IMRALDI 40mg / 0.8ml injection for pre-filled pen medication leaflet

Imraldi 40 mg solution for injection in pre-filled syringe

Imraldi 40 mg solution for injection in pre-filled pen

Imraldi 40 mg solution for injection in pre-filled syringe

Each 0.8 ml single dose pre-filled syringe contains 40 mg of adalimumab.

Imraldi 40 mg solution for injection in pre-filled pen

Each 0.8 ml single dose pre-filled pen contains 40 mg of adalimumab.

Adalimumab is a recombinant human monoclonal antibody produced in Chinese Hamster Ovary cells.

This medicinal product contains 20.0 mg sorbitol.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear, colourless solution.

Imraldi in combination with methotrexate, is indicated for:

- the treatment of moderate to severe, active rheumatoid arthritis in adult patients when theresponse to disease-modifying anti-rheumatic drugs including methotrexate has beeninadequate.

- the treatment of severe, active and progressive rheumatoid arthritis in adults not previouslytreated with methotrexate.

Imraldi can be given as monotherapy in case of intolerance to methotrexate or when continuedtreatment with methotrexate is inappropriate.

Adalimumab has been shown to reduce the rate of progression of joint damage as measured by X-rayand to improve physical function, when given in combination with methotrexate.

Imraldi in combination with methotrexate is indicated for the treatment of active polyarticular juvenileidiopathic arthritis, in patients from the age of 2 years who have had an inadequate response to one ormore disease-modifying anti-rheumatic drugs (DMARDs). Imraldi can be given as monotherapy incase of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate(for the efficacy in monotherapy see section 5.1). Adalimumab has not been studied in patients agedless than 2 years.

Imraldi is indicated for the treatment of active enthesitis-related arthritis in patients, 6 years of age andolder, who have had an inadequate response to, or who are intolerant of, conventional therapy (seesection 5.1).

Imraldi is indicated for the treatment of adults with severe active ankylosing spondylitis who have hadan inadequate response to conventional therapy.

Imraldi is indicated for the treatment of adults with severe axial spondyloarthritis without radiographicevidence of AS but with objective signs of inflammation by elevated CRP and/or MRI, who have hadan inadequate response to, or are intolerant to non-steroidal anti-inflammatory drugs (NSAIDs).

Imraldi is indicated for the treatment of active and progressive psoriatic arthritis in adults when theresponse to previous disease-modifying anti-rheumatic drug therapy has been inadequate.

Adalimumab has been shown to reduce the rate of progression of peripheral joint damage as measuredby X-ray in patients with polyarticular symmetrical subtypes of the disease (see Section 5.1) and toimprove physical function.

Imraldi is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patientswho are candidates for systemic therapy.

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

Imraldi is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acneinversa) in adults and adolescents from 12 years of age with an inadequate response to conventionalsystemic HS therapy (see sections 5.1 and 5.2).

Imraldi is indicated for treatment of moderately to severely active Crohn’s disease, in adult patientswho have not responded despite a full and adequate course of therapy with a corticosteroid and/or animmunosuppressant; or who are intolerant to or have medical contraindications for such therapies.

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

Imraldi is indicated for treatment of moderately to severely active ulcerative colitis in adult patientswho have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medicalcontraindications for such therapies.

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

Imraldi is indicated for the treatment of non-infectious intermediate, posterior and panuveitis in adultpatients who have had an inadequate response to corticosteroids, in patients in need of corticosteroid-sparing, or in whom corticosteroid treatment is inappropriate.

Paediatric uveitis

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

Imraldi treatment should be initiated and supervised by specialist physicians experienced in thediagnosis and treatment of conditions for which Imraldi is indicated. Ophthalmologists are advised toconsult with an appropriate specialist before initiation of treatment with Imraldi (see section 4.4).

Patients treated with Imraldi should be given the Patient Reminder Card.

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

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

The recommended dose of Imraldi for adult patients with rheumatoid arthritis is 40 mg adalimumabadministered every other week as a single dose via subcutaneous injection. Methotrexate should becontinued during treatment with Imraldi.

Glucocorticoids, salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), or analgesics can becontinued during treatment with Imraldi. Regarding combination with disease modifying anti-rheumatic drugs other than methotrexate see sections 4.4 and 5.1.

In monotherapy, some patients who experience a decrease in their response to Imraldi 40 mg everyother week dosing may benefit from an increase in dose to 40 mg adalimumab every week or 80 mgevery other week.

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.

There may be a need for dose interruption, for instance before surgery or if a serious infection occurs.

Available data suggest that re-introduction of adalimumab after discontinuation for 70 days or longerresulted in the same magnitudes of clinical response and similar safety profile as before doseinterruption.

Ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and psoriaticarthritis

The recommended dose of Imraldi for patients with ankylosing spondylitis, axial spondyloarthritiswithout radiographic evidence of AS and for patients with psoriatic arthritis is 40 mg adalimumabadministered every other week as a single dose via subcutaneous injection.

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.

The recommended dose of Imraldi for adult patients is an initial dose of 80 mg administeredsubcutaneously, followed by 40 mg subcutaneously given every other week starting one week after theinitial dose.

Continued therapy beyond 16 weeks should be carefully reconsidered in a patient not respondingwithin this time period.

Beyond 16 weeks, patients with inadequate response to Imraldi 40 mg every other week may benefitfrom an increase in dose to 40 mg every week or 80 mg every other week. The benefits and risks ofcontinued 40 mg weekly or 80 mg every other week therapy should be carefully reconsidered in apatient with an inadequate response after the increase in dose (see section 5.1). If adequate response isachieved with 40 mg every week or 80 mg every other week, the dose may subsequently be reduced to40 mg every other week.

The recommended Imraldi dose regimen for adult patients with hidradenitis suppurativa (HS) is160 mg initially at Day 1 (given as four 40 mg injections in one day or as two 40 mg injections per dayfor two consecutive days), followed by 80 mg two weeks later at Day 15 (given as two 40 mginjections in one day). Two weeks later (Day 29) continue with a dose of 40 mg every week or 80 mgevery other week (given as two 40 mg injections in one day). Antibiotics may be continued duringtreatment with Imraldi if necessary. It is recommended that the patient should use a topical antisepticwash on their HS lesions on a daily basis during treatment with Imraldi.

Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with noimprovement within this time period.

Should treatment be interrupted, Imraldi 40 mg every week or 80 mg every other week may be re-introduced (see section 5.1).

The benefit and risk of continued long-term treatment should be periodically evaluated (see section5.1).

The recommended Imraldi induction dose regimen for adult patients with moderately to severelyactive Crohn’s disease is 80 mg at week 0 followed by 40 mg at week 2. In case there is a need for amore rapid response to therapy, the regimen 160 mg at week 0 (given as four 40 mg injections in oneday or as two 40 mg injections per day for two consecutive days), followed by 80 mg at week 2 (givenas two 40 mg injections in one day), can be used with the awareness that the risk for adverse events ishigher during induction.

After induction treatment, the recommended dose is 40 mg every other week via subcutaneousinjection. Alternatively, if a patient has stopped Imraldi and signs and symptoms of disease recur,

Imraldi may be re-administered. There is little experience from re-administration after more than 8weeks since the previous dose.

During maintenance treatment, corticosteroids may be tapered in accordance with clinical practiceguidelines.

Some patients who experience decrease in their response to Imraldi 40 mg every other week maybenefit from an increase in dose to 40 mg Imraldi every week or 80 mg every other week.

Some patients who have not responded by week 4 may benefit from continued maintenance therapythrough week 12. Continued therapy should be carefully reconsidered in a patient not respondingwithin this time period.

The recommended Imraldi induction dose regimen for adult patients with moderate to severeulcerative colitis is 160 mg at week 0 (given as four 40 mg injections in one day or as two 40 mginjections per day for two consecutive days) and 80 mg at week 2 (given as two 40 mg injections inone day). After induction treatment, the recommended dose is 40 mg every other week viasubcutaneous injection.

During maintenance treatment, corticosteroids may be tapered in accordance with clinical practiceguidelines.

Some patients who experience decrease in their response to Imraldi 40 mg every other week maybenefit from an increase in dose to 40 mg Imraldi every week or 80 mg every other week.

Available data suggest that the clinical response is usually achieved within 2-8 weeks of treatment.

Imraldi therapy should not be continued in patients failing to respond within this time period.

The recommended dose of Imraldi for adult patients with uveitis is an initial dose of 80 mg, followedby 40 mg given every other week starting one week after the initial dose. There is limited experiencein the initiation of treatment with Imraldi alone. Treatment with Imraldi can be initiated incombination with corticosteroids and/or with other non-biologic immunomodulatory agents.

Concomitant corticosteroids may be tapered in accordance with clinical practice starting two weeksafter initiating treatment with Imraldi.

It is recommended that the benefit and risk of continued long-term treatment should be evaluated on ayearly basis (see section 5.1).

No dose adjustment is required.

Adalimumab has not been studied in these patient populations. No dose recommendations can bemade.

Imraldi pre-filled syringe and pre-filled pen are only available as a 40 mg dose. Thus, it is not possibleto administer Imraldi pre-filled syringe and pre-filled pen to paediatric patients that require less than afull 40 mg dose. If an alternative dose is required, other presentations offering such an option shouldbe used.

Polyarticular juvenile idiopathic arthritis from 2 years of age

The recommended dose of Imraldi for patients with polyarticular juvenile idiopathic arthritis from2 years of age is based on body weight (Table 1). Imraldi is administered every other week viasubcutaneous injection.

Table 1. Imraldi dose for patients with polyarticular juvenile idiopathic arthritis

Patient weight Dosing regimen10 kg to < 30 kg 20 mg every other week≥ 30 kg 40 mg every other week

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 adalimumab in patients aged less than 2 years for this indication.

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

Table 2. Imraldi dose for patients with enthesitis-related arthritis

Patient weight Dosing regimen15 kg to < 30 kg 20 mg every other week≥ 30 kg 40 mg every other week

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

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

Table 3. Imraldi dose for paediatric patients with plaque psoriasis

Patient weight Dosing regimen

Initial dose of 20 mg, followed by15 kg to < 30 kg 20 mg given every other weekstarting one week after the initialdose

Initial dose of 40 mg, followed by≥ 30 kg 40 mg given every other weekstarting one week after the initialdose

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

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

The safety of adalimumab in paediatric patients with plaque psoriasis has been assessed for a mean of13 months.

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

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

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

In adolescent patients with inadequate response to Imraldi 40 mg every other week, an increase indose to 40 mg every week or 80 mg every other week may be considered.

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

Imraldi.

Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with noimprovement within this time period.

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

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

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

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

Table 4. Imraldi dose for paediatric patients with crohn’s disease

Patient Induction dose Maintenanceweight dosestarting atweek 4

* 40 mg at week 0 and 20 mg at week 2< 40 kg In case there is a need for a more rapid response to therapy with the 20 mg everyawareness that the risk for adverse events may be higher with use of the other weekhigher induction dose, the following dose may be used:

* 80 mg at week 0 and 40 mg at week 2

* 80 mg at week 0 and 40 mg at week 2≥ 40 kg In case there is a need for a more rapid response to therapy with the 40 mg everyawareness that the risk for adverse events may be higher with use of the other weekhigher induction dose, the following dose may be used:

* 160 mg at week 0 and 80 mg at week 2

Patients who experience insufficient response may benefit from an increase in dose: < 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 adalimumab in children aged below 6 years for this indication.

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

Table 5 Imraldi dose for paediatric patients with ulcerative colitis

Patient Induction dose Maintenance doseweight starting at week 4*

* 80 mg at week 0 (given as two 40 mg< 40 kg injections in one day) and

* 40 mg at week 2 (given as one 40 mg * 40 mg every other weekinjection)

* 160 mg at week 0 (given as four 40 mginjections in one day or two 40 mg injections≥ 40 kg per day for two consecutive days) and * 80 mg every other week

* 80 mg at week 2 (given as two 40 mginjections in one day)

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

Continued therapy beyond 8 weeks should be carefully considered in patients not showing signs ofresponse 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 individualtreatment needs.

There is no relevant use of adalimumab in the paediatric population for the indications of ankylosingspondylitis and psoriatric arthritis.

Paediatric uveitis

The recommended dose of Imraldi for paediatric patients with uveitis from 2 years of age is basedon body weight (Table 6). Imraldi is administered via subcutaneous injection.

In paediatric uveitis, there is no experience in the treatment with adalimumab without concomitanttreatment with methotrexate.

Table 6 Imraldi dose for paediatric patients with uveitis

Patient weight Dosing regimen< 30 kg 20 mg every other week incombination with methotrexate≥ 30 kg 40 mg every other week incombination with methotrexate

When Imraldi therapy is initiated, a loading dose of 40 mg for patients < 30 kg or 80 mg forpatients ≥ 30 kg may be administered one week prior to the start of maintenance therapy. Noclinical 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 ona yearly basis (see section 5.1).

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

A 40 mg pre-filled syringe and pre-filled pen are available for patients to administer a full 40 mg dose.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active tuberculosis or other severe infections such as sepsis, and opportunistic infections (see section4.4).

Moderate to severe heart failure (NYHA class III/IV) (see section 4.4).

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

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

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

Patients who develop a new infection while undergoing treatment with Imraldi, should be monitoredclosely and undergo a complete diagnostic evaluation. Administration of Imraldi should bediscontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial orantifungal therapy should be initiated until the infection is controlled. Physicians should exercisecaution when considering the use of Imraldi in patients with a history of recurring infection or withunderlying conditions which may predispose patients to infections, including the use of concomitantimmunosuppressive medications.

Serious infections, including sepsis, due to bacterial, mycobacterial, invasive fungal, parasitic, viral, orother opportunistic infections such as listeriosis, legionellosis and pneumocystis have been reported inpatients receiving adalimumab.

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

Tuberculosis, including reactivation and new onset of tuberculosis, has been reported in patientsreceiving adalimumab. 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 ofpatient history of tuberculosis or possible previous exposure to people with active tuberculosis andprevious and/or current immunosuppressive therapy. Appropriate screening tests (i.e. tuberculin skintest and chest X-ray) should be performed in all patients (local recommendations may apply). It isrecommended that the conduct and results of these tests are recorded in the Patient Reminder Card.

Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patientswho are severely ill or immunocompromised.

If active tuberculosis is diagnosed, Imraldi therapy must not be initiated (see section 4.3).

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

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

If latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosisprophylaxis 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 fortuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequatecourse of treatment cannot be confirmed.

Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred inpatients treated with adalimumab. Some patients who have been successfully treated for activetuberculosis have redeveloped tuberculosis while being treated with adalimumab.

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

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

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 concomitantshock an invasive fungal infection should be suspected and administration of Imraldi should bepromptly discontinued. Diagnosis and administration of empiric antifungal therapy in these patientsshould be made in consultation with a physician with expertise in the care of patients with invasivefungal infections.

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

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

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

Serious allergic reactions associated with adalimumab were rare during clinical trials. Non-seriousallergic reactions associated with adalimumab were uncommon during clinical trials. Reports ofserious allergic reactions including anaphylaxis have been received following adalimumabadministration. If an anaphylactic reaction or other serious allergic reaction occurs, administration of

Imraldi should be discontinued immediately and appropriate therapy initiated.

In a study of 64 patients with rheumatoid arthritis that were treated with adalimumab, there was noevidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, orchange in enumeration of effector T-, B-, NK-cells, monocyte/macrophages, and neutrophils.

In the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies includinglymphoma have been observed among patients receiving a TNF-antagonist compared with controlpatients. However, the occurrence was rare. In the post marketing setting, cases of leukaemia havebeen reported in patients treated with a TNF-antagonist. There is an increased background risk forlymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active,inflammatory disease, which complicates the risk estimation. With the current knowledge, a possiblerisk 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 to22 years of age) treated with TNF-antagonists (initiation of therapy ≤18 years of age), includingadalimumab in the post marketing setting. Approximately half the cases were lymphomas. The othercases represented a variety of different malignancies and included rare malignancies usually associatedwith immunosuppression. A risk for the development of malignancies in children and adolescentstreated with TNF-antagonists cannot be excluded.

Rare postmarketing cases of hepatosplenic T-cell lymphoma have been identified in patients treatedwith adalimumab. This rare type of T-cell lymphoma has a very aggressive disease course and isusually fatal. Some of these hepatosplenic T-cell lymphomas with adalimumab have occurred inyoung adult patients on concomitant treatment with azathioprine or 6-mercaptopurine used forinflammatory bowel disease. The potential risk with the combination of azathioprine or 6-mercaptopurine and adalimumab should be carefully considered. A risk for the development ofhepatosplenic T-cell lymphoma in patients treated with Imraldi cannot be excluded (see section 4.8).

No studies have been conducted that include patients with a history of malignancy or in whomtreatment with adalimumab is continued following development of malignancy. Thus, additionalcaution should be exercised in considering adalimumab treatment of these patients (see section 4.8).

All patients, and in particular patients with a medical history of extensive immunosuppressant therapyor 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 cellcarcinoma have also been reported in patients treated with TNF-antagonists including adalimumab(see section 4.8).

In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patientswith moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly inthe 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 toheavy smoking.

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

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 adalimumab. All patients should be advised toseek 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 therapyshould be considered in patients with confirmed significant haematologic abnormalities.

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

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

Patients on adalimumab may receive concurrent vaccinations, except for live vaccines. Administrationof live vaccines (e.g., BCG vaccine) to infants exposed to adalimumab in utero is not recommendedfor 5 months following the mother’s last adalimumab injection during pregnancy.

In a clinical trial with another TNF-antagonist worsening congestive heart failure and increasedmortality due to congestive heart failure have been observed. Cases of worsening congestive heartfailure have also been reported in patients receiving adalimumab. Imraldi should be used with cautionin patients with mild heart failure (NYHA class I/II). Imraldi is contraindicated in moderate to severeheart failure (see section 4.3). Treatment with Imraldi must be discontinued in patients who developnew or worsening symptoms of congestive heart failure.

Treatment with Imraldi may result in the formation of autoimmune antibodies. The impact of long-term treatment with adalimumab on the development of autoimmune diseases is unknown. If a patientdevelops symptoms suggestive of a lupus-like syndrome following treatment with Imraldi and ispositive for antibodies against double-stranded DNA, further treatment with Imraldi should not begiven (see section 4.8).

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 thenature of the adverse events seen with the combination of etanercept and anakinra therapy, similartoxicities may also result from the combination of anakinra and other TNF-antagonists. Therefore, thecombination of adalimumab and anakinra is not recommended. (See section 4.5).

Concomitant administration of adalimumab with other biologic DMARDs (e.g, anakinra andabatacept) or other TNF-antagonists is not recommended based upon the possible increased risk forinfections, including serious infections and other potential pharmacological interactions. (See section4.5).

There is limited safety experience of surgical procedures in patients treated with adalimumab. Thelong half-life of adalimumab should be taken into consideration if a surgical procedure is planned. Apatient who requires surgery while on Imraldi should be closely monitored for infections, andappropriate actions should be taken. There is limited safety experience in patients undergoingarthroplasty while receiving adalimumab.

Failure to respond to treatment for Crohn’s disease may indicate the presence of fixed fibrotic stricturethat may require surgical treatment. Available data suggest that adalimumab does not worsen or causestrictures.

The frequency of serious infections among adalimumab 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. Particularattention regarding the risk for infection should be paid when treating the elderly.

See Vaccinations above.

Sorbitol

This medicinal product contains 20 mg sorbitol in each pre-filled syringe/pre-filled pen. Patients withhereditary fructose intolerance (HFI) should not take this medicinal product.

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8 ml dose, that is to sayessentially ‘sodium-free’.

Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis andpsoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitantmethotrexate. Antibody formation was lower when adalimumab was given together with methotrexatein comparison with use as monotherapy. Administration of adalimumab without methotrexate resultedin increased formation of antibodies, increased clearance and reduced efficacy of adalimumab (seesection 5.1).

The combination of Imraldi and anakinra is not recommended (see section 4.4 “Concurrentadministration of biologic DMARDs or TNF-antagonists”).

The combination of Imraldi and abatacept is not recommended (see section 4.4 “Concurrentadministration of biologic DMARDs or TNF-antagonists”).

Women of childbearing potential should consider the use of adequate contraception to preventpregnancy and continue its use for at least five months after the last Imraldi treatment.

A large number (approximately 2,100) of prospectively collected pregnancies exposed to adalimumabresulting in live birth with known outcomes, including more than 1,500 exposed during the firsttrimester, does not indicate an increase in the rate of malformation in the newborn.

In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn’s disease (CD)treated with adalimumab at least during the first trimester and 120 women with RA or CD not treatedwith adalimumab were enrolled. The primary endpoint was the birth prevalence of major birth defects.

The rate of pregnancies ending with at least one live born infant with a major birth defect was 6/69(8.7 %) in the adalimumab-treated women with RA and 5/74 (6.8 %) in the untreated women with RA(unadjusted OR 1.31, 95 % CI 0.38-4.52) and 16/152 (10.5 %) in the adalimumab-treated women with

CD and 3/32 (9.4 %) in the untreated women with CD (unadjusted OR 1.14, 95 % CI 0.31-4.16). Theadjusted OR (accounting for baseline differences) was 1.10 (95 % CI 0.45-2.73) with RA and CDcombined. There were no distinct differences between adalimumab-treated and untreated women forthe secondary endpoints spontaneous abortions, minor birth defects, preterm delivery, birth size andserious or opportunistic infections and no stillbirths or malignancies were reported. The interpretationof data may be impacted due to methodological limitations of the study, including small sample sizeand non-randomised design.

In a developmental toxicity study conducted in monkeys, there was no indication of maternal toxicity,embryotoxicity or teratogenicity. Preclinical data on postnatal toxicity of adalimumab are not available(see section 5.3).

Due to its inhibition of TNFα, adalimumab administered during pregnancy could affect normalimmune responses in the newborn. Adalimumab should only be used during pregnancy if clearlyneeded.

Adalimumab may cross the placenta into the serum of infants born to women treated with adalimumabduring pregnancy. Consequently, these infants may be at increased risk for infection. Administrationof live vaccines (e.g., BCG vaccine) to infants exposed to adalimumab in utero is not recommendedfor 5 months following the mother’s last adalimumab injection during pregnancy.

Limited information from the published literature indicates that adalimumab is excreted in breast milkat very low concentrations with the presence of adalimumab in human milk at concentrations of 0.1 %to 1 % of the maternal serum level. Given orally, immunoglobulin G proteins undergo intestinalproteolysis and have poor bioavailability. No effects on the breastfed newborns/infants are anticipated.

Consequently, adalimumab can be used during breastfeeding.

Preclinical data on fertility effects of adalimumab are not available.

Imraldi may have a minor influence on the ability to drive and use machines. Vertigo and visualimpairment may occur following administration of Imraldi (see section 4.8).

Adalimumab was studied in 9,506 patients in pivotal controlled and open-label trials for up to60 months or more. These trials included rheumatoid arthritis patients with short term and longstanding disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritiswithout radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis,hidradenitis suppurativa, and uveitis patients. The pivotal controlled studies involved 6,089 patientsreceiving adalimumab and 3,801 patients receiving placebo or active comparator during the controlledperiod.

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 adalimumab and 5.4 % for controltreated patients.

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

Serious adverse reactions have been reported for adalimumab. TNF-antagonists, such as adalimumabaffect the immune system and their use may affect the body’s defense against infection and cancer.

Fatal and life-threatening infections (including sepsis, opportunistic infections and TB), HBVreactivation and various malignancies (including leukaemia, lymphoma and HSTCL) have also beenreported with use of adalimumab.

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

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

The following list of adverse reactions is based on experience from clinical trials and onpostmarketing experience and are displayed by system organ class and frequency in Table 7 below:very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥ 1/10,000to <1/1,000); and not known (cannot be estimated from the available data). Within each frequencygrouping, undesirable effects are presented in order of decreasing seriousness. The highest frequencyseen among the various indications has been included. An asterisk (*) appears in the System Organ

Class (SOC) column if further information is found elsewhere in sections pct. 4.3, pct. 4.4 and 4.8.

Table 7

Undesirable effects

System organ class Frequency Adverse reaction

Infections and Very Respiratory tract infections (including lower and upperinfestations* common respiratory tract infection, pneumonia, sinusitis,pharyngitis, nasopharyngitis and pneumonia herpes viral)

Common Systemic infections (including sepsis, candidiasis andinfluenza),intestinal infections (including gastroenteritis viral),skin and soft tissue infections (including paronychia,cellulitis, impetigo, necrotising fasciitis and herpes zoster),ear infections,oral infections (including herpes simplex, oral herpes andtooth infections),

System organ class Frequency Adverse reactionreproductive tract infections (including vulvovaginalmycotic infection),urinary tract infections (including pyelonephritis),fungal infections,joint infections

Uncommon Neurological infections (including viral meningitis),opportunistic infections and tuberculosis (includingcoccidioidomycosis, histoplasmosis and mycobacteriumavium complex infection),bacterial infections,eye infections,diverticulitis1)

Neoplasms benign, Common Skin cancer excluding melanoma (including basal cellmalignant and carcinoma and squamous cell carcinoma),unspecified benign neoplasm(including cysts and Uncommon Lymphoma**,polyps)* solid organ neoplasm (including breast cancer, lungneoplasm and thyroid neoplasm),melanoma**

Rare Leukaemia1)

Not known Hepatosplenic T-cell lymphoma1)

Merkel cell carcinoma (neuroendocrine carcinoma of theskin)1), Kaposi’s sarcoma

Blood and the Very Leukopenia (including neutropenia and agranulocytosis),lymphatic system common anaemiadisorders* Common Leukocytosis,thrombocytopenia

Uncommon Idiopathic thrombocytopenic purpura

Rare Pancytopenia

Immune system Common Hypersensitivity,disorders* allergies (including seasonal allergy)

Uncommon Sarcoidosis1),vasculitis

Rare Anaphylaxis1)

Metabolism and Very Lipids increasednutrition disorders common

Common Hypokalaemia,uric acid increased,blood sodium abnormal,hypocalcaemia,hyperglycaemia,hypophosphatemia,dehydration

Psychiatric disorders Common Mood alterations (including depression),anxiety,

Insomnia

Nervous system Very Headachedisorders* common

Common Paraesthesias (including hypoesthesia),migraine,nerve root compression

Uncommon Cerebrovascular accident1),tremor,neuropathy

Rare Multiple sclerosis,

System organ class Frequency Adverse reactiondemyelinating disorders (e.g. optic neuritis, Guillain-Barrésyndrome)1)

Eye disorders Common Visual impairment,conjunctivitis,blepharitis,eye swelling

Uncommon Diplopia

Ear and labyrinth Common Vertigodisorders Uncommon Deafness,tinnitus

Cardiac disorders* Common Tachycardia

Uncommon Myocardial infarction1),arrhythmia,congestive heart failure

Rare Cardiac arrest

Vascular disorders Common Hypertension,flushing,haematoma

Uncommon Aortic aneurysm,vascular arterial occlusion,thrombophlebitis

Respiratory, thoracic Common Asthma,and mediastinal dyspnoea,disorders* cough

Uncommon Pulmonary embolism1),interstitial lung disease,chronic obstructive pulmonary disease,pneumonitis,pleural effusion1)

Rare Pulmonary fibrosis1)

Gastrointestinal Very Abdominal pain,disorders common nausea and vomiting

Common GI haemorrhage,dyspepsia,gastroesophageal reflux disease,sicca syndrome

Uncommon Pancreatitis,dysphagia,face oedema

Rare Intestinal perforation1)

Hepatobiliary Very Elevated liver enzymesdisorders* common

Uncommon Cholecystitis and cholelithiasis,hepatic steatosis,bilirubin increased

Rare Hepatitisreactivation of hepatitis B1)autoimmune hepatitis1)

Not Known Liver failure1)

Skin and Very Rash (including exfoliative rash)subcutaneous tissue commondisorders Common Worsening or new onset of psoriasis (includingpalmoplantar pustular psoriasis)1),urticaria,bruising (including purpura),

System organ class Frequency Adverse reactiondermatitis (including eczema),onychoclasis,hyperhidrosis,alopecia1),pruritus

Uncommon Night sweats,scar

Rare Erythema multiforme1),

Stevens-Johnson syndrome1),angioedema1),cutaneous vasculitis1)lichenoid skin reaction1)

Not known Worsening of symptoms of dermatomyositis1)

Musculoskeletal and Very Musculoskeletal painconnective tissue commondisorders Common Muscle spasms (including blood creatine phosphokinaseincreased)

Uncommon Rhabdomyolysis,systemic lupus erythematosus

Rare Lupus-like syndrome1)

Renal and urinary Common Renal impairment,disorders haematuria

Uncommon Nocturia

Reproductive system Uncommon Erectile dysfunctionand breast disorders

General disorders Very common Injection site reaction (including injection site erythema)and administration Common Chest pain,site conditions* oedema,pyrexia1)

Uncommon Inflammation

Investigations* Common Coagulation and bleeding disorders (including activatedpartial thromboplastin time prolonged),autoantibody test positive (including double stranded DNAantibody),blood lactate dehydrogenase increased

Not Known Weight increased2)

Injury, poisoning and Common Impaired healingproceduralcomplications

* further information is found elsewhere in sections pct. 4.3, pct. 4.4 and 4.8

** including open-label extension studies1) including spontaneous reporting data2) The mean weight change from baseline for adalimumab ranged from 0.3 kg to 1.0 kg across adultindications 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 exposuresof approximately 1-2 years without control group, particularly in patients with Crohn’s disease andulcerative colitis. The mechanism behind this effect is unclear but could be associated with the anti-inflammatory effect of adalimumab.

The safety profile for patients with HS treated with adalimumab weekly was consistent with theknown safety profile of adalimumab.

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

In the pivotal controlled trials in adults and children, 12.9 % of patients treated with adalimumabdeveloped injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), comparedto 7.2 % of patients receiving placebo or active control. Injection site reactions generally did notnecessitate discontinuation of the medicinal product.

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

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

In controlled and open-label adult and paediatric studies with adalimumab, serious infections(including fatal infections, which occurred rarely) have been reported, which include reports oftuberculosis (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 occurredwithin the first eight months after initiation of therapy and may reflect recrudescence of latent disease.

No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient yearsduring adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathicarthritis and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatricpatients 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 of80.0 patient years during an adalimumab trial in paediatric patients with chronic plaque psoriasis. Nomalignancies were observed in 93 paediatric patients with an exposure of 65.3 patient years during anadalimumab trial in paediatric patients with ulcerative colitis. No malignancies were observed in60 paediatric patients with an exposure of 58.4 patient years during an adalimumab trial in paediatricpatients with uveitis.

During the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in duration inpatients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axialspondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitissuppurativa, Crohn’s disease, ulcerative colitis, and uveitis, malignancies, other than lymphoma andnon-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per1,000 patient-years among 5,291 adalimumab treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000patient-years among 3,444 control patients (median duration of treatment was 4.0 months foradalimumab 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 adalimumab-treated patientsand 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cellcarcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years amongadalimumab-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 amongadalimumab-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 extensionstudies with a median duration of approximately 3.3 years including 6,427 patients and over26,439 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 oflymphomas is approximately 1.3 per 1,000 patient-years.

In post-marketing experience from January 2003 to December 2010, predominantly in patients withrheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient treatmentyears. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and0.3 per 1,000 patient treatment years, respectively (see section 4.4).

Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treatedwith adalimumab (see section 4.4).

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

In controlled Phase 3 trials of adalimumab in patients with rheumatoid arthritis and psoriatic arthritiswith a control period duration ranging from 4 to 104 weeks, ALT elevations ≥3 ×ULN occurred in3.7 % of adalimumab-treated patients and 1.6 % of control-treated patients.

In controlled Phase 3 trials of adalimumab in patients with polyarticular juvenile idiopathic arthritiswho were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations ≥3 ×

ULN occurred in 6.1 % of adalimumab-treated patients and 1.3 % of control-treated patients. Most

ALT elevations occurred with concomitant methotrexate use. No ALT elevations ≥3 × ULN occurredin the Phase 3 trial of adalimumab in patients with polyarticular juvenile idiopathic arthritis who were2 to <4 years.

In controlled Phase 3 trials of adalimumab in patients with Crohn’s disease and ulcerative colitis witha control period ranging from 4 to 52 weeks. ALT elevations ≥3 × ULN occurred in 0.9% ofadalimumab-treated patients and 0.9 % of controlled-treated patients.

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

In controlled Phase 3 trials of adalimumab in patients with plaque psoriasis with a control periodduration ranging from 12 to 24 weeks, ALT elevations ≥3 × ULN occurred in 1.8% of adalimumab-treated patients and 1.8 % of control-treated patients.

No ALT elevations ≥3 × ULN occurred in the Phase 3 trial of adalimumab in paediatric patients withplaque psoriasis.

In controlled trials of adalimumab (initial doses of 160 mg at week 0 and 80 mg at week 2, followedby 40 mg every week starting at week 4), in patients with hidradenitis suppurativa with a controlperiod duration ranging from 12 to 16 weeks, ALT elevations ≥3 × ULN occurred in 0.3 % ofadalimumab-treated patients and 0.6 % of control-treated patients.

In controlled trials of adalimumab (initial doses of 80 mg at week 0 followed by 40 mg every other weekstarting at week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 days and105.0 days in adalimumab-treated and control-treated patients, respectively, ALT elevations ≥3 × ULNoccurred in 2.4 % of adalimumab-treated patients and 2.4 % of control-treated patients.

In the controlled Phase 3 trial of adalimumab in patients with paediatric ulcerative colitis (N=93) whichevaluated 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 bodyweight adjusted induction dosing of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and1.2 mg/kg (maximum of 80 mg) at Week 2 (N=63), or an induction dose of 2.4 mg/kg (maximum of160 mg) at Week 0, placebo at Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=30), ALTelevations ≥ 3 X ULN occurred in 1.1% (1/93) of patients.

Across all indications in clinical trials patients with raised ALT were asymptomatic and in most caseselevations 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.

In adult Crohn’s disease studies, higher incidences of malignant and serious infection-related adverseevents were seen with the combination of adalimumab and azathioprine/6-mercaptopurine comparedwith adalimumab alone.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

ATC code: L04AB04

Imraldi is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency http://www.ema.europa.eu.

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

Adalimumab also modulates biological responses that are induced or regulated by TNF, includingchanges in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1,and ICAM-1 with an IC50 of 0.1-0.2 nM).

After treatment with adalimumab, 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) wasobserved, compared to baseline in patients with rheumatoid arthritis. Serum levels of matrixmetalloproteinases (MMP-1 and MMP-3) that produce tissue remodelling responsible for cartilagedestruction were also decreased after adalimumab administration. Patients treated with adalimumabusually experienced improvement in haematological signs of chronic inflammation.

A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathicarthritis, Crohn’s disease, ulcerative colitis, and hidradenitis suppurativa after treatment withadalimumab. In patients with Crohn’s disease, a reduction of the number of cells expressinginflammatory 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 adalimumabtreated patients.

Adalimumab was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. Theefficacy and safety of adalimumab were assessed in five randomised, double-blind and well-controlledstudies. 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 hadinsufficient 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 adalimumab 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. Dosesof 20 or 40 mg of adalimumab were given by subcutaneous injection every other week with placeboon alternative weeks or every week for 26 weeks; placebo was given every week for the sameduration. 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 havebeen intolerant to 10 mg of methotrexate every week. There were three groups in this study. The firstreceived placebo injections every week for 52 weeks. The second received 20 mg of adalimumabevery week for 52 weeks. The third group received 40 mg of adalimumab every other week withplacebo injections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled inan open-label extension phase in which 40 mg of adalimumab/MTX was administered every otherweek up to 10 years.

RA study IV primarily assessed safety in 636 patients with moderately to severely active rheumatoidarthritis 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 therapywas stable for a minimum of 28 days. These therapies include methotrexate, leflunomide,hydroxychloroquine, sulfasalazine and/or gold salts. Patients were randomised to 40 mg ofadalimumab or placebo every other week for 24 weeks.

RA study V evaluated 799 methotrexate-naïve, adult patients with moderate to severely active earlyrheumatoid arthritis (mean disease duration less than 9 months). This study evaluated the efficacy ofadalimumab 40 mg every other week/methotrexate combination therapy, adalimumab 40 mg everyother week monotherapy and methotrexate monotherapy in reducing the signs and symptoms and rateof progression of joint damage in rheumatoid arthritis for 104 weeks. Upon completion of the first104 weeks, 497 patients enrolled in an open-label extension phase in which 40 mg of adalimumab wasadministered 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 thepercent of patients who achieved an ACR 20 response at week 24 or 26. The primary endpoint in RAstudy 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.

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

Table 8.

Table 8

ACR responses in placebo controlled trials(Percent of patients)

RA study Ia** RA study IIa** RA study IIIa**

Response Placebo/ Adalimumabb/ Placebo Adalimumabb Placebo/ Adalimumabb/

MTXc MTXc MTXc MTXc

N=60 N=63 N=110 N=113 N=200 N=207

ACR 206 months 13.3% 65.1% 19.1% 46.0% 29.5% 63.3%12 months - - - - 24.0% 58.9%

ACR 506 months 6.7% 52.4% 8.2% 22.1% 9.5% 39.1%12 months - - - - 9.5% 41.5%

ACR 706 months 3.3% 23.8% 1.8% 12.4% 2.5% 20.8%12 months - - - - 4.5% 23.2%a RA study I at 24 weeks, RA study II at 26 weeks, and RA study III at 24 and 52 weeksb 40 mg adalimumab administered every other weekc MTX = methotrexate

**p <0.01, adalimumab versus placebo

- Not applicable

In RA studies I-IV, all individual components of the ACR response criteria (number of tender andswollen 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 maintainedresponse when followed for up to 10 years. Of 207 patients who were randomised to adalimumab40 mg every other week, 114 patients continued on adalimumab 40 mg every other week for 5 years.

Among those, 86 patients (75.4 %) had ACR 20 responses; 72 patients (63.2 %) had ACR 50responses; and 41 patients (36 %) had ACR 70 responses. Of 207 patients, 81 patients continued onadalimumab 40 mg every other week for 10 years. Among those, 64 patients (79.0 %) had ACR 20responses; 56 patients (69.1 %) had ACR 50 responses; and 43 patients (53.1 %) had ACR 70responses.

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

In RA studies I-IV, adalimumab -treated patients achieved statistically significant ACR 20 and 50responses 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, combinationtherapy with adalimumab and methotrexate led to faster and significantly greater ACR responses thanmethotrexate monotherapy and adalimumab monotherapy at week 52 and responses were sustained atweek 104 (see Table 9).

Table 9

ACR responses in RA study V(Percent of patients)

MTX Adalimumab Adalimumab/

Response MTX p-valuea p-valueb p-valuec

N=257 N=274 N=268

ACR 2052 week 62.6% 54.4% 72.8% 0.013 <0.001 0.043104 week 56.0% 49.3% 69.4% 0.002 <0.001 0.140

ACR 5052 week 45.9% 41.2% 61.6% <0.001 <0.001 0.317104 week 42.8% 36.9% 59.0% <0.001 <0.001 0.162

ACR 7052 week 27.2% 25.9% 45.5% <0.001 <0.001 0.656104 week 28.4% 28.1% 46.6% <0.001 <0.001 0.864a p-value is from the pairwise comparison of methotrexate monotherapy andadalimumab/methotrexate combination therapy using the Mann-Whitney U test.b p-value is from the pairwise comparison of adalimumab monotherapy andadalimumab/methotrexate combination therapy using the Mann-Whitney U testc p-value is from the pairwise comparison of adalimumab monotherapy and methotrexatemonotherapy using the Mann-Whitney U test

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

At week 52, 42.9 % of patients who received adalimumab/methotrexate combination therapy achievedclinical remission (DAS28 <2.6) compared to 20.6 % of patients receiving methotrexate monotherapyand 23.4 % of patients receiving adalimumab monotherapy. Adalimumab/methotrexate combinationtherapy was clinically and statistically superior to methotrexate (p <0.001) and adalimumabmonotherapy (p <0.001) in achieving a low disease state in patients with recently diagnosed moderateto severe rheumatoid arthritis. The response for the two monotherapy arms was similar (p = 0.447). Of342 subjects originally randomised to adalimumab monotherapy or adalimumab/methotrexatecombination therapy who entered the open-label extension study, 171 subjects completed 10 years ofadalimumab treatment. Among those, 109 subjects (63.7 %) were reported to be in remission at10 years.

In RA study III, where adalimumab treated patients had a mean duration of rheumatoid arthritis ofapproximately 11 years, structural joint damage was assessed radiographically and expressed aschange in modified Total Sharp Score (TSS) and its components, the erosion score and joint spacenarrowing score. Adalimumab /methotrexate patients demonstrated significantly less radiographicprogression than patients receiving methotrexate alone at 6 and 12 months (see Table 10).

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

Table 10

Radiographic mean changes over 12 months in RA study III

Adalimumab/MTX Placebo/MTX-

Placebo/MTXa 40 mg every other Adalimumab/MTXweek (95% confidence p-valueintervalb)

Total sharp score 2.7 0.1 2.6 (1.4, 3.8) <0.001c

Erosion score 1.6 0.0 1.6 (0.9, 2.2) <0.001

JSNd score 1.0 0.1 0.9 (0.3, 1.4) 0.002a methotrexateb 95 % confidence intervals for the differences in change scores between methotrexate andadalimumab.c Based on rank analysisd Joint Space Narrowing

In RA study V, structural joint damage was assessed radiographically and expressed as change inmodified Total Sharp Score (see Table 11).

Table 11

Radiographic mean changes at week 52 in RA study V

MTX Adalimumab Adalimumab

N=257 N=274 /MTX(95% (95% N=268 p-valuea p-valueb p-valuecconfidence confidence (95%interval) interval) confidenceinterval)

Total sharpscore 5.7 (4.2-7.3) 3.0 (1.7-4.3) 1.3 (0.5-2.1) <0.001 0.0020 <0.001

Erosion score 3.7 (2.7-4.7) 1.7 (1.0-2.4) 0.8 (0.4-1.2) <0.001 0.0082 <0.001

JSN score 2.0 (1.2-2.8) 1.3 (0.5-2.1) 0.5 (0-1.0) <0.001 0.0037 0.151a p-value is from the pairwise comparison of methotrexate monotherapy and adalimumab/methotrexatecombination therapy using the Mann-Whitney U testb p-value is from the pairwise comparison of adalimumab monotherapy and adalimumab/methotrexatecombination therapy using the Mann-Whitney U testc p-value is from the pairwise comparison of adalimumab monotherapy and methotrexate monotherapyusing the Mann-Whitney U test

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 withadalimumab/methotrexate combination therapy (63.8 % and 61.2 % respectively) compared tomethotrexate monotherapy (37.4 % and 33.5 % respectively, p <0.001) and adalimumab 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 randomised to methotrexatemonotherapy, adalimumab monotherapy and adalimumab/methotrexate combination therapy,respectively. The corresponding proportions of patients with no radiographic progression were 31.3 %,23.7 % and 36.7 % respectively.

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 ofadalimumab in all four studies showed statistically significantly greater improvement in the disabilityindex of the HAQ from baseline to Month 6 compared to placebo and in RA study III the same wasseen at week 52. Results from the Short Form Health Survey (SF 36) for all doses/schedules ofadalimumab in all four studies support these findings, with statistically significant physical componentsummary (PCS) scores, as well as statistically significant pain and vitality domain scores for the40 mg every other week dose. A statistically significant decrease in fatigue as measured by functionalassessment of chronic illness therapy (FACIT) scores was seen in all three studies in which it wasassessed (RA studies I, III, IV).

In RA study III, most subjects who achieved improvement in physical function and continuedtreatment maintained improvement through week 520 (120 months) of open-label treatment.

Improvement in quality of life was measured up to week 156 (36 months) and improvement wasmaintained through that time.

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

Adalimumab 40 mg every other week was assessed in 393 patients in two randomised, 24 weekdouble − blind, placebo − controlled studies in patients with active ankylosing spondylitis (meanbaseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)]was 6.3 in all groups) who have had an inadequate response to conventional therapy. Seventy-nine(20.1%) patients were treated concomitantly with disease modifying anti − rheumatic drugs, and 37(9.4%) patients with glucocorticoids. The blinded period was followed by an open − label periodduring which patients received adalimumab 40 mg every other week subcutaneously for up to anadditional 28 weeks. Subjects (n=215, 54.7%) who failed to achieve ASAS 20 at weeks 12, or 16 or 20received early escape open-label adalimumab 40 mg every other week subcutaneously and weresubsequently treated as non-responders in the double-blind statistical analyses.

In the larger AS study I with 315 patients, results showed statistically significant improvement of thesigns and symptoms of ankylosing spondylitis in patients treated with adalimumab compared toplacebo. Significant response was first observed at week 2 and maintained through 24 weeks(Table 12).

Table 12

Efficacy responses in placebo-controlled AS study - study Ireduction of signs and symptoms

Response Placebo Adalimumab

N=107 N=208

ASASa 20

Week 2 16% 42%***

Week 12 21% 58%***

Week 24 19% 51%***

ASAS 50

Week 2 3% 16%***

Week 12 10% 38%***

Week 24 11% 35%***

ASAS 70

Week 2 0% 7%**

Week 12 5% 23%***

Week 24 8% 24%***

BASDAIb 50

Week 2 4% 20%***

Week 12 16% 45%***

Week 24 15% 42%***

***,** Statistically significant at p < 0.001, < 0.01 for all comparisons between adalimumab andplacebo at weeks 2, 12 and 24a Assessments in Ankylosing Spondylitisb Bath Ankylosing Spondylitis Disease Activity Index

Adalimumab treated patients had significantly greater improvement at week 12 which was maintainedthrough week 24 in both the SF36 and Ankylosing Spondylitis Quality of Life Questionnaire(ASQoL).

Similar trends (not all statistically significant) were seen in the smaller randomised, double − blind,placebo controlled AS study II of 82 adult patients with active ankylosing spondylitis.

The safety and efficacy of adalimumab were assessed in two randomised, 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 studyin active nr-axSpA patients who achieved remission during open-label treatment with adalimumab.

Study nr-axSpA I

In study nr-axSpA I, adalimumab 40 mg every other week was assessed in 185 patients in arandomised, 12 week double - blind, placebo - controlled study in patients with active nr-axSpA(mean baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index(BASDAI)] was 6.4 for patients treated with adalimumab and 6.5 for those on placebo) who have hadan inadequate response to or intolerance to ≥1 NSAIDs, or a contraindication for NSAIDs.

Thirty-three (18 %) patients were treated concomitantly with disease modifying anti-rheumatic drugs,and 146 (79 %) patients with NSAIDs at baseline. The double-blind period was followed by an open-label period during which patients receive adalimumab 40 mg every other week subcutaneously for upto an additional 144 weeks. week 12 results showed statistically significant improvement of the signsand symptoms of active nr-axSpA in patients treated with adalimumab compared to placebo(Table 13).

Table 13

Efficacy response in placebo-controlled study nr-axSpA I

Double-blind Placebo Adalimumabresponse at week 12 N=94 N=91

ASASa 40 15% 36%***

ASAS 20 31% 52%**

ASAS 5/6 6% 31%***

ASAS partial remission 5% 16%*

BASDAIb 50 15% 35%**

ASDASc,d,e -0.3 -1.0***

ASDAS inactive disease 4% 24%***hs-CRPd,f,g -0.3 -4.7***

SPARCCh MRI sacroiliac jointsd,i -0.6 -3.2**

SPARCC MRI spined,j -0.2 -1.8**a Assessments in SpondyloArthritis International Societyb Bath Ankylosing Spondylitis Disease Activity Indexc Ankylosing Spondylitis Disease Activity Scored mean change from baselinee n=91 placebo and n=87 adalimumabf high sensitivity C-Reactive Protein (mg/L)g n=73 placebo and n=70 adalimumabh Spondyloarthritis Research Consortium of Canadai n=84 placebo and adalimumabj n=82 placebo and n=85 adalimumab

***, **, * Statistically significant at p <0.001, <0.01, and <0.05, respectively, for all comparisonsbetween adalimumab and placebo.

In the open-label extension, improvement in the signs and symptoms was maintained withadalimumab therapy through week 156.

Inhibition of inflammation

Significant improvement of signs of inflammation as measured by hs-CRP and MRI of both Sacroiliac

Joints and the Spine was maintained in adalimumab-treated patients through week 156 and week 104,respectively.

Health-related quality of life and physical function were assessed using the HAQ-S and the SF-36questionnaires. Adalimumab showed statistically significantly greater improvement in the HAQ-Stotal score and the SF-36 Physical Component Score (PCS) from baseline to week 12 compared toplacebo. Improvement in health-related quality of life and physical function was maintained during theopen-label extension through week 156.

Study nr-axSpA II673 patients with active nr-axSpA (mean baseline disease activity [BASDAI] was 7.0) who had aninadequate response to ≥ 2 NSAIDs, or an intolerance to or a contraindication for NSAIDs enrolledinto the open-label period of study nr-axSpA II during which they received adalimumab 40 mg everyother week for 28 weeks. These patients also had objective evidence of inflammation in the sacroiliacjoints or spine on MRI or elevated hs-CRP. Patients who achieved sustained remission for at least 12weeks (N=305) (ASDAS < 1.3 at Weeks 16, 20, 24, and 28) during the open-label period were thenrandomised to receive either continued treatment with adalimumab 40 mg every other week (N=152)or placebo (N=153) for an additional 40 weeks in a double-blind, placebo-controlled period (totalstudy duration 68 weeks). Subjects who flared during the double-blind period were allowedadalimumab 40 mg every other week rescue therapy for at least 12 weeks.

The primary efficacy endpoint was the proportion of patients with no flare by week 68 of the study.

Flare was defined as ASDAS ≥ 2.1 at two consecutive visits four weeks apart. A greater proportion ofpatients on adalimumab had no disease flare during the double-blind period, when compared withthose on placebo (70.4% vs. 47.1%, p<0.001) (Figure 1).

Figure 1: Kaplan-Meier curves summarising time to flare instudy nr-axSpA II

TIME (WEEKS)

Treatment Placebo Adalimumab ∆ Censored

Note: P = Placebo (number at risk (flared)); A = adalimumab (number at risk (flared)).

Among the 68 patients who flared in the group allocated to treatment withdrawal, 65 completed12 weeks of rescue therapy with adalimumab, out of which 37 (56.9%) had regained remission(ASDAS < 1.3) after 12 weeks of restarting the open-label treatment.

By Week 68, patients receiving continuous adalimumab treatment showed statistically significantgreater improvement of the signs and symptoms of active nr-axSpA as compared to patients allocatedto treatment withdrawal during the double-blind period of the study (Table 14).

Table 14

Efficacy response in placebo-controlled period for study nr-axSpA II

Double-blind Placebo Adalimumabresponse at week 68 N=153 N=152

ASASa,b 20 47.1% 70.4%***

ASASa,b 40 45.8% 65.8%***

ASASa partial remission 26.8% 42.1%**

ASDASc inactive disease 33.3% 57.2%***

Partial flared 64.1% 40.8%***a Assessment of SpondyloArthritis international Societyb Baseline is defined as open-label baseline when patients have active disease.c Ankylosing Spondylitis Disease Activity Scored Partial flare is defined as ASDAS ≥ 1.3 but < 2.1 at 2 consecutive visits.

PROBABILITY OF NO FLARE

***, ** Statistically significant at p < 0.001 and < 0.01, respectively, for all comparisons betweenadalimumab and placebo.

Adalimumab, 40 mg every other week, was studied in patients with moderately to severely activepsoriatic arthritis in two placebo-controlled studies, PsA studies I and II. PsA study I with 24 weekduration, treated 313 adult patients who had an inadequate response to non-steroidal anti-inflammatorydrug therapy and of these, approximately 50 % were taking methotrexate. PsA study II with 12-weekduration, treated 100 patients who had an inadequate response to DMARD therapy. Upon completionof both studies, 383 patients enrolled in an open-label extension study, in which 40 mg adalimumabwas administered every other week.

There is insufficient evidence of the efficacy of adalimumab in patients with ankylosing spondylitis-like psoriatic arthropathy due to the small number of patients studied.

Table 15

ACR response in placebo-controlled psoriatic arthritis studies(Percent of patients)

PsA study I PsA study II

Response Placebo Adalimumab Placebo Adalimumab

N=162 N=151 N=49 N=51

ACR 20

Week 12 14% 58%*** 16% 39%*

Week 24 15% 57%*** - -

ACR 50

Week 12 4% 36%*** 2% 25%***

Week 24 6% 39%*** - -

ACR 70

Week 12 1% 20%*** 0% 14%*

Week 24 1% 23%*** - -

*** p < 0.001 for all comparisons between adalimumab and placebo

* p < 0.05 for all comparisons between adalimumab and placebo

- Not applicable

ACR responses in PsA study I were similar with and without concomitant methotrexate therapy.

ACR responses were maintained in the open-label extension study for up to 136 weeks.

Radiographic changes were assessed in the psoriatic arthritis studies. Radiographs of hands, wrists,and feet were obtained at baseline and week 24 during the double-blind period when patients were onadalimumab or placebo and at week 48 when all patients were on open-label adalimumab. A modified

Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e. not identical to the TSSused for rheumatoid arthritis), was used.

Adalimumab treatment reduced the rate of progression of peripheral joint damage compared withplacebo treatment as measured by change from baseline in mTSS (mean ± SD) 0.8 ± 2.5 in the placebogroup (at week 24) compared with 0.0 ± 1.9; (p<0.001) in the adalimumab group (at week 48).

In subjects treated with adalimumab with no radiographic progression from baseline to week 48(n=102), 84% continued to show no radiographic progression through 144 weeks of treatment.

Adalimumab treated patients demonstrated statistically significant improvement in physical functionas assessed by HAQ and Short Form Health Survey (SF 36) compared to placebo at week 24.

Improved physical function continued during the open-label extension up to week 136.

The safety and efficacy of adalimumab were studied in adult patients with chronic plaque psoriasis(≥10% BSA involvement and Psoriasis Area and Severity Index (PASI) ≥12 or ≥10) who werecandidates for systemic therapy or phototherapy in randomised, double-blind studies. 73% of patientsenrolled in Psoriasis studies I and II had received prior systemic therapy or phototherapy. The safetyand efficacy of adalimumab were also studied in adult patients with moderate to severe chronic plaquepsoriasis with concomitant hand and/or foot psoriasis who were candidates for systemic therapy in arandomised double-blind study (Psoriasis study III).

Psoriasis study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A,patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every otherweek starting one week after the initial dose. After 16 weeks of therapy, patients who achieved at leasta PASI 75 response (PASI score improvement of at least 75 % relative to baseline), entered period Band received open-label 40 mg adalimumab every other week. Patients who maintained ≥PASI 75response at week 33 and were originally randomised to active therapy in Period A, were re-randomised in period C to receive 40 mg adalimumab every other week or placebo for an additional19 weeks. Across all treatment groups, the mean baseline PASI score was 18.9 and the baseline

Physician’s Global Assessment (PGA) score ranged from “moderate” (53 % of subjects included) to“severe” (41 %) to “very severe” (6 %).

Psoriasis study II (CHAMPION) compared the efficacy and safety of adalimumab versus methotrexateand placebo in 271 patients. Patients received placebo, an initial dose of MTX 7.5 mg and thereafterdose increases up to week 12, with a maximum dose of 25 mg or an initial dose of 80 mg adalimumabfollowed by 40 mg every other week (starting one week after the initial dose) for 16 weeks. There areno data available comparing adalimumab and MTX beyond 16 weeks of therapy. Patients receiving

MTX who achieved a ≥PASI 50 response at week 8 and/or 12 did not receive further dose increases.

Across all treatment groups, the mean baseline PASI score was 19.7 and the baseline PGA scoreranged from “mild” (<1%) to “moderate” (48%) to “severe” (46%) to “very severe” (6%).

Patients participating in all Phase 2 and Phase 3 psoriasis studies were eligible to enrol into an open-label extension trial, where adalimumab was given for at least an additional 108 weeks.

In Psoriasis studies I and II, a primary endpoint was the proportion of patients who achieved a PASI75 response from baseline at week 16 (see Tables 16 and 17).

Table 16

Ps study I (REVEAL) - efficacy results at 16 weeks

Placebo Adalimumab 40 mg every

N=398 other weekn (%) N=814n (%)≥ PASI 75a 26 (6.5) 578 (70.9)b

PASI 100 3 (0.8) 163 (20.0)b

PGA: clear/minimal 17 (4.3) 506 (62.2)ba Percent of patients achieving PASI 75 response was calculated as centre-adjusted rateb p<0.001, adalimumab vs. placebo

Table 17

Ps study II (CHAMPION) efficacy results at 16 weeks

Placebo MTX Adalimumab40 mg every other

N=53 N=110 weekn (%) n (%) N=108n (%)≥ PASI 75 10 (18.9) 39 (35.5) 86 (79.6)a, b

PASI 100 1 (1.9) 8 (7.3) 18 (16.7)c, d

PGA: clear/minimal 6 (11.3) 33 (30.0) 79 (73.1)a, ba p<0.001 adalimumab vs. placebob p<0.001 adalimumab vs. methotrexatec p<0.01 adalimumab vs. placebod p<0.05 adalimumab vs. methotrexate

In Psoriasis study I, 28 % of patients who were PASI 75 responders and were re-randomised toplacebo at week 33 compared to 5 % continuing on adalimumab, p<0.001, experienced “loss ofadequate response” (PASI score after week 33 and on or before week 52 that resulted in a <PASI 50response relative to baseline with a minimum of a 6-point increase in PASI score relative to week 33).

Of the patients who lost adequate response after re-randomisation to placebo who then enrolled intothe open-label extension trial, 38 % (25/66) and 55 % (36/66) regained PASI 75 response after 12 and24 weeks of re-treatment, respectively.

A total of 233 PASI 75 responders at week 16 and week 33 received continuous adalimumab therapyfor 52 weeks in Psoriasis study I, and continued adalimumab in the open-label extension trial. PASI 75and PGA of clear or minimal response rates in these patients were 74.7 % and 59.0 %, respectively,after an additional 108 weeks of open-label therapy (total of 160 weeks). In an analysis in which allpatients who dropped out of the study for adverse events or lack of efficacy, or who dose-escalated,were considered non-responders, PASI 75 and PGA of clear or minimal response rates in thesepatients were 69.6 % and 55.7 %, respectively, after an additional 108 weeks of open-label therapy(total of 160 weeks).

A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. During the withdrawal period, symptoms of psoriasis returned over time with amedian time to relapse (decline to PGA “moderate” or worse) of approximately 5 months. None ofthese patients experienced rebound during the withdrawal period. A total of 76.5% (218/285) ofpatients who entered the retreatment period had a response of PGA “clear” or “minimal” after 16weeks of retreatment, irrespective of whether they relapsed during withdrawal (69.1 %[123/178] and88.8 % [95/107] for patients who relapsed and who did not relapse during the withdrawal period,respectively). A similar safety profile was observed during retreatment as before withdrawal.

Significant improvements at week 16 from baseline compared to placebo (studies I and II) and MTX(study II) were demonstrated in the DLQI (Dermatology Life Quality Index). In study I, improvementsin the physical and mental component summary scores of the SF-36 were also significant compared toplacebo.

In an open-label extension study, for patients who dose escalated from 40 mg every other week to40 mg weekly due to a PASI response below 50 %, 26.4 % (92/349) and 37.8 % (132/349) of patientsachieved PASI 75 response at week 12 and 24, respectively.

Psoriasis study III (REACH) compared the efficacy and safety of adalimumab versus placebo in72 patients with moderate to severe chronic plaque psoriasis and hand and/or foot psoriasis. Patientsreceived an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one weekafter the initial dose) or placebo for 16 weeks. At week 16, a statistically significantly greaterproportion of patients who received adalimumab achieved PGA of 'clear' or 'almost clear' for the handsand/or feet compared to patients who received placebo (30.6% versus 4.3%, respectively [p = 0.014]).

Psoriasis study IV compared efficacy and safety of adalimumab versus placebo in 217 adult patientswith moderate to severe nail psoriasis. Patients received an initial dose of 80 mg adalimumab followedby 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followedby open-label adalimumab treatment for an additional 26 weeks. Nail psoriasis assessments includedthe 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 18).

Adalimumab demonstrated a treatment benefit in nail psoriasis patients with different extents of skininvolvement (BSA≥10 % (60 % of patients) and BSA<10 % and ≥5 % (40 % of patients)).

Table 18

Ps study IV efficacy results at 16, 26 and 52 weeks

Week 16 Week 26 Week 52

Placebo-controlled Placebo-controlled Open-label

Endpoint Placebo Adalimumab Placebo Adalimumab Adalimumab

N=108 40 mg every N=108 40 mg every 40 mg everyother week other week other week

N=109 N=109 N=80≥ mNAPSI 75 (%) 2.9 26.0a 3.4 46.6a 65.0

PGA-F clear/minimal 2.9 29.7a 6.9 48.9a 61.3and ≥2-gradeimprovement (%)

Percent change in -7.8 -44.2a -11.5 -56.2a -72.2totalfingernail NAPSI (%)a p<0.001, adalimumab vs. placebo

Adalimumab treated patients showed statistically significant improvements at week 26 compared withplacebo in the DLQI.

The safety and efficacy of adalimumab were assessed in randomised, double-blind, placebo-controlledstudies and an open-label extension study in adult patients with moderate to severe hidradenitissuppurativa (HS) who were intolerant, had a contraindication or an inadequate response to at least a 3-month trial of systemic antibiotic therapy. The patients in HS-I and HS-II had Hurley Stage II or IIIdisease with at least 3 abscesses or inflammatory nodules.

Study HS-I (PIONEER I) evaluated 307 patients with 2 treatment periods. In Period A, patientsreceived placebo or adalimumab at an initial dose of 160 mg at week 0, 80 mg at week 2, and 40 mgevery week starting at week 4 to week 11. Concomitant antibiotic use was not allowed during thestudy. After 12 weeks of therapy, patients who had received adalimumab in Period A were re-randomised in Period B to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab40 mg every other week, or placebo from week 12 to week 35). Patients who had been randomised toplacebo in Period A were assigned to receive adalimumab 40 mg every week in Period B.

Study HS-II (PIONEER II) evaluated 326 patients with 2 treatment periods. In Period A, patientsreceived placebo or adalimumab at an initial dose of 160 mg at week 0 and 80 mg at week 2 and40 mg every week starting at week 4 to week 11. 19.3 % of patients had continued baseline oralantibiotic therapy during the study. After 12 weeks of therapy, patients who had received adalimumabin Period A were re-randomised in Period B to 1 of 3 treatment groups (adalimumab 40 mg everyweek, adalimumab 40 mg every other week, or placebo from week 12 to week 35). Patients who hadbeen randomised to placebo in Period A were assigned to receive placebo in Period B.

Patients participating in studies HS-I and HS-II were eligible to enrol into an open-label extensionstudy in which adalimumab 40 mg was administered every week. Mean exposure in all adalimumabpopulation was 762 days. Throughout all 3 studies patients used topical antiseptic wash daily.

Clinical Response

Reduction of inflammatory lesions and prevention of worsening of abscesses and draining fistulas wasassessed using Hidradenitis Suppurativa Clinical Response (HiSCR; at least a 50 % reduction in totalabscess and inflammatory nodule count with no increase in abscess count and no increase in drainingfistula count relative to Baseline). Reduction in HS-related skin pain was assessed using a Numeric

Rating Scale in patients who entered the study with an initial baseline score of 3 or greater on a11 point scale.

At week 12, a significantly higher proportion of patients treated with adalimumab versus placeboachieved HiSCR. At week 12, a significantly higher proportion of patients in study HS-II experienceda clinically relevant decrease in HS-related skin pain (see Table 19). Patients treated with adalimumabhad significantly reduced risk of disease flare during the initial 12 weeks of treatment.

Table 19

Efficacy results at 12 weeks, HS studies I and II

HS study I HS study II

Placebo Adalimumab Placebo Adalimumab40 mg Weekly 40 mg Weekly

Hidradenitis

Suppurativa N=154 N=153 N=163 N=163clinical response 40 (26.0%) 64 (41.8%) * 45 (27.6%) 96 (58.9%) ***(HiSCR)a≥ 30% reduction in N=109 N=122 N=111 N=105skin painb 27 (24.8%) 34 (27.9%) 23 (20.7%) 48 (45.7%) ***

* p<0.05, ***p<0.001, adalimumab versus placeboa Among all randomised patientsb Among patients with baseline HS-related skin pain assessment ≥ 3, based on Numeric Rating Scale 0- 10; 0 = no skin pain, 10 = skin pain as bad as you can imagine

Treatment with adalimumab 40 mg every week significantly reduced the risk of worsening ofabscesses and draining fistulas. Approximately twice the proportion of patients in the placebo group inthe first 12 weeks of studies HS-I and HS-II, compared with those in the adalimumab groupexperienced worsening of abscesses (23.0 % vs 11.4 %, respectively) and draining fistulas (30.0 % vs13.9 %, respectively).

Greater improvements at week 12 from baseline compared to placebo were demonstrated in skinspecific health-related quality of life, as measured by the Dermatology Life Quality Index (DLQI;studies HS-I and HS-II), patient global satisfaction with medication treatment as measured by the

Treatment Satisfaction Questionnaire - medication (TSQM; studies HS-I and HS-II), and physicalhealth as measured by the physical component summary score of the SF-36 (study HS-I).

In patients with at least a partial response to adalimumab 40 mg weekly at week 12, the HiSCR rate atweek 36 was higher in patients who continued weekly adalimumab than in patients in whom dosingfrequency was reduced to every other week, or in whom treatment was withdrawn (see Table 20).

Table 20

Proportion of patientsa achieving HiSCRb at weeks 24 and 36 aftertreatment reassignment from weekly adalimumab at week 12

Placebo Adalimumab 40 mg Adalimumab 40 mg(treatment withdrawal) every other week weekly

N = 73 N = 70 N = 70

Week 24 24 (32.9%) 36 (51.4%) 40 (57.1%)

Week 36 22 (30.1%) 28 (40.0%) 39 (55.7%)a Patients with at least a partial response to adalimumab 40 mg weekly after 12 weeks of treatmentb Patients meeting protocol-specified criteria for loss of response or no improvement were required todiscontinue from the studies and were counted as nonresponders

Among patients who were at least partial responders at week 12, and who received continuousweekly adalimumab therapy, the HiSCR rate at week 48 was 68.3% and at Week 96 was 65.1%.

Longer term treatment with adalimumab 40 mg weekly for 96 weeks identified no new safety findings.

Among patients whose adalimumab treatment was withdrawn at week 12 in studies HS-I and HS-II,the HiSCR rate 12 weeks after re-introduction of adalimumab 40 mg weekly returned to levels similarto that observed before withdrawal (56.0 %).

The safety and efficacy of adalimumab were assessed in over 1,500 patients with moderately toseverely active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥220 and ≤450) inrandomised, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates,corticosteroids, and/or immunomodulatory agents were permitted and 80 % of patients continued toreceive at least one of these medications.

Induction of clinical remission (defined as CDAI <150) was evaluated in two studies, CD study I(CLASSIC I) and CD study II (GAIN). In CD study I, 299 TNF-antagonist naive patients wererandomised to one of four treatment groups; placebo at weeks 0 and 2, 160 mg adalimumab at week 0and 80 mg at week 2, 80 mg at week 0 and 40 mg at week 2, and 40 mg at week 0 and 20 mg at week2. In CD study II, 325 patients who had lost response or were intolerant to infliximab were randomisedto receive either 160 mg adalimumab at week 0 and 80 mg at week 2 or placebo at weeks 0 and 2. Theprimary non-responders were excluded from the studies and therefore these patients were not furtherevaluated.

Maintenance of clinical remission was evaluated in CD study III (CHARM). In CD study III,854 patients received open-label 80 mg at week 0 and 40 mg at week 2. At week 4 patients wererandomised to 40 mg every other week, 40 mg every week, or placebo with a total study duration of56 weeks. Patients in clinical response (decrease in CDAI ≥70) at week 4 were stratified and analysedseparately from those not in clinical response at week 4. Corticosteroid taper was permitted after week8.

CD study I and CD study II induction of remission and response rates are presented in Table 21.

Table 21

Induction of clinical remission and response(Percent of patients)

CD study I: infliximab naive patients CD study II: infliximabexperienced patients

Placebo Adalimumab Adalimumab Placebo Adalimumab80/40 mg 160/80 mg 160/80 mg

N=74 N=75 N=76 N=166 N=159

Week 4

Clinicalremission 12% 24% 36%* 7% 21%*

Clinical response(CR-100) 24% 37% 49%** 25% 38%**

All p-values are pairwise comparisons of proportions for adalimumab versus placebo

* p <0.001

** p <0.01

Similar remission rates were observed for the 160/80 mg and 80/40 mg induction regimens by week 8and adverse events were more frequently noted in the 160/80 mg group.

In CD study III, at week 4, 58 % (499/854) of patients were in clinical response and were assessed inthe primary analysis. Of those in clinical response at week 4, 48 % had been previously exposed toother TNF-antagonists. Maintenance of remission and response rates are presented in Table 22.

Clinical remission results remained relatively constant irrespective of previous TNF-antagonistexposure.

Disease-related hospitalisations and surgeries were statistically significantly reduced with adalimumabcompared with placebo at week 56.

Table 22

Maintenance of clinical remission and response(Percent of patients)

Placebo 40 mg 40 mg

Adalimumab Adalimumabevery other week every week

Week 26 N=170 N=172 N=157

Clinical remission 17 % 40 %* 47 %*

Clinical response (CR-100) 27 % 52 %* 52 %*

Patients in steroid-freeremission for >=90 daysa 3 % (2/66) 19% (11/58)** 15% (11/74)**

Week 56 N=170 N=172 N=157

Clinical remission 12 % 36 %* 41 %*

Clinical response (CR-100) 17 % 41 %* 48 %*

Patients in steroid-freeremission for >=90 daysa 5 % (3/66) 29 % (17/58)* 20 % (15/74)**

* p <0.001 for adalimumab versus placebo pairwise comparisons of proportions

** p <0.02 for adalimumab versus placebo pairwise comparisons of proportionsa Of those receiving corticosteroids at baseline

Among patients who were not in response at week 4, 43 % of adalimumab maintenance patientsresponded by week 12 compared to 30 % of placebo maintenance patients. These results suggest thatsome patients who have not responded by week 4 benefit from continued maintenance therapy throughweek 12. Therapy continued beyond 12 weeks did not result in significantly more responses (seesection 4.2).

117/276 patients from CD study I and 272/777 patients from CD studies II and III were followedthrough at least 3 years of open-label adalimumab therapy. 88 and 189 patients, respectively,continued to be in clinical remission. Clinical response (CR-100) was maintained in 102 and233 patients, respectively.

In CD study I and CD study II, statistically significant improvement in the disease-specificinflammatory bowel disease questionnaire (IBDQ) total score was achieved at week 4 in patientsrandomised to adalimumab 80/40 mg and 160/80 mg compared to placebo and was seen at weeks 26and 56 in CD study III as well among the adalimumab treatment groups compared to the placebogroup.

Ulcerative Colitis

The safety and efficacy of multiple doses of adalimumab were assessed in adult patients withmoderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopy subscore of 2 to 3)in randomised, double-blind, placebo-controlled studies.

In study UC-I, 390 TNF-antagonist naïve patients were randomised to receive either placebo at weeks0 and 2, 160 mg adalimumab at week 0 followed by 80 mg at week 2, or 80 mg adalimumab at week 0followed by 40 mg at week 2. After week 2, patients in both adalimumab arms received 40 mg everyother week. Clinical remission (defined as Mayo score ≤2 with no subscore >1) was assessed at week8.

In study UC-II, 248 patients received 160 mg of adalimumab at week 0, 80 mg at week 2 and 40 mgevery other week thereafter, and 246 patients received placebo. Clinical results were assessed forinduction of remission at week 8 and for maintenance of remission at week 52.

Patients induced with 160/80 mg adalimumab achieved clinical remission versus placebo at week 8 instatistically significantly greater percentages in study UC-I (18 % vs. 9 % respectively, p=0.031) andstudy UC-II (17 % vs. 9 % respectively, p=0.019). In study UC-II, among those treated withadalimumab who were in remission at week 8, 21/41 (51 %) were in remission at week 52.

Results from the overall UC-II study population are shown in Table 23.

Table 23

Response, remission and mucosal healing in study UC-II(Percent of patients)

Placebo Adalimumab40 mg every otherweek

Week 52 N=246 N=248

Clinical response 18 % 30 %*

Clinical remission 9 % 17 %*

Mucosal healing 15 % 25 %*

Steroid-free remission for ≥ 90 daysa 6 % 13 %*(N=140) (N=150)

Week 8 and 52

Sustained response 12 % 24 %**

Sustained remission 4 % 8 %*

Sustained mucosal healing 11 % 19 %*

Clinical remission is Mayo score ≤2 with no subscore >1;

Clinical response is decrease from baseline in Mayo score ≥3 points and ≥30% plus a decrease inthe rectal bleeding subscore [RBS] ≥1 or an absolute RBS of 0 or 1;

* p<0.05 for adalimumab vs. placebo pairwise comparison of proportions

** p<0.001 for adalimumab vs. placebo pairwise comparison of proportionsa Of those receiving corticosteroids at baseline

Of those patients who had a response at week 8, 47 % were in response, 29 % were in remission, 41 %had mucosal healing, and 20 % were in steroid-free remission for ≥90 days at week 52.

Approximately 40% of patients in study UC-II had failed prior anti-TNF treatment with infliximab.

The efficacy of adalimumab in those patients was reduced compared to that in anti-TNF naïvepatients. Among patients who had failed prior anti-TNF treatment, week 52 remission was achieved by3 % on placebo and 10 % on adalimumab.

Patients from studies UC-I and UC-II had the option to roll over into an open-label long-termextension study (UC III). Following 3 years of adalimumab therapy, 75 % (301/402) continued to bein clinical remission per partial Mayo score.

During 52 weeks of studies UC-I and UC-II, lower rates of all-cause hospitalisations and UC-relatedhospitalisations were observed for the adalimumab-treated arm compared to the placebo arm. Thenumber of all cause hospitalisations in the adalimumab treatment group was 0.18 per patient year vs.0.26 per patient year in the placebo group and the corresponding figures for UC-relatedhospitalisations were 0.12 per patient year vs. 0.22 per patient year.

In study UC-II, treatment with adalimumab resulted in improvements in the Inflammatory Bowel

Disease Questionnaire (IBDQ) score.

The safety and efficacy of adalimumab were assessed in adult patients with non-infectiousintermediate, posterior, and panuveitis, excluding patients with isolated anterior uveitis, in tworandomised, double- masked, placebo-controlled studies (UV I and II). Patients received placebo oradalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week afterthe initial dose. Concomitant stable doses of one non-biologic immunosuppressant were permitted.

Study UV I evaluated 217 patients with active uveitis despite treatment with corticosteroids (oralprednisone at a dose of 10 to 60 mg/day). All patients received a 2-week standardised dose ofprednisone 60 mg/day at study entry followed by a mandatory taper schedule, with completecorticosteroid discontinuation by week 15.

Study UV II evaluated 226 patients with inactive uveitis requiring chronic corticosteroid treatment(oral prednisone 10 to 35 mg/day) at baseline to control their disease. Patients subsequentlyunderwent a mandatory taper schedule, with complete corticosteroid discontinuation by week 19.

The primary efficacy endpoint in both studies was ´time to treatment failure´. Treatment failure wasdefined by a multi-component outcome based on inflammatory chorioretinal and/or inflammatoryretinal vascular lesions, anterior chamber (AC) cell grade, vitreous haze (VH) grade and bestcorrected visual acuity (BCVA).

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

Clinical Response

Results from both studies demonstrated statistically significant reduction of the risk of treatmentfailure in patients treated with adalimumab versus patients receiving placebo (See Table 24). Bothstudies demonstrated an early and sustained effect of adalimumab on the treatment failure rate versusplacebo (see Figure 2).

Table 24

Time to treatment failure in Studies UV I and UV II

Analysistreatment N Failure Median time to a CI 95% P

N (%) failure (months) HR for HRa valueb

Time to treatment failure at or after week 6 in study UV I

Primary analysis (ITT)

Placebo 107 84 (78.5) 3.0 - - -

Adalimumab 110 60 (54.5) 5.6 0.50 0.36,0.70 <0.001

Time to treatment failure at or after week 2 in study UV II

Primary analysis (ITT)

Placebo 111 61 (55.0) 8.3 - - -

Adalimumab 115 45 (39.1) NEc 0.57 0.39,0.84 0.004

Note: Treatment failure at or after week 6 (study UV I), or at or after week 2 (study UV II), wascounted as event. Drop outs due to reasons other than treatment failure were censored at the time ofdropping out.a HR of adalimumab vs placebo from proportional hazards regression with treatment as factorb 2-sided P value from log rank testc NE = not estimable. Fewer than half of at-risk subjects had an event

Figure 2: Kaplan-Meier curves summarising time to treatment failure on or after week 6(Study UV I) or week 2 (Study UV II)

Note: P# = Placebo (Number of Events/Number at Risk); A# = Adalimumab (Number of

Events/Number at Risk).

In study UV I statistically significant differences in favour of adalimumab versus placebo wereobserved for each component of treatment failure. In study UV II, statistically significant differenceswere observed for visual acuity only, but the other components were numerically in favour ofadalimumab.

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 todiabetic retinopathy, due to cataract surgery or vitrectomy) and were excluded from the primaryanalysis of efficacy. Of the 364 remaining patients, 269 evaluable patients (74%) reached 78 weeks ofopen-label adalimumab treatment. Based on the observed data approach, 216 (80.3%) were inquiescence (no active inflammatory lesions, AC cell grade ≤ 0.5+, VH grade ≤ 0.5+) with aconcomitant steroid dose ≤ 7.5 mg per day, and 178 (66.2%) were in steroid-free quiescence. BCVAwas either improved or maintained (< 5 letters deterioration) in 88.6 % of the eyes at week 78. Databeyond Week 78 were generally consistent with these results but the number of enrolled subjectsdeclined after this time. Overall, among the patients who discontinued the study, 18% discontinueddue to adverse events, and 8 % due to insufficient response to adalimumab treatment.

Quality of Life

Patient reported outcomes regarding vision-related functioning were measured in both clinicalstudies, using the NEI VFQ-25. Adalimumab was numerically favoured for the majority of subscoreswith statistically significant mean differences for general vision, ocular pain, near vision, mentalhealth, and total score in study UV I, and for general vision and mental health in study UV II. Visionrelated effects were not numerically in favour of adalimumab for colour vision in study UVI and forcolour vision, peripheral vision and near vision in study UV II.

Anti-adalimumab antibodies may develop during adalimumab treatment. Formation of anti-adalimumab antibodies is associated with increased clearance and reduced efficacy of adalimumab.

There is no apparent correlation between the presence of anti-adalimumab antibodies and theoccurrence of adverse events.

The safety and efficacy of adalimumab was assessed in two studies (pJIA I and II) in children withactive polyarticular or polyarticular course juvenile idiopathic arthritis, who had a variety of JIA onsettypes (most frequently rheumatoid-factor negative or positive polyarthritis and extendedoligoarthritis).

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 inphase (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/daymaximum). In the OL LI phase all patients received 24 mg/m2 up to a maximum of 40 mg adalimumabevery other week for 16 weeks. The distribution of patients by age and minimum, median andmaximum 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

Age group Number of patients at baseline N (%) Minimum, median and maximum4 to 7 years 31 (18.1) 10, 20 and 25 mg8 to 12 years 71 (41.5) 20, 25 and 40 mg13 to 17 years 69 (40.4) 25, 40 and 40 mg

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

Table 26

Paed ACR 30 responses in the JIA study

Stratum

Phase MTX Without MTX

OL-LI 16 weeks

Ped ACR 30 response (n/N) 94.1 % (80/85) 74.4 % (64/86)

Efficacy outcomes

Double blind 32 weeks Adalimumab /MTX Placebo/MTX Adalimumab Placebo(N=38) (N=37) (N=30) (N=28)

Disease flares at the end of32 weeksa (n/N) 36.8 % (14/38) 64.9 % (24/37)b 43.3 % (13/30) 71.4 % (20/28)c

Median time to disease flare >32 weeks 20 weeks >32 weeks 14 weeksa Ped ACR 30/50/70 responses week 48 significantly greater than those of placebo treated patientsb p = 0.015c p = 0.031

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

Overall responses were generally better and, fewer patients developed antibodies when treated withthe combination of adalimumab and MTX compared to adalimumab alone. Taking these results intoconsideration, adalimumab is recommended for use in combination with MTX and for use asmonotherapy 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 activepolyarticular JIA. The patients received 24 mg/m2 body surface area (BSA) of adalimumab up to amaximum of 20 mg every other week as a single dose via SC injection for at least 24 weeks. Duringthe 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 theobserved data approach. The proportions of subjects with PaedACR50/70/90 at week 12 and week 24were 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 weremaintained for up to 60 weeks in the OLE phase in patients who received adalimumab throughout thistime period. Overall, 20 subjects were treated for 60 weeks or longer.

The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind studyin 46 paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients wererandomised to receive either 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of40 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 of40 mg every other week subcutaneously for up to an additional 192 weeks. The primary endpoint wasthe percent change from Baseline to week 12 in the number of active joints with arthritis (swelling notdue to deformity or joints with loss of motion plus pain and/or tenderness), which was achieved withmean percent decrease of -62.6% (median percent change -88.9 %) in patients in the adalimumabgroup 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 throughweek 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 insecondary 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.

The efficacy of adalimumab was assessed in a randomised, double-blind, controlled study of114 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 ≥10with clinically relevant facial, genital, or hand/ foot involvement) who were inadequately controlledwith topical therapy and heliotherapy or phototherapy.

Patients received adalimumab 0.8 mg/kg every other week (up to 40 mg), 0.4 mg/kg every other week(up to 20 mg), or methotrexate 0.1 - 0.4 mg/kg weekly (up to 25 mg). At Week 16, more patientsrandomised to adalimumab 0.8 mg/kg had positive efficacy responses (e.g., PASI 75) than thoserandomised to 0.4 mg/kg every other week or MTX.

Table 27

Paediatric plaque psoriasis efficacy results at 16 weeks

MTXa Adalimumab 0.8 mg/kg every other

N=37 week

N=38

PASI 75b 12 (32.4%) 22 (57.9%)

PGA: clear/minimalc 15 (40.5%) 23 (60.5%)a MTX = methotrexateb P=0.027, adalimumab 0.8 mg/kg versus MTXc 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 to36 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 every other week for an additional 16 weeksand response rates observed during retreatment were similar to the previous double-blind period: PASI75 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 maintainedfor 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 adalimumabfor the treatment of adolescent patients with HS is predicted based on the demonstrated efficacy andexposure-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 exposurelevels. Safety of the recommended adalimumab dose in the adolescent HS population is based oncross-indication safety profile of adalimumab in both adults and paediatric patients at similar or morefrequent doses (see section 5.2).

Adalimumab was assessed in a multicentre, randomised, double-blind clinical trial designed toevaluate the efficacy and safety of induction and maintenance treatment with doses dependent on bodyweight (<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 corticosteroidand/or an immunomodulator) for CD. Subjects may also have previously lost response or beenintolerant 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, forsubjects <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

Patient weight Low dose Standard dose<40 kg 10 mg every other week 20 mg every other week≥40 kg 20 mg every other week 40 mg every other week

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 pointsfrom Baseline) rates are presented in Table 29. Rates of discontinuation of corticosteroids orimmunomodulators are presented in Table 30.

Table 29

Paediatric CD study

PCDAI clinical remission and response

Standard dose Low dose40/20 mg every other 20/10 mg every otherweek week P value*

N=93 N=95

Week 26

Clinical remission 38.7 % 28.4 % 0.075

Clinical response 59.1 % 48.4 % 0.073

Week 52

Clinical remission 33.3 % 23.2 % 0.100

Clinical response 41.9 % 28.4 % 0.038

* p value for Standard Dose versus Low Dose comparison

Table 30

Paediatric CD study

Discontinuation of corticosteroids or immunomodulators and fistula remission

Standard dose Low dose40/20 mg every 20/10 mg every P value1other week other week

Discontinued corticosteroids N=33 N=38

Week 26 84.8 % 65.8 % 0.066

Week 52 69.7 % 60.5 % 0.420

Discontinuation of immunomodulators2 N=60 N=57

Week 52 30.0 % 29.8 % 0.983

Fistula remission3 N=15 N=21

Week 26 46.7 % 38.1 % 0.608

Week 52 40.0 % 23.8 % 0.3031 p value for Standard Dose versus Low Dose comparison2 Immunosuppressant therapy could only be discontinued at or after week 26 at the investigator'sdiscretion if the subject met the clinical response criterion3 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 Indexand height velocity were observed for both treatment groups.

Statistically and clinically significant improvements from Baseline were also observed in bothtreatment 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-termextension study. After 5 years of adalimumab therapy, 74.0 % (37/50) of the 50 patients remaining inthe study continued to be in clinical remission, and 92.0 % (46/50) of patients continued to be inclinical response per PCDAI.

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

In the induction period of the study, 77 patients were randomised 3:2 to receive double-blind treatmentwith adalimumab at an induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and1.2 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 received0.6 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 withadalimumab at the induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and1.2 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 adecrease in PMS ≥ 2 points and ≥ 30% from Baseline) were randomised equally to receive double-blind maintenance treatment with adalimumab at a dose of 0.6 mg/kg (maximum of 40 mg) everyweek (ew), or a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week (eow). Prior toan amendment to the study design, 12 additional patients who demonstrated clinical response per PMSwere randomised 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 patientswith PMS of 5 to 6 at Week 8).

Patients who met criteria for disease flare at or after Week 12 were randomised 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) andcontinued 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 noindividual 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 responseper PMS at Week 8. Clinical remission rates per PMS at Week 8 for patients in each of theadalimumab double-blind induction groups are presented in Table 31.

Table 31

Clinical remission per PMS at 8 weeks

Adalimumaba Adalimumabb, cmaximum of 160 mg at week 0/ maximum of 160 mg at week 0

Placebo at week 1 and week 1

N=30 N=47

Clinical remission 13/30 (43.3%) 28/47 (59.6%)a Adalimumab 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 2b Adalimumab 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of80 mg) at Week 2c Not including open-label Induction dose of adalimumab 2.4 mg/kg (maximum of 160 mg) at Week 0and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2

Note 1: Both induction groups received 0.6 mg/kg (maximum of 40 mg) at Week 4 and Week 6

Note 2: Patients with missing values at Week 8 were considered as not having met the endpoint

At Week 52, clinical remission per FMS in Week 8 responders, clinical response per FMS (defined asa decrease in Mayo Score ≥ 3 points and ≥ 30% from Baseline) in Week 8 responders, mucosalhealing (defined as Mayo endoscopy subscore ≤ 1) in Week 8 responders, clinical remission per FMSin 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 maximum40 mg every other week (0.6 mg/kg) and maximum 40 mg every week (0.6 mg/kg) maintenance doses(Table 32).

Table 32

Efficacy results at 52 weeks

Adalimumaba bmaximum of 40 mg every other Adalimumabweek maximum of 40 mg every week

N=31 N=31

Clinical remission in week 8

PMS responders 9/31 (29.0%) 14/31 (45.2%)

Clinical response in week 8

PMS responders 19/31 (61.3%) 21/31 (67.7%)

Mucosal healing in week 8

PMS responders 12/31 (38.7%) 16/31 (51.6%)

Clinical remission in week 8

PMS remitters 9/21 (42.9%) 10/22 (45.5%)

Corticosteroid-free remissionin week 8 PMS respondersc 4/13 (30.8%) 5/16 (31.3%)a Adalimumab 0.6 mg/kg (maximum of 40 mg) every other weekb Adalimumab 0.6 mg/kg (maximum of 40 mg) every weekc In patients receiving concomitant corticosteroids at baseline

Note: Patients with missing values at Week 52 or who were randomised to receive re-induction ormaintenance treatment were considered non-responders for Week 52 endpoints

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) andclinical remission per PUCAI (defined as PUCAI < 10) at Week 8 and Week 52 (Table 33).

Table 33

Exploratory endpoints results per PUCAI

Week 8

Adalimumaba Adalimumabb,cmaximum of 160 mg at week 0/ maximum of 160 mg at week 0

Placebo at week 1 and week 1

N=30 N=47

Clinical remission per

PUCAI 10/30 (33.3%) 22/47 (46.8%)

Clinical response per PUCAI 15/30 (50.0%) 32/47 (68.1%)

Week 52

Adalimumabd emaximum of 40 mg every other Adalimumabweek maximum of 40 mg every week

N=31 N=31

Clinical remission per

PUCAI in week 8 PMS 14/31 (45.2%) 18/31 (58.1%)responders

Clinical response per PUCAIin week 8 PMS responders 18/31 (58.1%) 16/31 (51.6%)a Adalimumab 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 2b Adalimumab 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of80 mg) at Week 2c Not including open-label Induction dose of adalimumab 2.4 mg/kg (maximum of 160 mg) at Week 0and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2d Adalimumab 0.6 mg/kg (maximum of 40 mg) every other weeke Adalimumab 0.6 mg/kg (maximum of 40 mg) every week

Note 1: Both induction groups received 0.6 mg/kg (maximum of 40 mg) at Week 4 and Week 6

Note 2: Patients with missing values at Week 8 were considered as not having met the endpoints

Note 3: Patients with missing values at Week 52 or who were randomised to receive reinduction ormaintenance treatment were considered non-responders for Week 52 endpoints

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

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 thegroups 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) every week.

Paediatric uveitis

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

The primary endpoint was ‘time to treatment failure’. The criteria determining treatment failure wereworsening or sustained non-improvement in ocular inflammation, partial improvement withdevelopment of sustained ocular co-morbidities or worsening of ocular co-morbidities, non-permitteduse 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 subjectstreated with placebo, whereas the median time to treatment failure was not estimable for subjectstreated 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, asshown by the hazard ratio (HR = 0.25 [95 % CI: 0.12, 0.49]).

Figure 3: Kaplan-Meier curves summarising time to treatment failure in the paediatric uveitisstudy

TIME (WEEKS)

Treatment Placebo Adalimumab

Note: P = Placebo (number at risk); H = adalimumab (number at risk).

After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumabwas slow, with peak serum concentrations being reached about 5 days after administration. Theaverage absolute bioavailability of adalimumab estimated from three studies following a single 40 mgsubcutaneous 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

PROBABILITY OF FAILING TREATMENTto 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 severalrheumatoid arthritis patients ranged from 31-96 % of those in serum.

Following subcutaneous administration of 40 mg of adalimumab every other week in adult rheumatoidarthritis (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 dosefollowing 20, 40 and 80 mg subcutaneous dosing every other week and every week.

Following the administration of 24 mg/m2 (maximum of 40 mg) subcutaneously every other week topatients with polyarticular juvenile idiopathic arthritis (JIA) who were 4 to 17 years the mean troughsteady-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 kgdosed with adalimumab 24 mg/m2 , the mean trough steady-state serum adalimumab concentrationswas 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 (maximum of 40 mg) subcutaneously every other week topatients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state (valuesmeasured at week 24) serum adalimumab concentrations were 8.8 ± 6.6 μg/ml for adalimumabwithout concomitant methotrexate and 11.8 ± 4.3 μg/ml with concomitant methotrexate.

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 μg/ml.

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

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

In adult patients with hidradenitis suppurativa, a dose of 160 mg adalimumab on week 0 followed by80 mg on week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 μg/ml atweek 2 and week 4. The mean steady-state trough concentration at week 12 through week 36 wereapproximately 8 to 10 μg/ml during adalimumab 40 mg every week treatment.

Adalimumab exposure in adolescent HS patients was predicted using population pharmacokineticmodelling and simulation based on cross-indication pharmacokinetics in other paediatric patients(paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn’s disease, and enthesitis-relatedarthritis). The recommended adolescent HS dosing schedule is 40 mg every other week. Sinceexposure to adalimumab can be affected by body size, adolescents with higher body weight andinadequate response may benefit from receiving the recommended adult dose of 40 mg every week.

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

In paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was160/80 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 every other week) or

Low Dose (20/10 mg every other week) 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/mlfor 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 troughconcentrations 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 toreceive adalimumab treatment every other week for 52 weeks. For patients who dose escalated fromevery other week to weekly regimen, the mean (±SD) serum concentrations of adalimumab at week 52were 15.3±11.4 μg/ml (40/20 mg, weekly) and 6.7±3.5 μg/ml (20/10 mg, weekly).

In patients with ulcerative colitis, a loading dose of 160 mg adalimumab on week 0 followed by 80 mgadalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 12 μg/mlduring the induction period. Mean steady-state trough levels of approximately 8 μg/ml were observedin ulcerative colitis patients who received a maintenance dose of 40 mg adalimumab every other week.

Following the subcutaneous administration of body weight-based dosing of 0.6 mg/kg (maximum of40 mg) every other week to paediatric patients with ulcerative colitis, the mean trough steady-stateserum adalimumab concentration was 5.01±3.28 µg/ml at Week 52. For patients who received0.6 mg/kg (maximum of 40 mg) every week, the mean (±SD) trough steady-state serum adalimumabconcentration was 15.7±5.60 μg/ml at Week 52.

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

Adalimumab exposure in paediatric uveitis patients was predicted using population pharmacokineticmodelling and simulation based on cross-indication pharmacokinetics in other paediatric patients(paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn’s disease, and enthesitis-relatedarthritis). 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 aninitial increase in systemic exposure.

Population pharmacokinetic and pharmacokinetic/pharmacodynamic modelling and simulationpredicted comparable adalimumab exposure and efficacy in patients treated with 80 mg every otherweek 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 and UC).

Exposure-response relationship in paediatric population

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

Exposure-response relationships between adalimumab concentration and efficacy in paediatric patientswith 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 adalimumabconcentrations, both with a similar apparent EC50 of approximately 4.5 μg/ml (95% CI 0.4-47.6 and1.9-10.5, respectively).

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

Hepatic or renal impairment

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

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 incynomolgus monkeys at 0, 30 and 100 mg/kg (9-17 monkeys/group) and has revealed no evidence ofharm to the foetuses due to adalimumab. Neither carcinogenicity studies, nor a standard assessment offertility and postnatal toxicity, were performed with adalimumab due to the lack of appropriate modelsfor an antibody with limited cross-reactivity to rodent TNF and to the development of neutralisingantibodies in rodents.

Sodium citrate

Citric acid monohydrate

Histidine

Histidine hydrochloride monohydrate

Sorbitol

Polysorbate 20

Water for injections

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

42 months

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the pre-filled syringe or pre-filled pen in the outer carton in order to protect from light.

A single Imraldi pre-filled syringe or pre-filled pen may be stored at temperatures up to a maximum of25°C for a period of up to 28 days. The syringe or pen must be protected from light, and discarded ifnot used within the 28-day period.

Imraldi 40 mg solution for injection in pre-filled syringe0.8 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 (chlorobutyl), a plunger rod, a safe-shield body and a fingerflange 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 pen0.8 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 (chlorobutyl).

Packs of: 1 pre-filled pen, with 2 alcohol pads 2 pre-filled pens, each with 1 alcohol pad 4 pre-filled pens, each with 1 alcohol pad 6 pre-filled pens, each with 1 alcohol pad

Not all pack sizes may be marketed.

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

Samsung Bioepis NL B.V.

Olof Palmestraat 102616 LR Delft

The Netherlands

Imraldi 40 mg solution for injection in pre-filled syringe

EU/1/17/1216/001

EU/1/17/1216/002

EU/1/17/1216/003

EU/1/17/1216/004

Imraldi 40 mg solution for injection in pre-filled pen

EU/1/17/1216/005

EU/1/17/1216/006

EU/1/17/1216/007

EU/1/17/1216/008

Date of first authorisation: 24 August 2017

Date of latest renewal: 29 April 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.