence of methotrexate, a loading dose may lead to an initial increase in systemic exposure.

Exposure-response relationship in paediatric population

On the basis of clinical trial data in patients with JIA (pJIA and ERA), an exposure-response relationship was established between plasma concentrations and PedACR 50 response. The apparent adalimumab plasma concentration that produces half the maximum probability of PedACR 50 response (EC50) was 3 μg/ml (95% CI: 1-6 μg/ml).

Exposure-response relationships between adalimumab concentration and efficacy in paediatric patients with severe chronic plaque psoriasis were established for PASI 75 and PGA clear or minimal, respectively. PASI 75 and PGA clear or minimal increased with increasing adalimumab concentrations, both with a similar apparent EC50 of approximately 4.5 μg/mL (95% CI 0.4-47.6 and 1.9-10.5, respectively).

Adults

After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab was slow, with peak serum concentrations being reached about 5 days after administration. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg, concentrations were dose proportional. After doses of 0.5 mg/kg (~40 mg), clearances ranged from 11 to 15 ml/hour, the distribution volume (Vss) ranged from 5 to 6 litres and the mean terminal phase half-life was approximately two weeks. Adalimumab concentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31-96% of those in serum.

Following subcutaneous administration of 40 mg of adalimumab every other week in adult rheumatoid arthritis (RA) patients the mean steady-state trough concentrations were approximately 5 μg/ml (without concomitant methotrexate) and 8 to 9 μg/ml (with concomitant methotrexate), respectively. The serum adalimumab trough levels at steady-state increased roughly proportionally with dose following 20, 40 and 80 mg subcutaneous dosing every other week and every week.

In adult patients with psoriasis, the mean steady-state trough concentration was 5 μg/ml during adalimumab 40 mg every other week monotherapy treatment.

In patients with Crohn's disease, the loading dose of 80 mg Imraldi on Week 0 followed by 40 mg Imraldi on Week 2 achieves serum adalimumab trough concentrations of approximately 5.5 μg/ml during the induction period. A loading dose of 160 mg Imraldi on Week 0 followed by 80 mg Imraldi on Week 2 achieves serum adalimumab trough concentrations of approximately 12 μg/ml during the induction period. Mean steady-state trough levels of approximately 7 μg/ml were observed in Crohn's disease patients who received a maintenance dose of 40 mg Imraldi every other week.

In adult patients with uveitis, a loading dose of 80 mg adalimumab on Week 0 followed by 40 mg adalimumab every other week starting at Week 1, resulted in mean steady-state concentrations of approximately 8 to 10 μg/mL.

Population pharmacokinetic and pharmacokinetic/pharmacodynamic modelling and simulation predicted comparable adalimumab exposure and efficacy in patients treated with 80 mg every other week when compared with 40 mg every week (including adult patients with RA, HS, UC, CD or Ps, patients with adolescent HS, and paediatric patients > 40 kg with CD).

Elimination

Population pharmacokinetic analyses with data from over 1,300 RA patients revealed a trend toward higher apparent clearance of adalimumab with increasing body weight. After adjustment for weight differences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum levels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be lower in patients with measurable AAA.

Hepatic or renal impairment

Imraldi has not been studied in patients with hepatic or renal impairment.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Traceability

In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infections

Patients taking TNF -antagonists are more susceptible to serious infections. Impaired lung function may increase the risk for developing infections. Patients must therefore be monitored closely for infections, including tuberculosis, before, during and after treatment with Imraldi. Because the elimination of adalimumab may take up to four months, monitoring should be continued throughout this period.

Treatment with Imraldi should not be initiated in patients with active infections including chronic or localised infections until infections are controlled. In patients who have been exposed to tuberculosis and patients who have travelled in areas of high risk of tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis, the risk and benefits of treatment with Imraldi should be considered prior to initiating therapy (see Other opportunistic infections).

Patients who develop a new infection while undergoing treatment with Imraldi should be monitored closely and undergo a complete diagnostic evaluation. Administration of Imraldi should be discontinued if a patient develops a new serious infection or sepsis and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled. Physicians should exercise caution when considering the use of Imraldi in patients with a history of recurring infection or with underlying conditions which may predispose patients to infections, including the use of concomitant immunosuppressive medications.

Serious infections

Serious infections, including sepsis, due to bacterial, mycobacterial, invasive fungal, parasitic, viral, or other opportunistic infections such as listeriosis, legionellosis and pneumocystis have been reported in patients receiving Imraldi.

Other serious infections seen in clinical trials include pneumonia, pyelonephritis, septic arthritis and septicaemia. Hospitalisation or fatal outcomes associated with infections have been reported.

Tuberculosis

Tuberculosis, including reactivation and new onset of tuberculosis, has been reported in patients receiving Imraldi. Reports included cases of pulmonary and extra-pulmonary (i.e. disseminated) tuberculosis.

Before initiation of therapy with Imraldi, all patients must be evaluated for both active or inactive (“latent”) tuberculosis infection. This evaluation should include a detailed medical assessment of patient history of tuberculosis or possible previous exposure to people with active tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests (i.e. tuberculin skin test and chest X-ray) should be performed in all patients (local recommendations may apply). It is recommended that the conduct and results of these tests are recorded in the patient alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.

If active tuberculosis is diagnosed, Imraldi therapy must not be initiated.

In all situations described below, the benefit/risk balance of therapy should be very carefully considered.

If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be consulted.

If latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosis prophylaxis treatment before the initiation of Imraldi and in accordance with local recommendations.

Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of Imraldi in patients with several or significant risk factors for tuberculosis despite a negative test for tuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.

Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with Imraldi. Some patients who have been successfully treated for active tuberculosis have redeveloped tuberculosis while being treated with Imraldi.

Patients should be instructed to seek medical advice if signs/symptoms suggestive of a tuberculosis infection (e.g., persistent cough, wasting/weight loss, low grade fever, listlessness) occur during or after therapy with Imraldi.

Other opportunistic infections

Opportunistic infections, including invasive fungal infections have been observed in patients receiving Imraldi. These infections have not consistently been recognised in patients taking TNF-antagonists and this has resulted in delays in appropriate treatment, sometimes resulting in fatal outcomes.

For patients who develop the signs and symptoms such as fever, malaise, weight loss, sweats, cough, dyspnoea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant shock an invasive fungal infection should be suspected and administration of Imraldi should be promptly discontinued. Diagnosis and administration of empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the care of patients with invasive fungal infections.

Hepatitis B reactivation

Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including Imraldi, who are chronic carriers of this virus (i.e. surface antigen positive). Some cases have had a fatal outcome. Patients should be tested for HBV infection before initiating treatment with Imraldi. For patients who test positive for hepatitis B infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended.

Carriers of HBV who require treatment with Imraldi should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data from treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBV reactivation, Imraldi should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.

Neurological events

TNF-antagonists including Imraldi have been associated in rare instances with new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease including multiple sclerosis and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of Imraldi in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of Imraldi should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders. Neurologic evaluation should be performed in patients with non-infectious intermediate uveitis prior to the initiation of Imraldi therapy and regularly during treatment to assess for pre-existing or developing central demyelinating disorders.

Allergic reactions

Serious allergic reactions associated with Imraldi were rare during clinical trials. Non-serious allergic reactions associated with Imraldi were uncommon during clinical trials. Reports of serious allergic reactions including anaphylaxis have been received following Imraldi administration. If an anaphylactic reaction or other serious allergic reaction occurs, administration of Imraldi should be discontinued immediately and appropriate therapy initiated.

Immunosuppression

In a study of 64 patients with rheumatoid arthritis that were treated with Imraldi, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T-, B, - NK-cells, monocyte/macrophages, and neutrophils.

Malignancies and lymphoproliferative disorders

In the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies including lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare. In the post marketing setting, cases of leukaemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation. With the current knowledge, a possible risk for the development of lymphomas, leukaemia, and other malignancies in patients treated with a TNF-antagonist cannot be excluded.

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age), including adalimumab in the post marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.

Rare postmarketing cases of hepatosplenic T-cell lymphoma have been identified in patients treated with adalimumab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Some of these hepatosplenic T-cell lymphomas with Imraldi have occurred in young adult patients on concomitant treatment with azathioprine or 6-mercaptopurine used for inflammatory bowel disease. The potential risk with the combination of azathioprine or 6-mercaptopurine and Imraldi should be carefully considered. A risk for the development of hepatosplenic T-cell lymphoma in patients treated with Imraldi cannot be excluded.

No studies have been conducted that include patients with a history of malignancy or in whom treatment with Imraldi is continued following development of malignancy. Thus additional caution should be exercised in considering Imraldi treatment of these patients.

All patients, and in particular patients with a medical history of extensive immunosuppressant therapy or psoriasis patients with a history of PUVA treatment should be examined for the presence of non-melanoma skin cancer prior to and during treatment with Imraldi. Melanoma and Merkel cell carcinoma have also been reported in patients treated with TNF-antagonists including adalimumab.

In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung or head and neck, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist in COPD patients, as well as in patients with increased risk for malignancy due to heavy smoking.

With current data it is not known if adalimumab treatment influences the risk for developing dysplasia or colon cancer. All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations.

Haematologic reactions

Rare reports of pancytopenia including aplastic anaemia have been reported with TNF-antagonists. Adverse events of the haematologic system, including medically significant cytopenia (e.g. thrombocytopenia, leukopenia) have been reported with Imraldi. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor) while on Imraldi. Discontinuation of Imraldi therapy should be considered in patients with confirmed significant haematologic abnormalities.

Vaccinations

Similar antibody responses to the standard 23-valent pneumococcal vaccine and the influenza trivalent virus vaccination were observed in a study in 226 adult subjects with rheumatoid arthritis who were treated with adalimumab or placebo. No data are available on the secondary transmission of infection by live vaccines in patients receiving Imraldi.

It is recommended that paediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating Imraldi therapy.

Patients on Imraldi may receive concurrent vaccinations, except for live vaccines. Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for 5 months following the mother's last adalimumab injection during pregnancy.

Congestive heart failure

In a clinical trial with another TNF-antagonist worsening congestive heart failure and increased mortality due to congestive heart failure have been observed. Cases of worsening congestive heart failure have also been reported in patients receiving Imraldi. Imraldi should be used with caution in patients with mild heart failure (NYHA class I/II). Imraldi is contraindicated in moderate to severe heart failure. Treatment with Imraldi must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.

Autoimmune processes

Treatment with Imraldi may result in the formation of autoimmune antibodies. The impact of long-term treatment with Imraldi on the development of autoimmune diseases is unknown. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Imraldi and is positive for antibodies against double-stranded DNA, further treatment with Imraldi should not be given.

Concurrent administration of biologic DMARDS or TNF-antagonists

Serious infections were seen in clinical studies with concurrent use of anakinra and another TNF-antagonist, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse events seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNF-antagonists. Therefore, the combination of adalimumab and anakinra is not recommended..

Concomitant administration of adalimumab with other biologic DMARDS (e.g, anakinra and abatacept) or other TNF-antagonists is not recommended based upon the possible increased risk for infections, including serious infections and other potential pharmacological interactions..

Surgery

There is limited safety experience of surgical procedures in patients treated with Imraldi. The long half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Imraldi should be closely monitored for infections, and appropriate actions should be taken. There is limited safety experience in patients undergoing arthroplasty while receiving Imraldi.

Small bowel obstruction

Failure to respond to treatment for Crohn's disease may indicate the presence of fixed fibrotic stricture that may require surgical treatment. Available data suggest that Imraldi does not worsen or cause strictures.

Elderly

The frequency of serious infections among Imraldi treated subjects over 65 years of age (3.7%) was higher than for those under 65 years of age (1.5%). Some of those had a fatal outcome. Particular attention regarding the risk for infection should be paid when treating the elderly.

Paediatric population

See Vaccinations above.

Effects on ability to drive and use machines

Imraldi may have a minor influence on the ability to drive and use machines. Vertigo and visual impairment may occur following administration of Imraldi.

Dosage (Posology) and method of administration

Imraldi treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which Imraldi is indicated. Ophthalmologists are advised to consult with an appropriate specialist before initiation of treatment with Imraldi. Patients treated with Imraldi should be given the special alert card.

After proper training in injection technique, patients may self-inject with Imraldi if their physician determines that it is appropriate and with medical follow-up as necessary.

During treatment with Imraldi, other concomitant therapies (e.g., corticosteroids and/or immunomodulatory agents) should be optimised.

Posology

Paediatric population

Juvenile idiopathic arthritis

Polyarticular juvenile idiopathic arthritis from 2 years of age

The recommended dose of Imraldi for patients with polyarticular juvenile idiopathic arthritis from 2 years of age is based on body weight (Table 1). Imraldi is administered every other week via subcutaneous injection.

Table 1. Imraldi Dose for Patients with Polyarticular Juvenile Idiopathic Arthrtis

Available data suggest that clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.

There is no relevant use of Imraldi in patients aged less than 2 years for this indication.

Imraldi may be available in other strengths and/or presentations depending on the individual treatment needs.

Enthesitis-related arthritis

The recommended dose of Imraldi for patients with enthesitis-related arthritis from 6 years of age is based on body weight (Table 2). Imraldi is administered every other week via subcutaneous injection.

Table 2. Imraldi Dose for Patients with Enthesitis-Related Arthritis

Imraldi has not been studied in patients with enthesitis-related arthritis aged less than 6 years.

Imraldi may be available in other strengths and/or presentations depending on the individual treatment needs.

Paediatric plaque psoriasis

The recommended Imraldi dose for patients with plaque psoriasis from 4 to 17 years of age is based on body weight (Table 3). Imraldi is administered via subcutaneous injection.

Table 3. Imraldi Dose for Paediatric Patients with Plaque Psoriasis

Continued therapy beyond 16 weeks should be carefully considered in a patient not responding within this time period.

If retreatment with Imraldi is indicated, the above guidance on dose and treatment duration should be followed.

The safety of Imraldi in paediatric patients with plaque psoriasis has been assessed for a mean of 13 months.

There is no relevant use of Imraldi in children aged less than 4 years for this indication.

Imraldi may be available in other strengths and/or presentations depending on the individual treatment needs.

Paediatric Crohn's disease

The recommended dose of Imraldi for patients with Crohn's disease from 6 to 17 years of age is based on body weight (Table 4). Imraldi is administered via subcutaneous injection.

Table 4. Imraldi Dose for Paediatric Patients with Crohn's disease

Patients who experience insufficient response may benefit from an increase in dosage:

- < 40 kg: 20 mg every week

- > 40 kg: 40 mg every week or 80 mg every other week

Continued therapy should be carefully considered in a subject not responding by week 12.

There is no relevant use of Imraldi in children aged less than 6 years for this indication.

Imraldi may be available in other strengths and/or presentations depending on the individual treatment needs.

Paediatric Uveitis

The recommended dose of Imraldi for paediatric patients with uveitis from 2 years of age is based on body weight (Table 5). Imraldi is administered via subcutaneous injection.

In paediatric uveitis, there is no experience in the treatment with Imraldi without concomitant treatment with methotrexate.

Table 5. Imraldi Dose for Paediatric Patients with Uveitis

When Imraldi therapy is initiated, a loading dose of 40 mg for patients < 30 kg or 80 mg for patients > 30 kg may be administered one week prior to the start of maintenance therapy. No clinical data are available on the use of a Imraldi loading dose in children < 6 years of age.

There is no relevant use of Imraldi in children aged less than 2 years in this indication.

It is recommended that the benefit and risk of continued long-term treatment should be evaluated on a yearly basis.

Imraldi may be available in other strengths and/or presentations depending on the individual treatment needs.

Renal and/or hepatic impairment

Imraldi has not been studied in these patient populations. No dose recommendations can be made.

Method of administration

Imraldi is administered by subcutaneous injection. Full instructions for use are provided in the package leaflet.

Imraldi is available in other strengths and presentations.

Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.