Update to the following paragraph. Please see changes in bold.

"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)."

Section 4.8 – Undesirable effects

• “Weight increased” is now listed in Table 7, under Investigations (Frequency: Not known). 
  
  The following corresponding information has been included in the footnotes:
  
  “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.”

Section 10 – Date of Revision of the Text

• Amended to “04/2021”

Section 5.1

Sub-section Paediatric Uveitis, Efficay Results

The statement:

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 per FMS (defined as an Mayo endoscopy score ≤ 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 Humira 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).

amended to:

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 Humira 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).

Section 4.1

The following indication has ben added:

Paediatric ulcerative colitis

Humira 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

Dosing information updated to reflect Paediatric ulcerative colitis indication

Section 4.8

The following statement has been added under "Malignancies and lymphoproliferative disorders":

"No malignancies were observed in 93 paediatric patients with an exposure of 65.3 patient years during a Humira trial in paediatric patients with ulcerative colitis. "

The following statement has been added under "Hepato-biliary events":

"In the controlled Phase 3 trial of Humira 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

The following statement has been added:

"In patients with moderately to severely active paediatric ulcerative colitis, the rate of anti-adalimumab antibody development in patients receiving adalimumab was 3%."

Information on safety and efficay  from multicenter, randomized, double-blind clinical trial included.

Section 5.2

The following information has been added:

Following the subcutaneous administration of body weight-based dosing of 0.6 mg/kg (maximum of 40 mg) every other week to paediatric patients with ulcerative colitis, the mean trough steady-state serum adalimumab concentration was 5.01±3.28 µg/ml at Week 52. For patients who received 0.6 mg/kg (maximum of 40 mg) every week, the mean (±SD) trough steady-state serum adalimumab concentration was 15.7±5.60 μg/ml at Week 52.

Section 10.0

Date of revision:  11/2020

Section 4.8 – Undesirable effects

• Addition of Kaposi’s sarcoma (frequency: not known) to Table 6

Section 10 – Date of Revision of the Text

• Amended to 08/2020

• Section 4.1 Therapeutic indications
  Editorial change
  
  Humira is indicated for the treatment of adults with severe axial spondyloarthritis without radiographic evidence of AS but with objective signs of inflammation by elevated CRP and / or MRI, who have had an inadequate response to, or are intolerant to nonsteroidal anti-inflammatory drugs.
  
  amended to: 
  
  Humira is indicated for the treatment of adults with severe axial spondyloarthritis without radiographic evidence of AS but with objective signs of inflammation by elevated CRP and / or MRI, who have had an inadequate response to, or are intolerant to non-steroidal anti-inflammatory drugs (NSAIDs).

• Section 10. Date of Revision of Text
  Amended to 11/2019

Change to HPRA contact details

The following updates have been made to section 5.1 of the SmPC:

• Additional text describing enrolment into long term extension study

 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 Humira.

• Revision of study summary
  • Revision of subject numbers
  • Explanation that the number of enrolled subjects declined but data at later timepoints generally consistent with week 78
  • Updated overall numbers for discontinuations based on full duration of study

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.

• Section 4.2 and section 4.4: “Patient Alert Card” changed to “Patient Reminder Card”.

Summary of Changes

Section  4.8

• Revised to include “lichenoid skin reaction” as a rare event under Skin and subcutaneous tissue disorders

Section 10

• Date of Revision of Text updated to 26 July 2018

Update to Section 4.6 - Fertility, pregnancy and lactation

Summary of changes
 

• Section 4.2, Posology and method of administration
  • An 80mg every week (eow) dosing option has been included as an alternative to the current approved 40 mg weekly dose in the following relevant  indications:
    Rheumatoid arthritis
    Crohns disease
    Paedatric Crohns disease (patients  ≥ 40 kg)
    Psoraisis
    Ulcerative colitis
    Hidradenitis suppurativa
    Adolescent hidradenitis suppurativa
     
• Section 5.1, Pharmacodynamic properties
  • The following information added in relation to non-radiographic axial spondyloarthritis (nr-axSpA):
    
    The safety and efficacy of Humira were assessed in two randomized, double-blind placebo controlled studies in patients with non-radiographic axial spondyloarthritis (nr-axSpA). Study nr-axSpA I evaluated patients with active nr-axSpA. Study nr-axSpA II was a treatment withdrawal study in nr-axSpA patients who achieved remission during open-label treatment with Humira.
    
    SmPC now lists data in relation to  Study nr-axSpA II
    
     

• Section 5.2, Pharmacokinetic properties
  • The following text has been added in relation to 80mg every other week :
    
    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).
     
  • The following information has been added in relation to non-radiographic axial spondyloarthritis patients:
    
    Following subcutaneous administration of 40 mg of adalimumab every other week in adult non-radiographic axial spondyloarthritis patients, the mean (±SD) trough steady-state concentration at Week 68 was 8.0 ± 4.6 mg/ml.
    
     

• Section 10, Date of Revision of the Text
  • Updated to 23 April 2018
• Minor editoral and formatting changes made through out document

Section 5.1

Subsection – Adult Uveitis

The following information has been added:

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.

Summary of Changes

Section 4.1      Therapeutic indications

The following indication has been added:

Paediatric Uveitis

Humira 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 Posology and method of administration 

The following information has been added:

Paediatric Uveitis

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

Paediatric uveitis patients < 30 kg:

The recommended dose of Humira is 20 mg every other week in combination with methotrexate.

When Humira therapy is initiated, a loading dose of 40 mg may be administered one week prior to the start of maintenance therapy. No clinical data are available on the use of a Humira loading dose in children < 6 years of age (see section 5.2).

Paediatric uveitis patients ≥ 30 kg:

The recommended dose of Humira is 40 mg every other week in combination with methotrexate.

When Humira therapy is initiated, a loading dose of 80 mg may be administered one week prior to the start of maintenance therapy.

There is no relevant use of Humira 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).

The following text has been removed:

Paediatric uveitis

The safety and efficacy of Humira in children aged 2‑17 years have not yet been established. No data are available.

Section 4.8      Undesirable effects

The below paragraph has been amended as follows:

Malignancies and lymphoproliferative disorders

No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years during Humira 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 Humira 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 Humira 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 Humira trial in paediatric patients with uveitis.

Section 5.1  Pharmacodynamic properties

The following  sub-paragraph has been added:

Paediatric Uveitis

The safety and efficacy of Humira 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 2, 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 5.1

Sub-section:

Hidradenitis suppurativa

The paragraph:

Patients participating in Studies HS-I and HS-II were eligible to enroll into an open‑label extension study in which Humira 40mg was administered every week.   Throughout all 3 studies patients used topical antiseptic wash daily.

Has been amended to:

Patients participating in Studies HS-I and HS-II were eligible to enroll into an open‑label extension study in which Humira 40mg was administered every week. Mean exposure in all adalimumab population was 762 days.   Throughout all 3 studies patients used topical antiseptic wash daily.

Clinical Response

The paragraph:

Among patients who were at least partial responders at Week 12, and who received continuous weekly Humira therapy, the HiSCR rate at Week 48 was 64.3%.

Has been amended to:

Among patients who were at least partial responders at Week 12, and who received continuous weekly Humira therapy, the HiSCR rate at Week 48 was 68.3% and at Week 96 was 65.1%. Longer term treatment with Humira 40 mg weekly for 96 weeks identified no new safety findings.

Section 5.1 (Pharmacodynamic  properties)

Ø  Sub-section  Enthesitis-related arthritis

The statement:

Improvement in number of active joints with arthritis was maintained during the OL period through Week 52 of the study.

Has been amended to

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 Humira group who remained in the study.

Section 10 (Date of Revision of Text)

Ø  Updated to 19-Apr-17

Section 5.1 -Pharmacodynamic properties

The following information has been added:

Psoriasis Study IV compared efficacy and safety of Humira versus placebo in 217 adult patients with moderate to severe nail psoriasis. Patients received an initial dose of 80 mg Humira followed by 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followed by open-label Humira treatment for an additional 26 weeks. Nail psoriasis assessments included the Modified Nail Psoriasis Severity Index (mNAPSI), the Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) and the Nail Psoriasis Severity Index (NAPSI) (see Table 13). Humira demonstrated a treatment benefit in nail psoriasis patients with different extents of skin involvement (BSA≥10% (60% of patients) and BSA<10% and ≥5% (40% of patients)).

Table 13

Ps Study IV Efficacy Results at 16, 26 and 52 Weeks

Humira treated patients showed statistically significant improvements at Week 26 compared with placebo in the DLQI.

Section 10.  Date of Revision of Text

Amended to 26 January 2017

Note:

Minor editorial changes have been made throughout the document

Section 4.1 (Therapeutic indications)

Updated to include Adolescent hidradenitis suppurativa (HS)

“Hidradenitis suppurativa (HS)

Humira is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) in adults and adolescents from 12 years of age with an inadequate response to conventional systemic HS therapy (see sections 5.1 and 5.2).”

Section 4.2   (Posology and method of administration) 

Updated to reflect approval of adolescent HS indication:

Adolescent hidradenitis suppurativa (from 12 years of age, weighing at least 30 kg)

There are no clinical trials with Humira in adolescent patients with HS.  The posology of Humira in these patients has been determined from pharmacokinetic modelling and simulation (see section 5.2).

The recommended Humira dose is 80 mg at Week 0 followed by 40 mg every other week starting at Week 1 via subcutaneous injection.

In adolescent patients with inadequate response to Humira 40 mg every other week, an increase in dosing frequency to 40 mg every week may be considered.

Antibiotics may be continued during treatment with Humira if necessary.  It is recommended that the patient should use a topical antiseptic wash on their HS lesions on a daily basis during treatment with Humira.

Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no improvement within this time period. 

Should treatment be interrupted, Humira may be re-introduced as appropriate.

The benefit and risk of continued long-term treatment should be periodically evaluated (see adult data in section 5.1).

There is no relevant use of Humira in children aged less than 12 years in this indication.

The following section has been deleted:
Paediatric hidradenitis suppurativa

The safety and efficacy of Humira in children aged 12-17 years have not yet been established for hidradenitis suppurativa.   No data are available. There is no relevant use of Humira in children aged below 12 years for this indication.

Section 5.1          Pharmacodynamic properties

The following sections have been added:

Adolescent hidradenitis suppurativa

There are no clinical trials with Humira 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).

The following paragraph has been amended:

From:

“Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of the studies with Humira in one or more subsets of the paediatric population in ulcerative colitis, hidradenitis suppurativa and non-infectious uveitis, see section 4.2 for information on paediatric use.”

To:

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of the studies with Humira in one or more subsets of the paediatric population in ulcerative colitis and non-infectious uveitis, see section 4.2 for information on paediatric use.

Section 5.2          Pharmacokinetic properties

Absorption and distribution sub-section:

The following paragraph has been amended

From:

In patients with hidradenitis suppurativa, a dose of 160 mg Humira on Week 0 followed by 80 mg on Week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 μg/mL at Week 2 and Week 4.  The mean steady-state trough concentration at Week 12 through Week 36 were approximately 8 to 10 μg/mL during adalimumab 40 mg every week treatment. 

To:

In adult patients with hidradenitis suppurativa, a dose of 160 mg Humira on Week 0 followed by 80 mg on Week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 μg/mL at Week 2 and Week 4.  The mean steady-state trough concentration at Week 12 through Week 36 were approximately 8 to 10 μg/mL during adalimumab 40 mg every week treatment. 

The following information has been added:

Adalimumab exposure in adolescent HS 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). The recommended adolescent HS dosing schedule is 40 mg every other week. Since exposure to adalimumab can be affected by body size, adolescents with higher body weight and inadequate response may benefit from receiving the recommended adult dose of 40 mg every week.

Humira SmPC has been updated to reflect approval of V156 - addition of long term data from DE013 (PREMIER) to section 5.1 the SmPC.

The following is a summary of the changes to section 5.1 (Pharmacodynamic properties)

The following paragraph (within “Rheumatoid arthritis” has been amended as follows:

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 Humira 40 mg every other week/methotrexate combination therapy, Humira 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.

now reads:

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 Humira 40 mg every other week/methotrexate combination therapy, Humira 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 Humira was administered every other week up to 10 years.

The following information has been added underneath Table 3:

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 Humira 40 mg every other week, 170 patients continued on Humira 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.

The 2nd paragraph beneath  Table 3 (Humira Pen and Pre-filled Syringe SmPC) / Table 7 (Humira Vial SmPC)  has been amended as follows:

At Week 52, 42.9% of patients who received Humira/methotrexate combination therapy achieved clinical remission (DAS28 < 2.6) compared to 20.6% of patients receiving methotrexate monotherapy and 23.4% of patients receiving Humira monotherapy. Humira/methotrexate combination therapy was clinically and statistically superior to methotrexate (p < 0.001) and Humira 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).

now reads:

At Week 52, 42.9% of patients who received Humira/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 Humira monotherapy. Humira/methotrexate combination therapy was clinically and statistically superior to methotrexate (p < 0.001) and Humira 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 Humira monotherapy or Humira/methotrexate combination therapy who entered the open-label extension study, 171 subjects completed 10 years of Humira treatment. Among those, 109 subjects (63.7%) were reported to be in remission at 10 years.

The following information has been added as a second paragraph beneath Table 5:

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, Humira monotherapy and Humira/methotrexate combination therapy, respectively. The corresponding proportions of patients with no radiographic progression were 31.3%, 23.7% and 36.7% respectively.

The 3^rd paragraph, beneath “ Quality of Life and physical function” has been amended to read as follows:

In RA study V, the improvement in the HAQ disability index and the physical component of the SF 36 showed greater improvement (p < 0.001) for Humira/methotrexate combination therapy versus methotrexate monotherapy and Humira monotherapy at week 52, which was maintained through Week 104.

Now reads:

In RA study V, the improvement in the HAQ disability index and the physical component of the SF 36 showed greater improvement (p < 0.001) for Humira/methotrexate combination therapy versus methotrexate monotherapy and Humira monotherapy at week 52, which was maintained through Week 104. Among the 250 subjects who completed the open-label extension study, improvements in physical function were maintained through 10 years of treatment.

"Paediatric Crohn's disease

 Humira 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 Crohn's disease

Paediatric Crohn's disease patients < 40 kg:    

The recommended Humira induction dose regimen for paediatric subjects with moderately to severely active Crohn's disease is 40 mg at Week 0 followed by 20 mg at Week 2.  In case there is a need for a more rapid response to therapy, the regimen 80 mg at Week 0 (dose can be administered as two injections in one day), 40 mg at Week 2 can be used, with the awareness that the risk for adverse events may be higher with use of the higher induction dose.

After induction treatment, the recommended dose is 20 mg every other week via subcutaneous injection.  Some subjects who experience insufficient response may benefit from an increase in dosing frequency to 20 mg Humira every week. 

Paediatric Crohn's disease patients ≥ 40 kg:  

The recommended Humira induction dose regimen for paediatric subjects with moderately to severely active Crohn's disease is 80 mg at Week 0 followed by 40 mg at Week 2.  In case there is a need for a more rapid response to therapy, the regimen 160 mg at Week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days), 80 mg at Week 2 can be used, with the awareness that the risk for adverse events may be higher with use of the higher induction dose.

After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection.  Some subjects who experience insufficient response may benefit from an increase in dosing frequency to 40 mg Humira every week. 

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

"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."


The following has been added under the subsection Immunogenicity:

"In patients with moderately to severely active paediatric Crohn’s disease, the rate of anti-adalimumab antibody development in patients receiving adalimumab was 3.3%."

Section 2  QUALITATIVE AND QUANTITATIVE COMPOSITION

• Injection volume has changed from 0.8ml to 0.4 ml

Section 4.2  Posology and method of administration 

Dosing tables  have been removed from the following  indications listed under Paediatric Population section:

Juvenile idiopathic arthritis & Enthesitis-related arthritis 
Paediatric plaque psoriasis.  

A statement has been added that for paediatric dosing information, see Summary of Product Characteristics for Humira 40 mg/0.8 ml solution for injection for paediatric use.

Section 6.1 List of excipients

List of excipients has changed - the following excipients have been removed:
Sodium citrate
Sodium dihydrogen phosphate dihydrate
Disodium phosphate dihydrate
Sodium chloride
Sodium hydroxide

Section 6.5    Nature and contents of container 
Updated to reflect new Pen & Syringe fill volume (0.4ml)

Section 8 Marketing Authorisation Numbers:
Updated to reflect new MA numbers:

EU/1/03/256/012

EU/1/03/256/013

EU/1/03/256/014

EU/1/03/256/015

EU/1/03/256/016

EU/1/03/256/017

EU/1/03/256/018

EU/1/03/256/019

• The indication for Psorias has been changed from:

"Humira is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA."

to

"Humira is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy."

Section 4.2

• The following statement has been added under the sub-section,  Rheumatoid Arthritis:
  
  "Available data suggest that the clinical response is usually achieved within 12 weeks of treatment.  Continued therapy should be reconsidered in a patient not responding within this time period."
  
• Within the Sub-section, Ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and psoriatic arthritis the following statement has been amended:
  
  From:
  
  For all of the above indications, available data suggest that the 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.
  
  to:
  
  Available data suggest that the clinical response is usually achieved within 12 weeks of treatment.  Continued therapy should be reconsidered in a patient not responding within this time period.

Section 5.1

• Hidradenitis suppurativa sub-section:  Under Clinical Response, the following statement has been amended:

Reduction of inflammatory lesions and prevention of worsening of abscesses and draining fistulas was assessed using Hidradenitis Suppurativa Clinical Response (HiSCR; at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count relative to Baseline). 

Section 3
"Clear solution for injection" changed to "Solution for injection.  Clear, colourless solution"

Section 4.1 & 4.2
Minor formatting changes

Section 4.4
"Older people" changed to "Elderly people"

Section 4.6
The following text has been repositioned to the top of section 4.6.

"Women of child bearing potential/Contraception in males and females

Women of childbearing potential are strongly recommended to use adequate contraception to prevent pregnancy and continue its use for at least five months after the last Humira treatment"

Section 4.8
"Summary of the safety profile" moved to the top of section 4.8.
Minor formatting changes made throughout section 4.8.

Section 5.1
Minor formatting changes

The following information has been added to sub-section, Axial spondyloarthritis without radiographic evidence of AS

-          Addition of statement on maintenance of efficacy up to 156 Weeks

-          Addition of ASDAS response data at week 12 (secondary endpoint from Study M10-791)

-          Addition of ASDAS-ID response data at week 12 (non-ranked secondary endpoint from Study M10-791)

-          Addition of data on reduction of inflammation (CRP and SPARCC MRI scores; secondary endpoints from Study M10-791) at week 12 as well as a statement regarding long term maintenance of efficacy as measured by CRP and MRI up to Weeks 156 and Week 104, respectively

-          Addition of statement regarding long term maintenance of improvements on quality of life and physical function

Section 6.3
24 months changed to 2 years

Section 6.6

"Humira 40mg solution for injection does not contain preservatives" changed to "Humira does not contain preservatives"

Section 4.4, Special warnings and precautions for use has been updated to add the text listed below under the following headings

Other opportunistic infections

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.

Malignancies and lymphoproliferative disorders

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-blocking agents (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-blockers cannot be excluded.

Deletion of the following information

Psoriasis: New-onset and Worsening

Cases of new onset psoriasis, including pustular psoriasis and palmoplantar psoriasis, and cases of worsening of pre-existing psoriasis have been reported with the use of TNF-blockers, including Humira. Many of these patients were taking concomitant immunosuppressants (e.g., MTX, corticosteroids). Some of these patients required hospitalization. Most patients had improvement of their psoriasis following discontinuation of their TNF-blocker. Some patients have had recurrences of the psoriasis when they were re-challenged with a different TNF-blocker. Discontinuation of Humira should be considered for severe cases and those that do not improve or that worsen despite topical treatments.

Section 4.8 Undesirable effects

Leukemia has been added to Table 2

Section 10 Date of revision of text

Has been updated to March 2010

The MAH address has been changed

Section 4.4: Update to section under Infections (more information about patients with TB), Serious Infections (new infections added), other Opportunistic infections (more information on infections and signs and symptoms of infections).

Section 4.8: Update to Table 1 and Table 2, section on Neoplasms benign and section under Infections to add extrapulmonary, blastomycosis, coccidioidomycosis, pneumocystis and candidiasis and delete pneumocystis carinii pneumonia.

Section 5.1:  Typographical changes

Section 6.3: Update to shelf life

Section 10: Date of revision changed to February 2009

Change to section 4.4 pf SmPC