HYRIMOZ 40mg / 0.4ml injection solution in pre-filled syringe medication leaflet

Hyrimoz 20 mg solution for injection in pre-filled syringe

Hyrimoz 40 mg solution for injection in pre-filled syringe

Hyrimoz 40 mg solution for injection in pre-filled pen

Hyrimoz 80 mg solution for injection in pre-filled syringe

Hyrimoz 80 mg solution for injection in pre-filled pen

Hyrimoz 20 mg solution for injection in pre-filled syringe

Each 0.2 ml single-dose pre-filled syringe contains 20 mg of adalimumab.

Hyrimoz 40 mg solution for injection in pre-filled syringe

Each 0.4 ml single-dose pre-filled syringe contains 40 mg of adalimumab.

Hyrimoz 40 mg solution for injection in pre-filled pen

Each 0.4 ml single-dose pre-filled pen contains 40 mg of adalimumab.

Hyrimoz 80 mg solution for injection in pre-filled syringe

Each 0.8 ml single-dose pre-filled syringe contains 80 mg of adalimumab.

Hyrimoz 80 mg solution for injection in pre-filled pen

Each 0.8 ml single-dose pre-filled pen contains 80 mg of adalimumab.

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

For the full list of excipients, see section 6.1.

Solution for injection (injection) in pre-filled syringe

Solution for injection (injection) in pre-filled pen (SensoReady)

Clear to slightly opalescent, colourless or slightly yellowish solution.

Hyrimoz 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 notpreviously treated with methotrexate.

Hyrimoz 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.

Hyrimoz in combination with methotrexate is indicated for the treatment of active polyarticularjuvenile idiopathic arthritis, in patients from the age of 2 years who have had an inadequate responseto one or more disease-modifying anti-rheumatic drugs (DMARDs). Hyrimoz can be given asmonotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate isinappropriate (for the efficacy in monotherapy, see section 5.1). Adalimumab has not been studied inpatients aged less than 2 years.

Hyrimoz is indicated for the treatment of active enthesitis-related arthritis in patients, 6 years of ageand older, who have had an inadequate response to, or who are intolerant of, conventional therapy(see section 5.1).

Hyrimoz is indicated for the treatment of adults with severe active ankylosing spondylitis who havehad an inadequate response to conventional therapy.

Hyrimoz is indicated for the treatment of adults with severe axial spondyloarthritis withoutradiographic evidence of AS but with objective signs of inflammation by elevated CRP and/or MRI,who have had an inadequate response to, or are intolerant to non-steroidal anti-inflammatory drugs(NSAIDs).

Hyrimoz 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.

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

Hyrimoz 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.

Hyrimoz 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).

Hyrimoz 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.

Hyrimoz 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.

Hyrimoz 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.

Hyrimoz 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.

Hyrimoz 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

Hyrimoz 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.

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

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

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

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

The recommended dose of Hyrimoz 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 Hyrimoz.

Glucocorticoids, salicylates, non-steroidal anti-inflammatory drugs, or analgesics can be continuedduring treatment with Hyrimoz. Regarding combination with disease-modifying anti-rheumatic drugsother than methotrexate, see sections 4.4 and 5.1.

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

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

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 Hyrimoz 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 Hyrimoz 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.

Hyrimoz 40 mg solution for injection in pre-filled syringe and/or pre-filled pen is available for themaintenance 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 Hyrimoz 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.

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

The recommended Hyrimoz dose regimen for adult patients with hidradenitis suppurativa (HS) is160 mg initially at Day 1 (given as two 80 mg injections or four 40 mg injections in one day or as one80 mg injection or two 40 mg injections per day for two consecutive days), followed by 80 mg twoweeks later at Day 15 (given as one 80 mg injection or two 40 mg injections in one day). Two weekslater (Day 29) continue with a dose of 40 mg every week or 80 mg every other week (given as one80 mg injection or two 40 mg injections in one day). Antibiotics may be continued during treatmentwith Hyrimoz, if necessary. It is recommended that the patient should use a topical antiseptic wash ontheir HS lesions on a daily basis during treatment with Hyrimoz.

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

Should treatment be interrupted, Hyrimoz 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 (seesection 5.1).

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

The recommended Hyrimoz 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 two 80 mg injections or four40 mg injections in one day or as one 80 mg injection or two 40 mg injections per day for twoconsecutive days), followed by 80 mg at Week 2 (given as one 80 mg injection or two 40 mginjections in one day), can be used with the awareness that the risk for adverse events is higher duringinduction.

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

Hyrimoz may be re-administered. There is little experience from re-administration after more than8 weeks 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 Hyrimoz 40 mg every other week maybenefit from an increase in dose to 40 mg Hyrimoz 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.

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

The recommended Hyrimoz induction dose regimen for adult patients with moderate to severeulcerative colitis is 160 mg at Week 0 (given as two 80 mg injections or four 40 mg injections in oneday or as one 80 mg injection or two 40 mg injections per day for two consecutive days) and 80 mg at

Week 2 (given as one 80 mg injection or two 40 mg injections in one day). After induction treatment,the recommended dose is 40 mg every other week via subcutaneous injection.

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

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

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

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

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

The recommended dose of Hyrimoz 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. Hyrimoz 40 mg solution forinjection in pre-filled syringe and/or pre-filled pen is available for the maintenance dose. There islimited experience in the initiation of treatment with adalimumab alone. Treatment with Hyrimoz canbe initiated in combination with corticosteroids and/or with other non-biologic immunomodulatoryagents. Concomitant corticosteroids may be tapered in accordance with clinical practice starting twoweeks after initiating treatment with Hyrimoz.

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

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

No dose adjustment is required.

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

Polyarticular juvenile idiopathic arthritis from 2 years of age

The recommended dose of Hyrimoz for patients with polyarticular juvenile idiopathic arthritisfrom 2 years of age is based on body weight (Table 1). Hyrimoz is administered every other weekvia subcutaneous injection.

Table 1. Hyrimoz dose for patients withpolyarticular 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 thistime period.

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

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

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

Table 2. Hyrimoz 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.

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

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

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

Table 3. Hyrimoz dose for paediatric patients with plaque psoriasis

Patient weight Dosing regimen

Initial dose of 20 mg, followed by15 kg to < 30 kg 20 mg every other week startingone week after the initial dose

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 respondingwithin this time period.

If re-treatment with adalimumab is indicated, the above guidance on dose and treatment durationshould be followed.

The safety of adalimumab in paediatric patients with plaque psoriasis has been assessed for amean of 13 months.

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

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

There are no clinical studies 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 Hyrimoz dose is 80 mg at Week 0 followed by 40 mg every other week starting at

Week 1 via subcutaneous injection.

In adolescent patients with inadequate response to Hyrimoz 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 Hyrimoz if necessary. It is recommended that thepatient should use a topical antiseptic wash on their HS lesions on a daily basis during treatment with

Hyrimoz.

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

Should treatment be interrupted, Hyrimoz 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.

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

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

Table 4. Hyrimoz dose for paediatric patients with Crohn’s disease

Patient Maintenanceweight Induction dose dose starting at

Week 4< 40 kg * 40 mg at Week 0 and 20 mg at Week 2

In case there is a need for a more rapid response to therapy withthe awareness that the risk for adverse events may be higher 20 mg everywith use of the higher induction dose, the following dose may other weekbe used:

* 80 mg at Week 0 and 40 mg at Week 2≥ 40 kg * 80 mg at Week 0 and 40 mg at Week 2 40 mg everyother week

In case there is a need for a more rapid response to therapy withthe awareness that the risk for adverse events may be higherwith use of the higher induction dose, the following dose maybe 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 less than 6 years for thisindication.

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

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

Table 5. Hyrimoz Dose for Paediatric Patients with Ulcerative Colitis

Patient Weight Induction Dose Maintenance Dose

Starting at Week 4*< 40 kg * 80 mg at Week 0 (given as one * 40 mg every other week80 mg injection or two 40 mginjections in one day) and

* 40 mg at Week 2 (given as one40 mg injection)≥ 40 kg * 160 mg at Week 0 (given as * 80 mg every other week (giventwo 80 mg injections or four as one 80 mg injection or two40 mg injections in one day or 40 mg injections in one day)one 80 mg injection or two40 mg injections per day fortwo consecutive days) and

* 80 mg at Week 2 (given as one80 mg injection or two 40 mginjections in one day)

* Paediatric patients who turn 18 years of age while on Hyrimoz should continue theirprescribed maintenance 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 Hyrimoz in children aged less than 6 years in this indication.

Hyrimoz may be available in different strengths and/or pharmaceutical forms depending on theindividual treatment needs.

Paediatric uveitis

The recommended dose of Hyrimoz for paediatric patients with uveitis from 2 years ofage is based on body weight (Table 6). Hyrimoz is administered via subcutaneousinjection.

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

Table 6. Hyrimoz 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 Hyrimoz therapy is initiated, a loading dose of 40 mg for patients < 30 kg or 80 mgfor patients ≥ 30 kg may be administered one week prior to the start of maintenancetherapy. No clinical data are available on the use of an adalimumab loading dose inchildren < 6 years of age (see section 5.2).

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

It is recommended that the benefit and risk of continued long-term treatment should beevaluated on a yearly basis (see section 5.1).

Hyrimoz may be available in other strengths and/or pharmaceutical forms depending on the individualtreatment needs.

Hyrimoz is administered by subcutaneous injection.

Full instructions for use are provided in the package leaflet.

Adalimumab is available in other strengths and pharmaceutical forms.

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 section 4.4).

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

In order to improve traceability of biological medicinal products, the name and the batch number ofthe 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 Hyrimoz. Because theelimination of adalimumab may take up to four months, monitoring should be continued throughoutthis period.

Treatment with Hyrimoz 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

Hyrimoz should be considered prior to initiating therapy (see Other opportunistic infections).

Patients who develop a new infection while undergoing treatment with Hyrimoz should be monitoredclosely and undergo a complete diagnostic evaluation. Administration of Hyrimoz 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 Hyrimoz in patients with a history of recurring infection or withunderlying conditions which may predispose patients to infections, including the use of concomitantimmunosuppressive medicinal products.

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 studies include pneumonia, pyelonephritis, septic arthritisand septicaemia. 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 Hyrimoz, all patients must be evaluated for both active and 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, Hyrimoz 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 Hyrimoz, and in accordance with localrecommendations.

Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of

Hyrimoz 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 Hyrimoz.

Opportunistic infections, including invasive fungal infections have been observed in patientsreceiving adalimumab. These infections have not consistently been recognised in patients taking

TNF-antagonists and this has resulted in delays in appropriate treatment, sometimes resulting infatal outcomes.

For patients who develop the signs and symptoms such as fever, malaise, weight loss, sweats,cough, dyspnoea, and/or pulmonary infiltrates or other serious systemic illness with or withoutconcomitant shock an invasive fungal infection should be suspected and administration of

Hyrimoz should be promptly discontinued. Diagnosis and administration of empiric antifungaltherapy in these patients should be made in consultation with a physician with expertise in thecare of patients with invasive fungal infections.

Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist includingadalimumab, who are chronic carriers of this virus (i.e. surface antigen positive). Some cases havehad a fatal outcome. Patients should be tested for HBV infection before initiating treatment with

Hyrimoz. For patients who test positive for hepatitis B infection, consultation with a physician withexpertise in the treatment of hepatitis B is recommended.

Carriers of HBV who require treatment with Hyrimoz should be closely monitored for signs andsymptoms of active HBV infection throughout therapy and for several months followingtermination of therapy. Adequate data from treating patients who are carriers of HBV with anti-viraltherapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are not available.

In patients who develop HBV reactivation, Hyrimoz should be stopped and effective anti-viraltherapy with appropriate 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 consideringthe use of Hyrimoz in patients with pre-existing or recent-onset central or peripheral nervoussystem demyelinating disorders; discontinuation of Hyrimoz should be considered if any of thesedisorders develop. There is a known association between intermediate uveitis and centraldemyelinating disorders. Neurologic evaluation should be performed in patients with non-infectious intermediate uveitis prior to the initiation of Hyrimoz therapy and regularly duringtreatment to assess for pre-existing or developing central demyelinating disorders.

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

Hyrimoz should be discontinued immediately and appropriate therapy initiated.

In a study of 64 patients with rheumatoid arthritis that were treated with adalimumab, there wasno evidence of depression of delayed-type hypersensitivity, depression of immunoglobulinlevels, or change in enumeration of effector T-, B-, NK-cells, monocyte/macrophages, andneutrophils.

In the controlled portions of clinical studies of TNF-antagonists, more cases of malignanciesincluding lymphoma have been observed among patients receiving a TNF-antagonist compared withcontrol patients. However, the occurrence was rare. In the post marketing setting, cases of leukaemiahave been reported in patients treated with a TNF-antagonist. There is an increased background riskfor lymphoma 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 usuallyassociated with immunosuppression. A risk for the development of malignancies in children andadolescents treated 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 Hyrimoz should be carefully considered. A risk for the development ofhepatosplenic T-cell lymphoma in patients treated with Hyrimoz 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 Hyrimoz 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 Hyrimoz. Melanoma and Merkel cellcarcinoma have also been reported in patients treated with TNF-antagonists including adalimumab(see section 4.8).

In an exploratory clinical study evaluating the use of another TNF-antagonist, infliximab, in patientswith moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostlyin the lung or head and neck, were reported in infliximab-treated patients compared with controlpatients. All patients had a history of heavy smoking. Therefore, caution should be exercised whenusing any TNF-antagonist in COPD patients, as well as in patients with increased risk for malignancydue to heavy 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 advisedto seek immediate medical attention if they develop signs and symptoms suggestive of blooddyscrasias (e.g. persistent fever, bruising, bleeding, pallor) while on Hyrimoz. Discontinuation of

Hyrimoz therapy should be considered in patients with confirmed significant haematologicabnormalities.

Similar antibody responses to the standard 23-valent pneumococcal vaccine and the influenzatrivalent virus vaccination were observed in a study in 226 adult subjects with rheumatoid arthritiswho were treated with adalimumab or placebo. No data are available on the secondarytransmission of infection by 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 Hyrimoz therapy.

Patients on Hyrimoz 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 study 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. Hyrimoz should be used withcaution in patients with mild heart failure (NYHA class I/II). Hyrimoz is contraindicated inmoderate to severe heart failure (see section 4.3). Treatment with Hyrimoz must be discontinued inpatients who develop new or worsening symptoms of congestive heart failure.

Treatment with Hyrimoz may result in the formation of autoimmune antibodies. The impact oflong-term treatment with adalimumab on the development of autoimmune diseases is unknown. Ifa patient develops symptoms suggestive of a lupus-like syndrome following treatment with

Hyrimoz and is positive for antibodies against double-stranded DNA, further treatment with

Hyrimoz should not be given (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 ofthe nature 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 (seesection 4.5).

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.

A patient who requires surgery while on Hyrimoz 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 fibroticstricture that may require surgical treatment. Available data suggest that adalimumab does notworsen or cause strictures.

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 fataloutcome. Particular attention regarding the risk for infection should be paid when treating theelderly.

See Vaccinations above.

This medicinal product contains less than 1 mmol sodium (23 mg) per 0.8 ml, per 0.4 ml or per0.2 ml dose, that is to say essentially ‘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 withmethotrexate in comparison with use as monotherapy. Administration of adalimumab withoutmethotrexate resulted in increased formation of antibodies, increased clearance and reduced efficacyof adalimumab (see section 5.1).

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

The combination of adalimumab 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 Hyrimoz treatment.

A large number (approximately 2 100) of prospectively collected pregnancies exposed toadalimumab resulting in live birth with known outcomes, including more than 1 500 exposed duringthe first trimester, 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 birthdefects. The rate of pregnancies ending with at least one live born infant with a major birth defectwas 6/69 (8.7 %) in the adalimumab-treated women with RA and 5/74 (6.8 %) in the untreatedwomen 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). The adjusted OR (accounting for baseline differences) was 1.10 (95 % CI 0.45-2.73) with RA and CD combined. There were no distinct differences between adalimumab-treatedand untreated women for the secondary endpoints spontaneous abortions, minor birth defects,preterm delivery, birth size and serious or opportunistic infections and no stillbirths or malignancieswere reported. The interpretation of data may be impacted due to methodological limitations of thestudy, including small sample size and non-randomized design.

In a developmental toxicity study conducted in monkeys, there was no indication of maternaltoxicity, embryotoxicity or teratogenicity. Preclinical data on postnatal toxicity of adalimumab arenot 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 withadalimumab during pregnancy. Consequently, these infants may be at increased risk for infection.

Administration of live vaccines (e.g., BCG vaccine) to infants exposed to adalimumab in utero is notrecommended for 5 months following the mother’s last adalimumab injection during pregnancy.

Limited information from the published literature indicates that adalimumab is excreted inbreast milk at very low concentrations with the presence of adalimumab in human milk atconcentrations of 0.1 % to 1 % of the maternal serum level. Given orally, immunoglobulin Gproteins undergo intestinal proteolysis and have poor bioavailability. No effects on thebreastfed newborns/infants are anticipated. Consequently, Hyrimoz can be used duringbreastfeeding.

Preclinical data on fertility effects of adalimumab are not available.

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

Adalimumab was studied in 9 506 patients in pivotal controlled and open label studies for up to60 months or more. These studies 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 control-treated 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 defence 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 seenin adult patients.

The following list of adverse reactions is based on experience from clinical studies and onpostmarketing experience and are displayed by system organ class (SOC) and frequency in Table 7below: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare(≥ 1/10 000 to < 1/1 000); and not known (cannot be estimated from the available data). Within eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness.

The highest frequency seen among the various indications has been included. An asterisk (*)appears in the SOC column if further information is found elsewhere in sections pct. 4.3, pct. 4.4 and 4.8.

Table 7. Adverse reactions

System Organ Class Frequency Adverse Reaction

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

Common Systemic infections (including sepsis,candidiasis and influenza),intestinal infections (including gastroenteritisviral),skin and soft tissue infections (includingparonychia, cellulitis, impetigo, necrotisingfasciitis and herpes zoster),ear infections,oral infections (including herpes simplex, oralherpes and tooth infections),reproductive tract infections (includingvulvovaginal mycotic infection),urinary tract infections (includingpyelonephritis),fungal infections, joint infections

Uncommon Neurological infections (including viralmeningitis),opportunistic infections and tuberculosis(including coccidioidomycosis, histoplasmosisand mycobacterium avium complex infection),bacterial infections,eye infections, diverticulitis1)

Neoplasms benign, Common Skin cancer excluding melanoma (includingmalignant and basal cell carcinoma and squamous cellunspecified (including carcinoma)cysts and polyps)* benign neoplasm

System Organ Class Frequency Adverse Reaction

Uncommon Lymphoma**,solid organ neoplasm (including breast cancer,lung neoplasm and thyroid neoplasm),melanoma**

Rare Leukaemia1)

Not known Hepatosplenic T-cell lymphoma1)

Merkel cell carcinoma (neuroendocrinecarcinoma of the skin)1)

Kaposi`s sarcoma

Blood and the Very common Leucopaenia (including neutropaenia andlymphatic system agranulocytosis),disorders* anaemia

Common Leucocytosis,thrombocytopaenia

Uncommon Idiopathic thrombocytopaenic purpura

Rare Pancytopaenia

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

Uncommon Sarcoidosis1),vasculitis

Rare Anaphylaxis1)

Metabolism and Very common Lipids increasednutrition disorders

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

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

Nervous system Very common Headachedisorders*

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

Uncommon Cerebrovascular accident1), tremor,neuropathy

System Organ Class Frequency Adverse Reaction

Rare Multiple sclerosis,demyelinating disorders (e.g. optic neuritis,

Guillain-Barré syndrome)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 common Abdominal pain,disorders nausea and vomiting

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

Uncommon Pancreatitis,dysphagia,face oedema

System Organ Class Frequency Adverse Reaction

Rare Intestinal perforation1)

Hepato-biliary Very common Elevated liver enzymesdisorders*

Uncommon Cholecystitis and cholelithiasis,hepatic steatosis,bilirubin increased

Rare Hepatitis,reactivation of hepatitis B1),autoimmune hepatitis1)

Not known Liver failure1)

Skin and subcutaneous Very common Rash (including exfoliative rash)tissue disorders

Common Worsening or new onset of psoriasis (includingpalmoplantar pustular psoriasis)1),urticaria,bruising (including purpura),dermatitis (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 common Musculoskeletal painconnective tissuedisorders Common Muscle spasms (including blood creatinephosphokinase increased)

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

System Organ Class Frequency Adverse Reaction

General disorders and Very common Injection site reaction (including injection siteadministration site erythema)conditions*

Common Chest pain,oedema,pyrexia1)

Uncommon Inflammation

Investigations* Common Coagulation and bleeding disorders (includingactivated partial thromboplastin time prolonged),autoantibody test positive (including doublestranded DNA antibody),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 acrossadult indications compared to (minus) -0.4 kg to 0.4 kg for placebo over a treatment period of 4-6 months. Weight increase of 5-6 kg has also been observed in long-term extension studies withmean exposures of approximately 1-2 years without control group, particularly in patients with

Crohn’s disease and ulcerative colitis. The mechanism behind this effect is unclear but could beassociated 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 studies 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 studies in adults and children, the rate of infection was 1.51 per patient yearin the 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 and0.03 per 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 latentdisease.

No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient yearsduring adalimumab studies in patients with juvenile idiopathic arthritis (polyarticular juvenileidiopathic arthritis and enthesitis-related arthritis). In addition, no malignancies were observed in192 paediatric patients with an exposure of 498.1 patient years during adalimumab studies inpaediatric patients with Crohn’s disease. No malignancies were observed in 77 paediatric patientswith an exposure of 80.0 patient years during an adalimumab study in paediatric patients withchronic plaque psoriasis. No malignancies were observed in 93 paediatric patients with an exposureof 65.3 patient years during an adalimumab study in paediatric patients with ulcerative colitis. Nomalignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years duringan adalimumab study in paediatric patients with uveitis.

During the controlled portions of pivotal adalimumab studies in adults of at least 12 weeks induration in patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis,axial spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis,hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other thanlymphoma and non-melanoma skin cancer, were observed at a rate (95 % confidence interval) of6.8 (4.4, 10.5) per 1 000 patient years among 5 291 adalimumab-treated patients versus a rate of6.3 (3.4, 11.8) per 1 000 patient years among 3 444 control patients (median duration of treatmentwas 4.0 months for adalimumab 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 yearsamong adalimumab-treated patients and 3.2 (1.3, 7.6) per 1 000 patient years among controlpatients. Of these skin cancers, squamous cell carcinomas occurred at rates (95 % confidenceinterval) of 2.7 (1.4, 5.4) per 1 000 patient years among adalimumab-treated patients and 0.6 (0.1,4.5) per 1 000 patient years among control patients. The rate (95 % confidence interval) oflymphomas was 0.7 (0.2, 2.7) per 1 000 patient years among adalimumab-treated patients and 0.6(0.1, 4.5) per 1 000 patient years among control patients.

When combining controlled portions of these studies and ongoing and completed open labelextension studies with a median duration of approximately 3.3 years including 6 427 patients andover 26 439 patient years of therapy, the observed rate of malignancies, other than lymphoma andnon-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 patientswith rheumatoid arthritis, the spontaneously reported rate of malignancies is approximately 2.7 per1 000 patient treatment years. The spontaneously reported rates for non-melanoma skin cancersand lymphomas are approximately 0.2 and 0.3 per 1 000 patient treatment years, respectively (seesection 4.4).

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

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

In controlled Phase 3 studies of adalimumab in patients with rheumatoid arthritis and psoriaticarthritis with a control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULNoccurred in 3.7 % of adalimumab-treated patients and 1.6 % of control-treated patients.

In controlled Phase 3 studies of adalimumab in patients with polyarticular juvenile idiopathicarthritis who were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALTelevations ≥ 3 x ULN occurred in 6.1 % of adalimumab-treated patients and 1.3 % of control-treatedpatients. Most ALT elevations occurred with concomitant methotrexate use. No ALT elevations≥ 3 x ULN occurred in the Phase 3 study of adalimumab in patients with polyarticular juvenileidiopathic arthritis who were 2 to < 4 years.

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

In the Phase 3 study 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 x ULN occurred in2.6 % (5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline.

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

No ALT elevations ≥ 3 x ULN occurred in the Phase 3 study of adalimumab in paediatricpatients with plaque psoriasis.

In controlled studies 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 x ULN occurred in 0.3 % ofadalimumab-treated patients and 0.6 % of control-treated patients.

In controlled studies of adalimumab (initial doses of 80 mg at Week 0 followed by 40 mg everyother week starting at Week 1) in adult patients with uveitis up to 80 weeks with a median exposureof 166.5 days and 105.0 days in adalimumab-treated and control-treated patients, respectively, ALTelevations ≥ 3 x ULN occurred in 2.4 % of adalimumab-treated patients and 2.4 % of control-treatedpatients.

In the controlled Phase 3 study of adalimumab in patients with paediatric ulcerative colitis (N=93)which evaluated efficacy and safety of a maintenance dose of 0.6 mg/kg (maximum of 40 mg) everyother week (N=31) and a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every week (N=32),following body weight adjusted induction dosing of 2.4 mg/kg (maximum of 160 mg) at Week 0 and

Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=63), or an induction dose of 2.4 mg/kg(maximum of 160 mg) at Week 0, placebo at Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2(N=30), ALT elevations ≥ 3 X ULN occurred in 1.1 % (1/93) of patients.

Across all indications in clinical studies patients with raised ALT were asymptomatic and in mostcases elevations were transient and resolved on continued treatment. However, there have also beenpost- marketing reports of liver failure as well as less severe liver disorders that may precede liverfailure, 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 studies. The highest dose level evaluatedhas been multiple intravenous doses of 10 mg/kg, which is approximately 15 times therecommended dose.

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

ATC code: L04AB04

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

European Medicines Agency https://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 TNF-α wasseen. Endoscopic studies in intestinal mucosa have shown evidence of mucosal healing inadalimumab-treated patients.

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

RA study I evaluated 271 patients with moderately to severely active rheumatoid arthritis who were≥ 18 years old, had failed therapy with at least one disease-modifying, anti-rheumatic drug and 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 placebo onalternative weeks or every week for 26 weeks; placebo was given every week for the same duration.

No other disease-modifying anti-rheumatic drugs were allowed.

RA study III evaluated 619 patients with moderately to severely active rheumatoid arthritis who were≥ 18 years old, and who had an ineffective response to methotrexate at doses of 12.5 to 25 mg or 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 adalimumab everyweek for 52 weeks. The third group received 40 mg of adalimumab every other week with placeboinjections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab/MTX was administered every other week up to10 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 andrate of progression of joint damage in rheumatoid arthritis for 104 weeks. Upon completion of thefirst 104 weeks, 497 patients enrolled in an open-label extension phase in which 40 mg ofadalimumab was administered every other week up to 10 years.

The primary end point in RA studies I, II and III and the secondary endpoint in RA study IV was 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 studies(percent of patients)response RA Study Ia** RA Study IIa** RA Study IIIa**placebo/MTXc adalimumabb/M placebo adalimumabb placebo/MTXc adalimumabb/Mn = 60 TXc n = 110 n = 113 n = 200 TXcn = 63 n = 207

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

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

A CR 706 months 3.3 % 23.8 % 1.8 % 12.4 % 2.5 % 20.8 %12 months NA NA NA NA 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

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 RAstudy 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 for5 years. Among those, 86 patients (75.4 %) had ACR 20 responses; 72 patients (63.2 %) had ACR50 responses; and 41 patients (36 %) had ACR 70 responses. Of 207 patients, 81 patients continuedon adalimumab 40 mg every other week for 10 years. Among those, 64 patients (79.0 %) had ACR20 responses; 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 carewas statistically 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,combination therapy with adalimumab and methotrexate led to faster and significantly greater

ACR responses than methotrexate monotherapy and adalimumab monotherapy at Week 52 andresponses were sustained at Week 104 (see Table 9).

Table 9. ACR responses in RA study V(percent of patients)response MTX adalimumab adalimumab/MT p-valuea p-valueb p-valuecn = 257 n = 274 Xn = 268

ACR 20

Week 52 62.6 % 54.4 % 72.8 % 0.013 < 0.001 0.043

Week 104 56.0 % 49.3 % 69.4 % 0.002 < 0.001 0.140

ACR 50

Week 52 45.9 % 41.2 % 61.6 % < 0.001 < 0.001 0.317

Week 104 42.8 % 36.9 % 59.0 % < 0.001 < 0.001 0.162

ACR 70

Week 52 27.2 % 25.9 % 45.5 % < 0.001 < 0.001 0.656

Week 104 28.4 % 28.1 % 46.6 % < 0.001 < 0.001 0.864ap-value is from the pairwise comparison of methotrexate monotherapy andadalimumab/methotrexate combination therapy using the Mann-Whitney U test.bp-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 methotrexatemonotherapy using the Mann-Whitney U test

In the open-label extension for RA study V, ACR response rates were maintained when followedfor up 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 therapyachieved clinical remission (DAS28 < 2.6) compared to 20.6 % of patients receiving methotrexatemonotherapy and 23.4 % of patients receiving adalimumab monotherapy.

Adalimumab/methotrexate combination therapy was clinically and statistically superior tomethotrexate (p < 0.001) and adalimumab monotherapy (p < 0.001) in achieving a low diseasestate in patients with recently diagnosed moderate to severe rheumatoid arthritis. The response forthe two monotherapy arms was similar (p = 0.447).

Of 342 subjects originally randomized to adalimumab monotherapy or adalimumab/methotrexatecombination therapy who entered the open-label extension study, 171 subjects completed 10 yearsof adalimumab 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 arthritisof approximately 11 years, structural joint damage was assessed radiographically and expressedas change in modified Total Sharp Score (TSS) and its components, the erosion score and jointspace narrowing score. Adalimumab/methotrexate patients demonstrated significantly lessradiographic progression 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 structuraldamage is maintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patientsoriginally treated with 40 mg adalimumab every other week were evaluated radiographically.

Among those, 48 patients showed no progression of structural damage defined by a change frombaseline in the mTSS of 0.5 or less. At 10 years, 79 of 207 patients originally treated with 40 mgadalimumab every other week were evaluated radiographically. Among those, 40 patients showedno progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less.

Table 10. Radiographic mean changes over 12 months in RA study IIIaplacebo/MTX adalimumab/MTX placebo/MTX- p-value40 mg every other adalimumab/MTXweek (95 % confidencebinterval )total Sharp score 2.7 0.1 2.6 (1.4, 3.8) c< 0.001erosion score 1.6 0.0 1.6 (0.9, 2.2) < 0.001d

JSN 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 andadalimumabc 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 n = 257 adalimumab adalimumab/M(95 % n = 274 (95 % TX n=268confidence confidence (95 %interval) interval) confidence p-valueap-valueb cp-valueinterval)total Sharp 5.7 (4.2-7.3) 3.0 (1.7-4.3) 1.3 (0.5-2.1) < 0.001 0.0020 < 0.001scoreerosion 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 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

F ollowing 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 were31.3 %, 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 studies,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 the 40 mgevery 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 improvementwas maintained 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 through

Week 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 (mean baselinescore of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.3 inall 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 period during whichpatients received adalimumab 40 mg every other week subcutaneously for up to an additional28 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 ofthe signs 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 symptomsresponse 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 comparisonsbetween adalimumab and placebo 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 wasmaintained through 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 randomized, double-blind placebo-controlled studies in patients with non-radiographic axial spondyloarthritis (nr-axSpA). Study nr-axSpA I evaluated patients with active nr-axSpA. Study nr-axSpA II was a treatment withdrawalstudy in active nr-axSpA patients who achieved remission during open-label treatment withadalimumab.

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 (meanbaseline 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 had aninadequate 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 Idouble-blind placebo adalimumab

N=94 N=91response at Week 12

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 assessment of 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 duringthe open- 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 eowfor 28 weeks. These patients also had objective evidence of inflammation in the sacroiliac joints orspine on MRI or elevated hs-CRP. Patients who achieved sustained remission for at least 12 weeks(N=305) (ASDAS < 1.3 at Weeks 16, 20, 24, and 28) during the open-label period were thenrandomized to receive either continued treatment with adalimumab 40 mg eow (N=152) or placebo(N=153) for an additional 40 weeks in a double-blind, placebo-controlled period (total study duration68 weeks). Subjects who flared during the double-blind period were allowed adalimumab 40 mg eowrescue 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 proportionof patients 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 summarizing time to flare in study 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).

PROBABILITY OF NO FLARE

Table 14. Efficacy response in placebo-controlled period for study nr-axSpA IIdouble-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.

***, ** 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-inflammatory drug therapy and of these, approximately 50 % were taking methotrexate. PsA study

II with 12-week duration, treated 100 patients who had an inadequate response to DMARD therapy.

Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which40 mg adalimumab was administered every other week (eow).

There is insufficient evidence of the efficacy of adalimumab in patients with ankylosingspondylitis-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 IIresponse placebo adalimumab placebo adalimumab

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

ACR 20

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

Week 24 15 % 57 %***

N/A N/A

ACR 50

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

Week 24 6 % 39 %***

N/A N/A

ACR 70

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

Week 24 1 % 23 %***

N/A N/A

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

* p < 0.05 for all comparisons between adalimumab and placebo

N/A 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. Amodified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e. not identical tothe TSS used 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 theplacebo group (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 chronicplaque psoriasis with concomitant hand and/or foot psoriasis who were candidates for systemictherapy in a randomised 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 atleast a PASI 75 response (PASI score improvement of at least 75 % relative to baseline), enteredperiod B and received open-label 40 mg adalimumab every other week. Patients who maintained≥PASI 75 response at Week 33 and were originally randomised to active therapy in period A, werere-randomised in period C to receive 40 mg adalimumab every other week or placebo for anadditional 19 weeks. Across all treatment groups, the mean baseline PASI score was 18.9 and thebaseline Physician’s Global Assessment (PGA) score ranged from “moderate” (53 % of subjectsincluded) to “severe” (41 %) to “very severe” (6 %).

Psoriasis Study II (CHAMPION) compared the efficacy and safety of adalimumab versusmethotrexate and placebo in 271 patients. Patients received placebo, an initial dose of MTX 7.5 mgand thereafter dose increases up to Week 12, with a maximum dose of 25 mg or an initial dose of80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) for16 weeks. There are no 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 receivefurther dose increases. Across all treatment groups, the mean baseline PASI score was 19.7 and thebaseline PGA score ranged from “mild” (< 1 %) to “moderate” (48 %) to “severe” (46 %) to “verysevere” (6 %).

Patients participating in all Phase 2 and Phase 3 psoriasis studies were eligible to enrol into an open-label extension study, 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

PASI 75 response from baseline at Week 16 (see Tables 16 and 17).

Table 16. Ps study I (REVEAL) - efficacy results at 16 weeksplacebo N = 398 adalimumab 40 mg eown (%) N = 814 n (%)≥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 PASI75 response was calculated as centre-adjusted rateb p< 0.001, adalimumab vs. placebo

Table 17. Ps study II (CHAMPION) efficacy results at 16 weeksplacebo MTX N = 110 adalimumab 40 mg eow

N = 53 n (%) n (%) N=108 n (%)≥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: 6 (11.3) 33 (30.0) 79 (73.1) a, bclear/minimala 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 St udy 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 < PASI50 response 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 thenenrolled into the open-label extension study, 38 % (25/66) and 55 % (36/66) regained PASI 75response after 12 and 24 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 study. PASI75 and 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 these patientswere 69.6 % and 55.7 %, respectively, after an additional 108 weeks of open-label therapy (total of160 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 witha median 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” after16 weeks of retreatment, irrespective of whether they relapsed during withdrawal (69.1 % [123/178]and 88.8 % [95/107] for patients who relapsed and who did not relapse during the withdrawalperiod, 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,improvements in the physical and mental component summary scores of the SF-36 were alsosignificant compared to placebo.

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) ofpatients achieved 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 thehands and/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 adalimumabfollowed by 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeksfollowed by open-label adalimumab treatment for an additional 26 weeks. Nail psoriasis assessmentsincluded the Modified Nail Psoriasis Severity Index (mNAPSI), the Physician’s Global Assessment of

Fingernail Psoriasis (PGA-F) and the Nail Psoriasis Severity Index (NAPSI) (see Table 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 weeksendpoint Week 16 Week 26 Week 52placebo-controlled placebo-controlled open-labelplacebo adalimumab adalimumab adalimumab

N = 108 40 mg eow placebo

N = 109 N = 108 40 mg eow 40 mg eow

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

PGA-F clear/minimaland ≥ 2-grade 2.9 29.7a 6.9 48.9a 61.3improvement (%)percent change in total a afingernail NAPSI (%) -7.8 -44.2 -11.5 -56.2 -72.2a p < 0.001, adalimumab vs. placebo

A dalimumab-treated patients showed statistically significant improvements at Week 26 comparedwith placebo 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 a3-month study of systemic antibiotic therapy. The patients in HS-I and HS-II had Hurley Stage II or

III disease 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 randomisedto placebo 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 receivedadalimumab in period A were re-randomised in period B to 1 of 3 treatment groups (adalimumab40 mg every week, adalimumab 40 mg every other week, or placebo from Week 12 to Week 35).

Patients who had been randomised to placebo in period A were assigned to receive placebo inperiod 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.

Reduction of inflammatory lesions and prevention of worsening of abscesses and draining fistulaswas assessed using Hidradenitis Suppurativa Clinical Response (HiSCR; at least a 50 % reduction intotal abscess and inflammatory nodule count with no increase in abscess count and no increase indraining fistula 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 greateron a 11 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-IIexperienced a clinically relevant decrease in HS-related skin pain (see Table 19). Patients treatedwith adalimumab had significantly reduced risk of disease flare during the initial 12 weeks oftreatment.

Table 19. Efficacy results at 12 weeks, HS studies I and II

HS study I HS study IIadalimumab adalimumabplacebo 40 mg placebo 40 mgweekly weeklyhidradenitis suppurativa N = 154 N = 153 N = 163 N = 163clinical response (HiSCR)a40 (26.0 %) 64 (41.8 %)*45 (27.6 %) 96 (58.9 %)***≥30% reduction in skin N = 109 N = 122 N = 111 N = 105painb27 (24.8 %) 34 (27.9 %) 23 (20.7 %) 48 (45.7 %)***

* p < 0.05,

*** p < 0.001, adalimumab versus placeboa among all randomised patients.b 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 groupin the 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 %vs 13.9 %, respectively).

Greater improvements at Week 12 from baseline compared to placebo were demonstrated in skin-specific health-related quality of life, as measured by the Dermatology Life Quality Index (DLQI;

Studies HS-I and HS-II), patient global satisfaction with medicinal product treatment as measuredby the Treatment Satisfaction Questionnaire - medication (TSQM; Studies HS-I and HS-II), andphysical health 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 HiSCRrate at Week 36 was higher in patients who continued weekly adalimumab than in patients inwhom dosing frequency 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 36after treatment reassignment from weekly adalimumab at Week 12placebo adalimumab adalimumab(treatment 40 mg every 40 mg weeklywithdrawal) other week N = 70

N = 73 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 after12 weeks of treatment.b patients meeting protocol-specified criteria for loss of response or noimprovement were required to discontinue from the studies and were counted asnon-responders.

Among pa tients who were at least partial responders at Week 12, and who received continuous weeklyadalimumab therapy, the HiSCR rate at Week 48 was 68.3 % and at Week 96 was 65.1 %. Longerterm 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-Iand HS-II, the HiSCR rate 12 weeks after re-introduction of adalimumab 40 mg weeklyreturned to levels similar to 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 ofaminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted and 80 % ofpatients continued to receive at least one of these medicinal products.

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 naïve patients wererandomised to one of four treatment groups; placebo at Weeks 0 and 2, 160 mg adalimumab at

Week 0 and 80 mg at Week 2, 80 mg at Week 0 and 40 mg at Week 2, and 40 mg at Week 0 and20 mg at Week 2. In CD Study II, 325 patients who had lost response or were intolerant to infliximabwere randomised to receive either 160 mg adalimumab at Week 0 and 80 mg at Week 2 or placebo at

Weeks 0 and 2. The primary non-responders were excluded from the studies and therefore thesepatients were not further evaluated.

Maintenance of clinical remission was evaluated in CD study III (CHARM). In CD study III, 854patients 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 durationof 56 weeks. Patients in clinical response (decrease in CDAI ≥ 70) at Week 4 were stratified andanalysed separately from those not in clinical response at Week 4. Corticosteroid taper waspermitted after Week 8.

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-naïve CD study II: infliximab-patients experienced patientsplacebo adalimumab adalimumab placebo adalimumab

N = 74 80/40 mg 160/80 mg N=166 160/80 mg

N = 75 N = 76 N = 159

Week 4clinical remission 12 % 24 % 36 %*7 % 21 %*clinical response (CR- 24 % 37 % 49 %**25 % 38 %**100)

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 8 and 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 assessedin the primary analysis. Of those in clinical response at Week 4, 48 % had been previously exposedto other 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 withadalimumab compared with placebo at Week 56.

Table 22. Maintenance of clinical remission and response(percent of patients)placebo 40 mg adalimumab 40 mg adalimumabevery other week every week

Week 26 N = 170 N = 172 N = 157clinical remission 17 % 40 %* 47 %*clinical response (CR-100) 27 % 52 %* 52 %*patients in steroid-free remission 3 % (2/66) 19 % (11/58)** 15 % (11/74)**for > = 90 daysa

Week 56 N = 170 N = 172 N = 157clinical remission 12 % 36 %* 41 %*clinical response (CR-100) 17 % 41 %* 48 %*patients in steroid-free remission 5 % (3/66) 29 % (17/58)* 20 % (15/74)**for > = 90 daysa

* 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 suggestthat some patients who have not responded by Week 4 benefit from continued maintenance therapythrough Week 12. Therapy continued beyond 12 weeks did not result in significantly moreresponses (see section 4.2).

117/276 patients from CD study I and 272/777 patients from CD studies II and III werefollowed through 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 maintainedin 102 and 233 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 26 and 56 in CD study III as well among the adalimumab treatment groups compared to theplacebo group.

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 to3) in randomised, double-blind, placebo-controlled studies.

In study UC-I, 390 TNF-antagonist naïve patients were randomised to receive either placebo at

Weeks 0 and 2, 160 mg adalimumab at Week 0 followed by 80 mg at Week 2, or 80 mg adalimumab at

Week 0 followed by 40 mg at Week 2. After Week 2, patients in both adalimumab arms received40 mg eow. Clinical remission (defined as Mayo score ≤ 2 with no subscore > 1) was assessed at

Week 8.

In study UC-II, 248 patients received 160 mg of adalimumab at Week 0, 80 mg at Week 2 and 40 mgeow thereafter, and 246 patients received placebo. Clinical results were assessed for induction ofremission 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 in statistically significantly greater percentages in study UC-I (18 % vs. 9 % respectively,p = 0.031) and study UC-II (17 % vs. 9 % respectively, p = 0.019). In study UC-II, among thosetreated with adalimumab 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 adalimumab 40 mgeow

Week 52 N = 246 N = 248clinical 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 52sustained 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 in therectal 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 inremission, 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 achievedby 3 % 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 continueon study medicinal product beyond Week 78 until they had access to adalimumab.

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 IIanalysis N failure median time to HRa CI 95 % p Value btreatment N (%) failure (months) for HRatime to treatment failure at or after Week 6 in study UV Iprimary analysis (ITT)placebo 107 84 (78.5) 3.0 -- -- --adalimumab 110 60 (54.5) 5.6 0.50 0.36, 0.70 < 0.001time to treatment failure at or after Week 2 in study UV IIprimary analysis (ITT)placebo 111 61 (55.0) 8.3 -- -- --adalimumab 115 45 (39.1) NEc0.57 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 factor.b 2-sided p value from log rank test.c NE = not estimable. Fewer than half of at-risk subjects had an event.

Figure 2: Kaplan-Meier curves summarizing 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 % discontinued dueto 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 UV I 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 efficacyof adalimumab. There is no apparent correlation between the presence of anti-adalimumab antibodiesand the occurrence 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 JIAonset types (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 LIphaseage group number of patients at baseline n (%) Minimum, median and maximumdose4 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 randomisedinto the double blind (DB) phase and received either adalimumab 24 mg/m2 up to a maximum of40 mg, or placebo every other week for an additional 32 weeks or until disease flare. Disease flarecriteria were defined as a worsening of ≥ 30 % from baseline in ≥ 3 of 6 paediatric ACR corecriteria, ≥ 2 active joints, and improvement of > 30 % in no more than 1 of the 6 criteria. After32 weeks or at disease flare, patients were eligible to enrol into the open label extension phase.

Table 26. Ped ACR 30 responses in the JIA studystratum MTX without MTXphase

OL-LI 16 weeksped ACR 30 94.1 % (80/85) 74.4% (64/86)response (n/N)efficacy outcomesdouble blind 32 weeks adalimumab/M placebo/MTX adalimumab placebo

TX (N =38) (N = 37) (N = 30) (N = 28)disease flares at 36.8 % (14/38) 64.9 % (24/37)b43.3 % (13/30) 71.4 % (20/28)cthe end of 32weeksa (n/N)median time to >32 weeks 20 weeks >32 weeks 14 weeksdisease flarea 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 responseswere maintained for up to six years in the OLE phase in patients who received adalimumabthroughout the study. Over all 19 subjects, of which 11 of the baseline age group 4 to 12 and 8 ofthe baseline age group 13 to 17 years were treated 6 years or longer.

Overall responses were generally better and, fewer patients developed antibodies when treated withthe combination of adalimumab and MTX compared to adalimumab alone. Taking these results intoconsideration, Hyrimoz 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 active polyarticular

JIA. The patients received 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of20 mg every other week as a single dose via SC injection for at least 24 weeks. During the study, mostsubjects used concomitant MTX, with fewer reporting use of corticosteroids or NSAIDs.

At Week 12 and Week 24, PedACR30 response was 93.5 % and 90.0 %, respectively, using theobserved data approach. The proportions of subjects with PedACR50/70/90 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 study in46 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 of 40 mgevery other week subcutaneously for up to an additional 192 weeks. The primary endpoint was thepercent 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 through

Week 156 for the 26 of 31 (84 %) patients in the adalimumab group who remained in the study.

Although not statistically significant, the majority of patients demonstrated clinical improvement insecondary endpoints such as number of sites of enthesitis, tender joint count (TJC), swollen jointcount (SJC), paediatric ACR 50 response, and paediatric ACR 70 response.

The efficacy of adalimumab was assessed in a randomised, double-blind, controlled study of 114paediatric patients from 4 years of age with severe chronic plaque psoriasis (as defined by a

Physician’s Global Assessment (PGA) ≥ 4 or > 20 % BSA involvement or > 10 % BSA involvementwith very thick lesions or Psoriasis Area and Severity Index (PASI) ≥ 20 or ≥ 10 with clinicallyrelevant facial, genital, or hand/foot involvement) who were inadequately controlled with topicaltherapy and heliotherapy or phototherapy.

Patients received adalimumab 0.8 mg/kg eow (up to 40 mg), 0.4 mg/kg eow (up to 20 mg), ormethotrexate 0.1-0.4 mg/kg weekly (up to 25 mg). At Week 16, more patients randomised toadalimumab 0.8 mg/kg had positive efficacy responses (e.g., PASI 75) than those randomised to0.4 mg/kg eow or MTX.

Table 27. Paediatric plaque psoriasis efficacy results at 16 weeks

MTXaadalimumab 0.8 mg/kg eow N=38

N = 37

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 eow for an additional 16 weeks and responserates observed during retreatment were similar to the previous double-blind period: PASI 75 responseof 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 weremaintained for up to an additional 52 weeks with no new safety findings.

Adolescent hidradenitis suppurativa

There are no clinical studies 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 study designed toevaluate the efficacy and safety of induction and maintenance treatment with doses dependent onbody weight (< 40 kg or ≥ 40 kg) in 192 paediatric subjects between the ages of 6 and17 (inclusive) years, with moderate to severe Crohn’s disease (CD) defined as Paediatric Crohn’s

Disease Activity Index (PCDAI) score > 30. Subjects had to have failed conventional therapy(including a corticosteroid and/or an immunomodulator) for CD. Subjects may also have previouslylost response or been intolerant to infliximab.

All subjects received open-label induction therapy at a dose based on their Baseline body weight:160 mg at Week 0 and 80 mg at Week 2 for subjects ≥ 40 kg, and 80 mg and 40 mg, respectively, 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 regimenpatient low dose standardweight dose< 40 kg 10 mg eow 20 mg eow≥ 40 kg 20 mg eow 40 mg eow

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 rem ission and responsestandard dose low dose p value*40/20 mg eow 20/10 mg eow

N = 93 N = 95

Week 26clinical remission 38.7 % 28.4 % 0.075clinical response 59.1 % 48.4 % 0.073

Week 52clinical remission 33.3 % 23.2 % 0.100clinical response 41.9 % 28.4 % 0.038

* p-value for standard dose versus low dose comparison.

Table 30. Paediatric CD studydiscontinuation of corticosteroids or im munomodulators and fistula remissionstandard dose low dose p value140/20 mg eow 20/10 mg eowdiscontinued corticosteroids N = 33 N = 38

Week 26 84.8 % 65.8 % 0.066

Week 52 69.7 % 60.5 % 0.420discontinuation of Immunomodulators2 N = 60 N = 57

Week 52 30.0 % 29.8 % 0.983fistula 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 comparison.2 immunosuppressant therapy could only be discontinued at or after Week 26at the investigator's discretion if the subject met the clinical responsecriterion3 defined as a closure of all fistulas that were draining at Baseline for at least 2 consecutivepost-Baseline visits

Statistically significant increases (improvement) from Baseline to Week 26 and 52 in Body Mass

Index and height velocity were observed for both treatment groups.

Statistically and clinically significant improvements from Baseline were also observed in 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 multicenter, randomized, double-blind, studyin 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 randomized 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 randomized 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 randomized to receive placebo but were not included in the confirmatory analysis of efficacy.

Disease flare was defined as an increase in PMS of at least 3 points (for patients with PMS of 0 to 2 at

Week 8), at least 2 points (for patients with PMS of 3 to 4 at Week 8), or at least 1 point (for patientswith PMS of 5 to 6 at Week 8).

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

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 the adalimumab doubleblindinduction groups are presented in Table 31.

Table 31. Clinical remission per PMS at 8 weeks

Adalimumab a Adalimumab b, c

Maximum of 160 mg at Week Maximum of 160 mg at Week0/Placebo at Week 1 0 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, and1.2 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 of 80 mg) at Week 2c Not including open-label Induction dose of adalimumab 2.4 mg/kg (maximum of160 mg) at Week 0 and 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 theendpoint

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 per FMS (defined as an Mayo endoscopy subscore ≤ 1) in Week 8 responders, clinicalremission per FMS in Week 8 remitters, and the proportion of subjects in corticosteroid-freeremission per FMS in Week 8 responders were assessed in patients who received adalimumab at thedouble-blind maximum 40 mg eow (0.6 mg/kg) and maximum 40 mg ew (0.6 mg/kg) maintenancedoses ( 32).

Table 32. Efficacy results at 52 weeks

Adalimumab a Adalimumab b

Maximum of 40 mg eow Maximum of 40 mg ew

N=31 N=31

Clinical remission in Week8 PMS responders 9/31 (29.0%) 14/31 (45.2%)

Clinical response in Week8 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 Week8 PMS remitters 9/21 (42.9%) 10/22 (45.5%)

Corticosteroid-freeremission in Week 8 4/13 (30.8%) 5/16 (31.3%)

PMS respondersca 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 randomized to receivere-induction or maintenance 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

Adalimumab a Adalimumab b,c

Maximum of 160 mg at Maximum of 160 mg

Week 0/Placebo at Week 1 at Week 0 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

Adalimumab d Adalimumab e

Maximum of 40 mg eow Maximum of 40 mg ew

N=31 N=31

Clinical remission per PUCAI 14/31 (45.2%) 18/31 (58.1%)in Week 8 PMS responders

Clinical response per PUCAI 18/31 (58.1%) 16/31 (51.6%)in Week 8 PMS respondersa Adalimumab 2.4 mg/kg (maximum of 160 mg) at Week 0, placebo at Week 1, and1.2 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 of 80 mg) at Week 2c Not including open-label Induction dose of adalimumab 2.4 mg/kg (maximum of160 mg) at Week 0 and 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 theendpoints

Note 3: Patients with missing values at Week 52 or who were randomized to receivereinduction or maintenance treatment were considered non-responders for Week 52endpoints

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 forthe groups treated with adalimumab, and clinically meaningful increases (improvement) from

Baseline in Body Mass Index were observed for subjects on the high maintenance dose of maximum40 mg (0.6 mg/kg) ew.

Paediatric uveitis

The safety and efficacy of adalimumab was assessed in a randomized, double-masked, controlledstudy of 90 paediatric patients from 2 to < 18 years of age with active JIA-associated non-infectiousanterior 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 medicinal products, and suspension of treatment for an extended period of time.

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 forsubjects treated with placebo, whereas the median time to treatment failure was not estimable forsubjects treated with adalimumab because less than one-half of these subjects experienced treatmentfailure. Adalimumab significantly decreased the risk of treatment failure by 75 % relative to placebo,as shown by the hazard ratio (HR = 0.25 [95 % CI: 0.12, 0.49]).

Figure 3: Kaplan-Meier curves summarizing time to treatment failure in the paediatricuveitis study

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 11to 15 ml/hour, the distribution volume (Vss) ranged from 5 to 6 litres and the mean terminal phasehalf-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 adultrheumatoid arthritis (RA) patients the mean steady-state trough concentrations wereapproximately 5 µg/ml (without concomitant methotrexate) and 8 to 9 µg/ml (with concomitantmethotrexate), respectively. The serum adalimumab trough levels at steady-state increased roughlyproportionally with dose following 20, 40 and 80 mg subcutaneous dosing every other week andevery week.

Following the administration of 24 mg/m2 (a 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 was5.6 ± 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 aboveweighing < 15 kg dosed with adalimumab 24 mg/m2, the mean trough steady-state serumadalimumab concentrations was 6.0 ± 6.1 µg/ml (101 % CV) for adalimumab without concomitantmethotrexate and 7.9 ± 5.6 µg/ml (71.2 % CV) with concomitant methotrexate.

Following the administration of 24 mg/m2 (a maximum of 40 mg) subcutaneously every other weekto patients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state(values measured at Week 24) serum adalimumab concentrations were 8.8 ± 6.6 μg/ml foradalimumab without 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 (a maximum of 40 mg) subcutaneously every other weekto paediatric 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/mlat Week 2 and Week 4. The mean steady-state trough concentration at Week 12 through Week 36were approximately 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 by40 mg adalimumab on Week 2 achieves serum adalimumab trough concentrations of approximately5.5 µg/ml during the induction period. A loading dose of 160 mg adalimumab on Week 0 followed by80 mg adalimumab on Week 2 achieves serum adalimumab trough concentrations of approximately12 µg/ml during the induction period. Mean steady-state trough levels of approximately 7 µg/ml wereobserved in Crohn’s disease patients who received a maintenance dose of 40 mg adalimumab everyother 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 eow) or Low Dose(20/10 mg eow) maintenance treatment groups based on their body weight. The mean (± SD) serumadalimumab trough concentrations achieved at Week 4 were 15.7 ± 6.6 µg/ml for patients ≥ 40 kg(160/80 mg) and 10.6 ± 6.1 µg/ml for patients < 40 kg (80/40 mg).

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

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 by40 mg adalimumab every other week starting at Week 1, resulted in mean steady-stateconcentrations of approximately 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 study 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 evidenceof harm to the foetuses due to adalimumab. Neither carcinogenicity studies, nor a standardassessment of fertility and postnatal toxicity, were performed with adalimumab due to the lack ofappropriate models for an antibody with limited cross-reactivity to rodent TNF and to thedevelopment of neutralising antibodies in rodents.

Adipic acid

Mannitol (E 421)

Polysorbate 80 (E 433)

Hydrochloric acid (for pH adjustment) (E 507)

Sodium hydroxide (for pH adjustment) (E 524)

Water for injections

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

2 years

Store in a refrigerator (2°C-8°C). Do not freeze. Keep the pre-filled syringe/pre-filled pen in theouter carton in order to protect from light.

A single Hyrimoz pre-filled syringe/pre-filled pen may be stored at temperatures up to a maximum of25°C for a period of up to 42 days. The pre-filled syringe/pre-filled pen must be protected from light,and discarded if not used within the 42-day period.

Hyrimoz 20 mg solution for injection in pre-filled syringe0.2 ml solution in a single-use clear type I glass syringe with a rubber stopper (bromobutyl rubber) anda stainless steel 29 gauge needle with finger flange, rubber needle cap (thermoplastic elastomer) andplastic plunger.

Multipack containing 2 (2 packs of 1) pre-filled syringes.

Hyrimoz 40 mg solution for injection in pre-filled syringe0.4 ml solution in a single-use clear type I glass syringe with a rubber stopper (bromobutyl rubber) anda stainless steel 29 gauge needle with an automatic needle guard with finger flange, rubber needle cap(thermoplastic elastomer) and plastic plunger.

Packs of 1 and 2 pre-filled syringes in a blister

Multipack containing 6 (3 packs of 2) pre-filled syringes in a blister

Hyrimoz 40 mg solution for injection in pre-filled pen0.4 ml solution in a single-use pre-filled syringe assembled into a triangular-shaped pen withtransparent window and label. The syringe inside the pen is made of type I glass with a stainless steel29 gauge needle, an inner rubber needle cap (thermoplastic elastomer), and a rubber stopper(bromobutyl rubber).

Packs of 1, 2 and 4 pre-filled pens

Multipack containing 6 (3 packs of 2) pre-filled pens

Hyrimoz 80 mg solution for injection in pre-filled syringe0.8 ml solution in a single-use clear type I glass syringe with a rubber stopper (bromobutyl rubber) anda stainless steel 29 gauge needle with an automatic needle guard with finger flange, rubber needle cap(thermoplastic elastomer) and plastic plunger.

Packs of 1 and 2 pre-filled syringes in a blister

Hyrimoz 80 mg solution for injection in pre-filled pen0.8 ml solution in a single-use pre-filled syringe assembled into a triangular-shaped pen withtransparent window and label. The syringe inside the pen is made of type I glass with a stainless steel29 gauge needle, an inner rubber needle cap (thermoplastic elastomer), and a rubber stopper(bromobutyl rubber).

Packs of 1, 2 and 3 pre-filled pens

Not all pack sizes may be marketed.

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

Full instructions for use are given in the package leaflet, section 7, 'Instructions for Use'.

Sandoz GmbH

Biochemiestr. 106250 Kundl

Austria

Hyrimoz 20 mg solution for injection in pre-filled syringe

EU/1/18/1286/019

Hyrimoz 40 mg solution for injection in pre-filled syringe

EU/1/18/1286/012

EU/1/18/1286/013

EU/1/18/1286/014

Hyrimoz 40 mg solution for injection in pre-filled pen

EU/1/18/1286/015

EU/1/18/1286/016

EU/1/18/1286/017

EU/1/18/1286/018

Hyrimoz 80 mg solution for injection in pre-filled syringe

EU/1/18/1286/008

EU/1/18/1286/009

Hyrimoz 80 mg solution for injection in pre-filled pen

EU/1/18/1286/010

EU/1/18/1286/011

EU/1/18/1286/020

Date of first authorisation: 26 July 2018

Date of latest renewal: 15 February 2023

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

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