Imraldi 40mg solution for injection in pre-filled pen

SmPC – Section 4.8

In post-marketing experience from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis, the spontaneously reported rate of malignancies is approximately 2.7 per 1,000 patient treatment years. The spontaneously reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 0.3 per 1,000 patient treatment years, respectively (see section 4.4).

Update to section 6. Contents of the pack and other information

 Imraldi 40 mg solution for injection in pre-filled syringe is supplied as a 0.8 ml clear to opalescent and colourless to pale brown solution.

Update to section 7. Instructions for use

(update of graphic for Inspect medicine & expiry date)

Always make sure your medicine is clear to opalescent, colourless to pale brown, free of particles, and has not expired. If your medication is not clear to opalescent, colourless to pale brown, free of particles, or expired, do not use it.

Change to Section 3. Pharmaceutical Form

Clear to opalescent, colourless to pale brown solution

Document format update

Change to Section 6.3 Shelf Life:

2 years 30 months

New product formulation that is citrate-free and in a lower volume.

New product formulation that is citrate-free and in a lower volume.

The period of time that patients should keep the Patient Reminder card on them at all times and inform their doctor of any problems has changed to 4 months after the last injection with Imraldi.

Black triangle has been removed and minor editorial changes in PL are mostly of editorial nature to align with the adalimumab reference product.

Minor editorial changes in SPC are mostly of editorial nature to align with the adalimumab reference product.

1.       What Imraldi is and what it is used for

…

Ulcerative colitis in adults and children

Ulcerative colitis is an inflammatory disease of the bowel large intestine.

Imraldi is used to treat moderate to severe ulcerative colitis in adults and children aged 6 to 17 years. If you have ulcerative colitis you will may first be given other medicines. If these medicines do not work well enough, you will be given Imraldi to reduce the signs and symptoms of your disease.

3.       How to use Imraldi

…

Adults with ulcerative colitis

The usual Imraldi dose for adults with ulcerative colitis is 160 mg initially (as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days) followed by 80 mg (as two 40 mg injections in one day) two weeks later and thereafter 40 mg every other week. If this dose does not work well enough, your

doctor may increase the dose to 40 mg every week or 80 mg every other week.

Children and adolescents with ulcerative colitis

Children and adolescents from 6 years of age weighing less than 40 kg

The usual Imraldi dose is 80 mg (as two 40 mg injections in one day) initially

followed by 40 mg (as one 40 mg injection) two weeks later. Thereafter, the usual dose is 40 mg every other week.

Patients who turn 18 years of age while on 40 mg every other week, should continue their prescribed dose.

Children and adolescents from 6 years of age weighing 40 kg or more

The usual Imraldi dose is 160 mg (as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days) initially, followed by 80 mg (as two

40 mg injections in one day) two weeks later. Thereafter the usual dose is 80 mg every other week.

Patients who turn 18 years of age while on 80 mg every other week, should continue their prescribed dose.

Section 4.1

Paediatric ulcerative colitis

Imraldi is indicated for the treatment of moderately to severely active ulcerative colitis in paediatric patients (from 6 years of age) who have had an inadequate response to conventional therapy including corticosteroids and/or 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.

Section 4.2  

The safety and efficacy of adalimumab in children aged 4-17 years have not yet been established. No data are available. There is no relevant use of Imraldi in children aged less than 4 years for this indication.

The recommended dose of Imraldi for patients from 6 to 17 years of age with ulcerative colitis is based on body weight (Table 5). Imraldi is administered via subcutaneous injection.

Table 5 Imraldi Dose for Paediatric Patients with Ulcerative Colitis

* Paediatric patients who turn 18 years of age while on Imraldi should continue their prescribed maintenance dose.

Continued therapy beyond 8 weeks should be carefully considered in patients not showing signs of response within this time period.

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

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

Section 4.8:

Malignancies and lymphoproliferative disorders

No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years during adalimumab 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 adalimumab 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 an adalimumab trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 93 paediatric patients with an exposure of 65.3 patient years during an adalimumab trial in paediatric patients with ulcerative colitis. No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during an adalimumab trial in paediatric patients with uveitis.

.......

In the controlled Phase 3 trial of adalimumab in patients with paediatric ulcerative colitis (N=93) which evaluated efficacy and safety of a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week (N=31) and a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every Week (N=32), following body weight adjusted induction dosing of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=63), or an induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0, placebo at Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=30), ALT elevations ≥ 3 X ULN occurred in 1.1% (1/93) of patients.

Section 5.1:

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of the studies with the reference medicinal product containing adalimumab in one or more subsets of the paediatric population in ulcerative colitis, see section 4.2 for information on paediatric use.

Sections on Juvenile idiopathic arthritis (JIA), Enthesitis-related arthritis, Paediatric plaque psoriasis, Adolescent hidradenitis suppurativa, Paediatric Crohn’s disease and Paediatric Uveitis have been deleted and the following text has been added:

Juvenile idiopathic arthritis (JIA)

Polyarticular juvenile idiopathic arthritis (pJIA)

The safety and efficacy of adalimumab 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 adalimumab 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 non-steroidal anti-inflammatory drugs (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 adalimumab 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 25.

Table 25

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

Patients demonstrating a Paediatric ACR 30 response at week 16 were eligible to be randomised into the double blind (DB) phase and received either adalimumab 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 Paediatric 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 26

Paed 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 Paediatric ACR 30/50/70/90 responses were maintained for up to six years in the OLE phase in patients who received adalimumab 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 adalimumab and MTX compared to adalimumab alone. Taking these results into consideration, adalimumab is recommended for use in combination with MTX and for use as monotherapy in patients for whom MTX use is not appropriate (see section 4.2).

pJIA II

The safety and efficacy of adalimumab 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 adalimumab 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, PaedACR30 response was 93.5% and 90.0%, respectively, using the observed data approach. The proportions of subjects with PaedACR50/70/90 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 (Paediatric ACR 30) at week 24 (n=27 out of 30 patients), the Paediatric ACR 30 responses were maintained for up to 60 weeks in the OLE phase in patients who received adalimumab throughout this time period. Overall, 20 subjects were treated for 60 weeks or longer.

Enthesitis-related arthritis

The safety and efficacy of adalimumab 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 adalimumab 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 adalimumab 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 adalimumab 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 adalimumab 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), Paediatric ACR 50 response, and Paediatric ACR 70 response.

Paediatric plaque psoriasis

The efficacy of adalimumab was assessed in a randomised, double-blind, controlled study of 114 paediatric patients from 4 years of age with severe chronic plaque psoriasis (as defined by a PGA ≥4 or >20% BSA involvement or >10 % BSA involvement with very thick lesions or PASI ≥20 or ≥10 with clinically relevant facial, genital, or hand/ foot involvement) who were inadequately controlled with topical therapy and heliotherapy or phototherapy.

Patients received adalimumab 0.8 mg/kg eow (up to 40 mg), 0.4 mg/kg eow (up to 20 mg), or methotrexate 0.1 – 0.4 mg/kg weekly (up to 25 mg). At Week 16, more patients randomised to adalimumab 0.8 mg/kg had positive efficacy responses (e.g., PASI 75) than those randomised to 0.4 mg/kg eow or MTX.

Table 27

Paediatric Plaque Psoriasis Efficacy Results at 16 Weeks

^a MTX = methotrexate

^b P=0.027, adalimumab 0.8 mg/kg versus MTX

^c P=0.083, adalimumab 0.8 mg/kg versus MTX

Patients who achieved PASI 75 and PGA clear or minimal were withdrawn from treatment for up to 36 weeks and monitored for loss of disease control (i.e. a worsening of PGA by at least 2 grades). Patients were then re-treated with adalimumab 0.8 mg/kg eow for an additional 16 weeks and response rates observed during retreatment were similar to the previous double-blind period: PASI 75 response of 78.9 % (15 of 19 subjects) and PGA clear or minimal of 52.6 % (10 of 19 subjects).

In the open label period of the study, PASI 75 and PGA clear or minimal responses were maintained for up to an additional 52 weeks with no new safety findings.

Adolescent hidradenitis suppurativa

There are no clinical trials with adalimumab in adolescent patients with HS. Efficacy of adalimumab for the treatment of adolescent patients with HS is predicted based on the demonstrated efficacy and exposure-response relationship in adult HS patients and the likelihood that the disease course, pathophysiology, and drug effects are substantially similar to that of adults at the same exposure levels. Safety of the recommended adalimumab dose in the adolescent HS population is based on cross-indication safety profile of adalimumab in both adults and paediatric patients at similar or more frequent doses (see section 5.2).

Paediatric Crohn’s disease

Adalimumab was assessed in a multicentre, randomised, double-blind clinical trial designed to evaluate the efficacy and safety of induction and maintenance treatment with doses dependent on body weight (<40 kg or ≥40 kg) in 192 paediatric subjects between the ages of 6 and 17 (inclusive) years, with moderate to severe Crohn´s disease (CD) defined as Paediatric Crohn's Disease Activity Index (PCDAI) score >30. Subjects had to have failed conventional therapy (including a corticosteroid and/or an immunomodulator) for CD. Subjects may also have previously lost response or been intolerant to infliximab.

All subjects received open-label induction therapy at a dose based on their Baseline body weight: 160 mg at week 0 and 80 mg at week 2 for subjects ≥40 kg, and 80 mg and 40 mg, respectively, for subjects <40 kg.

At week 4, subjects were randomised 1:1 based on their body weight at the time to either the Low Dose or Standard Dose maintenance regimens as shown in Table 28.

Table 28

Maintenance regimen 

Efficacy results

The primary endpoint of the study was clinical remission at week 26, defined as PCDAI score ≤10.

Clinical remission and clinical response (defined as reduction in PCDAI score of at least 15 points from Baseline) rates are presented in Table 29. Rates of discontinuation of corticosteroids or immunomodulators are presented in Table 30.

Table 29

Paediatric CD Study

PCDAI Clinical Remission and Response 

* p value for Standard Dose versus Low Dose comparison 

Table 30

Paediatric CD Study

Discontinuation of Corticosteroids or Immunomodulators and Fistula Remission 

¹ p value for Standard Dose versus Low Dose comparison

² Immunosuppressant therapy could only be discontinued at or after week 26 at the investigator's discretion if the subject met the clinical response criterion

³ Defined as a closure of all fistulas that were draining at Baseline for at least 2 consecutive post-Baseline visits

Statistically significant increases (improvement) from Baseline to week 26 and 52 in Body Mass Index and height velocity were observed for both treatment groups.

Statistically and clinically significant improvements from Baseline were also observed in both treatment groups for quality of life parameters (including IMPACT III).

One hundred patients (n=100) from the Paediatric CD study continued in an open-label long-term extension study. After 5 years of adalimumab therapy, 74.0 % (37/50) of the 50 patients remaining in the study continued to be in clinical remission, and 92.0 % (46/50) of patients continued to be in clinical response per PCDAI.

Paediatric ulcerative colitis

The safety and efficacy of adalimumab was assessed in a multicenter, randomized, double-blind, trial in 93 paediatric patients from 5 to 17 years of age with moderate to severe ulcerative colitis (Mayo score 6 to 12 with endoscopy subscore of 2 to 3 points, confirmed by centrally read endoscopy) who had an inadequate response or intolerance to conventional therapy. Approximately 16% of patients in the study had failed prior anti-TNF treatment. Patients who received corticosteroids at enrollment were allowed to taper their corticosteroid therapy after Week 4.

In the induction period of the study, 77 patients were randomized 3:2 to receive double-blind treatment with adalimumab at an induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2; or an induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0, placebo at Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2. Both groups received 0.6 mg/kg (maximum of 40 mg) at Week 4 and Week 6. Following an amendment to the study design, the remaining 16 patients who enrolled in the induction period received open-label treatment with adalimumab at the induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2.

At Week 8, 62 patients who demonstrated clinical response per Partial Mayo Score (PMS; defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) were randomized equally to receive double-blind maintenance treatment with adalimumab at a dose of 0.6 mg/kg (maximum of 40 mg) every week (ew), or a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week (eow). Prior to an amendment to the study design, 12 additional patients who demonstrated clinical response per PMS were randomized to receive placebo but were not included in the confirmatory analysis of efficacy.

Disease flare was defined as an increase in PMS of at least 3 points (for patients with PMS of 0 to 2 at Week 8), at least 2 points (for patients with PMS of 3 to 4 at Week 8), or at least 1 point (for patients with PMS of 5 to 6 at Week 8).

Patients who met criteria for disease flare at or after Week 12 were randomized to receive a re-induction dose of 2.4 mg/kg (maximum of 160 mg) or a dose of 0.6 mg/kg (maximum of 40 mg) and continued to receive their respective maintenance dose regimen afterwards.

Efficacy Results

The co-primary endpoints of the study were clinical remission per PMS (defined as PMS ≤ 2 and no individual subscore > 1) at Week 8, and clinical remission per FMS (Full Mayo Score) (defined as a Mayo Score ≤ 2 and no individual subscore > 1) at Week 52 in patients who achieved clinical response per PMS at Week 8. Clinical remission rates per PMS at Week 8 for patients in each of the adalimumab doubleblind induction groups are presented in Table 31.

Table 31

Clinical Remission per PMS at 8 Weeks 

At Week 52, clinical remission per FMS in Week 8 responders, clinical response per FMS (defined as a decrease in Mayo Score ≥ 3 points and ≥ 30% from Baseline) in Week 8 responders, mucosal healing (defined as Mayo endoscopy subscore ≤ 1) in Week 8 responders, clinical remission per FMS in Week 8 remitters, and the proportion of subjects in corticosteroid-free remission per FMS in Week 8 responders were assessed in patients who received adalimumab at the double-blind maximum 40 mg eow (0.6 mg/kg) and maximum 40 mg ew (0.6 mg/kg) maintenance doses (Table 32). 

Table 32

Efficacy Results at 52 Weeks

Additional exploratory efficacy endpoints included clinical response per the Paediatric Ulcerative Colitis Activity Index (PUCAI) (defined as a decrease in PUCAI ≥ 20 points from Baseline) and clinical remission per PUCAI (defined as PUCAI < 10) at Week 8 and Week 52 (Table 33).

Table 33

Exploratory Endpoints Results per PUCAI

Of the adalimumab-treated patients who received re-induction treatment during the maintenance period, 2/6 (33%) achieved clinical response per FMS at Week 52.

Quality of life

Clinically meaningful improvements from Baseline were observed in IMPACT III and the caregiver Work Productivity and Activity Impairment (WPAI) scores for the groups treated with adalimumab. Clinically meaningful increases (improvement) from Baseline in height velocity were observed for the groups treated with adalimumab, and clinically meaningful increases (improvement) from Baseline in Body Mass Index were observed for subjects on the high maintenance dose of maximum 40 mg (0.6 mg/kg) ew.

Paediatric Uveitis

The safety and efficacy of adalimumab was assessed in a randomized, double-masked, controlled study of 90 paediatric patients from 2 to < 18 years of age with active JIA-associated noninfectious anterior uveitis who were refractory to at least 12 weeks of methotrexate treatment. Patients received either placebo or 20 mg adalimumab (if < 30 kg) or 40 mg adalimumab (if ≥ 30 kg) every other week in combination with their baseline dose of methotrexate.

The primary endpoint was ‘time to treatment failure’. The criteria determining treatment failure were worsening or sustained non-improvement in ocular inflammation, partial improvement with development of sustained ocular co-morbidities or worsening of ocular co-morbidities, non-permitted use of concomitant medications, and suspension of treatment for an extended period of time.

Clinical Response

Adalimumab significantly delayed the time to treatment failure, as compared to placebo (See Figure 3, P < 0.0001 from log rank test). The median time to treatment failure was 24.1 weeks for subjects treated with placebo, whereas the median time to treatment failure was not estimable for subjects treated with adalimumab because less than one-half of these subjects experienced treatment failure. Adalimumab significantly decreased the risk of treatment failure by 75 % relative to placebo, as shown by the hazard ratio (HR = 0.25 [95 % CI: 0.12, 0.49]).

Figure 3: Kaplan-Meier Curves Summarizing Time to Treatment Failure in the Paediatric Uveitis Study has also been added- please see SPC for image.

Section 6.5:

Imraldi 40 mg solution for injection in pre-filled syringe

0.8 ml solution for injection in single-use pre-filled syringe (type I glass) with a stainless steel needle, a rigid needle shield, a rubber plunger (bromobutyl chlorobutyl), a plunger rod, a safe-shield body and a finger flange for patient use.

Packs of:

• 1 pre-filled syringe, with 2 alcohol pads
• 2 pre-filled syringes, each with 1 alcohol pad
• 4 pre-filled syringes, each with 1 alcohol pad
• 6 pre-filled syringes, each with 1 alcohol pad
   Imraldi 40 mg solution for injection in pre-filled pen
   
  0.8 ml solution for injection in single-use pre-filled pen for patient use containing a pre-filled syringe. The syringe inside the pen is made from type I glass with a stainless steel needle, a rigid needle shield, a rubber plunger (bromobutyl chlorobutyl).
   

• Name of manufacturer responsible for batch release changed from Biogen (Denmark) Manufacturing ApS to FUJIFILM Diosynth Biotechnologies Denmark ApS

Section 6.3 has been updated as shelf life has been extended from 36 to 42 months.

The following text has been added to the 'Not Known' section of 'Possible Side Effects':

weight gain (for most patients, the weight gain was small).

Section 4.8 Undesirable effects has been updated to add : “Weight increased²⁾” with frequency Not known added.

²⁾ The mean weight change from baseline for  adalimumab ranged from 0.3 kg to 1.0 kg across adult indications compared to (minus) -0.4 kg to 0.4 kg for placebo over a treatment period of 4-6 months. Weight increase of 5-6 kg has also been observed in long-term extension studies with mean exposures of approximately 1-2 years without control group, particularly in patients with Crohn’s disease and ulcerative colitis. The mechanism behind this effect is unclear but could be associated with the anti-inflammatory effect of adalimumab.

The following information was added to section 3:

Paediatric population

Section 6 was updated as follows:

Name and address of the manufacturer(s) responsible for batch release

 Biogen (Denmark) Manufacturing ApS

Biogen Allé 1

3400 Hillerød

Denmark

 Samsung Bioepis NL B.V.

Olof Palmestraat 10

2616 LR Delft

The Netherlands

Section 7 was updated as follows:

You may see 1 or more bubbles, and that is okay

The following changes have been made:

Section 4.1, 4.2 and 5.1: Update of Imraldi PI to align with originator re wording for NSAIDs:

…non-steroidal anti-inflammatory drugs (NSAIDs)

…non-steroidal anti-inflammatory drugs (NSAIDs)

Section 4.2- the following text has been added:

Paediatric population

Section 4 has been updated to include the following:

• Kaposi’s sarcoma, a rare cancer related to infection with human herpes virus 8. Kaposi’s sarcoma most commonly appears as purple lesions on the skin.

Section 4.8 has been updated to include Kaposi’s sarcoma as an undesirable effect.

Changes to section 4.4 and section 4.6 were of a formatting nature only.

Changes to section 5.1 were as follows:

…..Uvetis

The following paragraph was added:

'Patients who completed Studies UV I and UV II were eligible to enroll in an uncontrolled long-term extension study with an originally planned duration of 78 weeks. Patients were allowed to continue on study medication beyond Week 78 until they had access to adalimumab.'...

the following paragraph has been updated from:

Of the 417 subjects included in the uncontrolled long-term extension of studies UV I and UV II, 46 subjects were regarded ineligible (e.g. developed complications secondary to diabetic retinopathy, due to cataract surgery or vitrectomy) and were excluded from the primary analysis of efficacy. Of the 371 remaining patients, 276 evaluable patients reached 78 weeks of open-label adalimumab treatment. Based on the observed data approach, 222 (80.4​​%) were in quiescence (no active inflammatory lesions, AC cell grade ≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose ≤ 7.5 mg per day, and 184 (66.7​​%) were in steroid-free quiescence. BCVA was either improved or maintained (< 5 letters deterioration) in 88.4​​% of the eyes at week 78. Among the patients who discontinued the study prior to week 78, 11% discontinued due to adverse events, and 5​​% due to insufficient response to adalimumab treatment.

to:

Of the 424 subjects included in the uncontrolled long-term extension of studies UV I and UV II, 60 subjects were regarded ineligible (e.g. due to deviations or due to complications secondary to diabetic retinopathy, due to cataract surgery or vitrectomy) and were excluded from the primary analysis of efficacy. Of the 364 remaining patients, 269 evaluable patients (74%) reached 78 weeks of open-label adalimumab treatment. Based on the observed data approach, 216 (80.3%) were in quiescence (no active inflammatory lesions, AC cell grade ≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose ≤ 7.5 mg per day, and 178 (66.2%) were in steroid-free quiescence. BCVA was either improved or maintained (< 5 letters deterioration) in 88.6​​% of the eyes at week 78. Data beyond Week 78 were generally consistent with these results but the number of enrolled subjects declined after this time. Overall, among the patients who discontinued the study, 18% discontinued due to adverse events, and 8​​% due to insufficient response to adalimumab treatment.

Reference to Imraldi being only available as a 40mg pre filled syringe and pre filled pen has been deleted, as Imraldi is now available in a 40mg/0.8ml vial presentation and can be administered as a less than full 40mg dose. 

Also, section 1 has been updated as follows:

• non-infectious uveitis affecting the back of the eye.

Reference to Imraldi being only available as a 40mg pre filled syringe and pre filled pen has been deleted, as Imraldi is now available in a 40mg/0.8ml vial presentation and can be administered as a less than full 40mg dose. 

Also, section 1 has been updated as follows:

• non-infectious uveitis affecting the back of the eye.

Section 4.2 of the SPC has been updated. Reference to Imraldi being only available as a 40mg pre filled syringe and pre filled pen has been deleted, as Imraldi is now available in a 40mg/0.8ml vial presentation and can be administered as a less than full 40mg dose.  

Section 4.2: The Patient Alert card has been renamed as 'Patient Reminder Card'

Section 4.4:The Patient Alert card has been renamed as 'Patient Reminder Card'

The previous version of this SPC uploaded was not a consolidated version, and did not include the approved updates of the paed. uveitis indication. This version corrects the error.

Section 6.4 - the storage conditions at room temperature (25C) have been extended from a maximum of 14 to a maximum of 28 days.

- Section 4.1 has been updated to include the following text:

Paediatric Uveiti

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.

 - Section 4.2 been updated to include the following text:

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 adalimumab without concomitant treatment with methotrexate.

Table 5 Imraldi Dose for Paediatric Patients with Uveitis

- Not applicable, Imraldi is only available as 40 mg pre-filled syringe and pre-filled pen

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 an adalimumab loading dose in children < 6 years of age (see section 5.2).

 There is no relevant use of adalimumab 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 (see section 5.1).

 - Section 4.8 been updated to include the following text:

No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during an adalimumab trial in paediatric patients with uveitis.

  - Section 5.1 been updated to include the following text:

Paediatric Uveitis

 The safety and efficacy of adalimumab was assessed in a randomized, double-masked, controlled study of 90 paediatric patients from 2 to < 18 years of age with active JIA-associated noninfectious anterior uveitis who were refractory to at least 12 weeks of methotrexate treatment. Patients received either placebo or 20 mg adalimumab (if < 30 kg) or 40 mg adalimumab (if ≥ 30 kg) every other week in combination with their baseline dose of methotrexate.

 The primary endpoint was ‘time to treatment failure’. The criteria determining treatment failure were worsening or sustained non-improvement in ocular inflammation, partial improvement with development of sustained ocular co-morbidities or worsening of ocular co-morbidities, non-permitted use of concomitant medications, and suspension of treatment for an extended period of time.

 Clinical Response

 Adalimumab significantly delayed the time to treatment failure, as compared to placebo (See Figure 3, P < 0.0001 from log rank test). The median time to treatment failure was 24.1 weeks for subjects treated with placebo, whereas the median time to treatment failure was not estimable for subjects treated with adalimumab because less than one-half of these subjects experienced treatment failure. Adalimumab significantly decreased the risk of treatment failure by 75 % relative to placebo, as shown by the hazard ratio (HR = 0.25 [95 % CI:  0.12, 0.49]).

  -Section 5.2 been updated to include the following text:

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.

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