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

Yuflyma 40 mg solution for injection in pre-filled syringe

Yuflyma 40 mg solution for injection in pre-filled pen

Yuflyma 40 mg solution for injection in pre-filled syringe

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

Yuflyma 40 mg solution for injection in pre-filled pen

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

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

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear to slightly opalescent, colourless to pale brown solution.

Yuflyma in combination with methotrexate, is indicated for:

* the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response todisease-modifying anti-rheumatic drugs including methotrexate has been inadequate.

* the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treatedwith methotrexate.

Yuflyma can be given as monotherapy in case of intolerance to methotrexate or when continued treatmentwith methotrexate is inappropriate.

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

Yuflyma in combination with methotrexate is indicated for the treatment of active polyarticular juvenileidiopathic arthritis, in patients from the age of 2 years who have had an inadequate response to one or moredisease-modifying anti-rheumatic drugs (DMARDs). Yuflyma can be given as monotherapy in case ofintolerance to methotrexate or when continued treatment with methotrexate is inappropriate (for the efficacyin monotherapy see section 5.1). Adalimumab has not been studied in patients aged less than 2 years.

Yuflyma is indicated for the treatment of active enthesitis-related arthritis in patients, 6 years of age andolder, who have had an inadequate response to, or who are intolerant of, conventional therapy (see section5.1).

Yuflyma is indicated for the treatment of adults with severe active ankylosing spondylitis who have had aninadequate response to conventional therapy.

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

Yuflyma 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 measured by X-ray in patients with polyarticular symmetrical subtypes of the disease (see section 5.1) and to improvephysical function.

Yuflyma is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients whoare candidates for systemic therapy.

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

Yuflyma is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) inadults and adolescents from 12 years of age with an inadequate response to conventional systemic HStherapy (see sections 5.1 and 5.2).

Yuflyma is indicated for treatment of moderately to severely active Crohn’s disease, in adult patients whohave 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.

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

Yuflyma is indicated for treatment of moderately to severely active ulcerative colitis in adult patients whohave had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-

MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.

Yuflyma 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 or havemedical contraindications for such therapies.

Yuflyma 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

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

Yuflyma treatment should be initiated and supervised by specialist physicians experienced in the diagnosisand treatment of conditions for which Yuflyma is indicated. Ophthalmologists are advised to consult with anappropriate specialist before initiation of treatment with Yuflyma (see section 4.4). Patients treated with

Yuflyma should be given the Patient Reminder Card.

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

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

The recommended dose of Yuflyma 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 Yuflyma.

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

In monotherapy, some patients who experience a decrease in their response to Yuflyma 40 mg every otherweek may benefit from an increase in dosage to 40 mg adalimumab every week or 80 mg every other week.

Available data suggest that the clinical response is usually achieved within 12 weeks of treatment.

Continued therapy should be reconsidered in a patient not responding within this time period.

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

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

The recommended dose of Yuflyma for patients with ankylosing spondylitis, axial spondyloarthritis withoutradiographic evidence of AS and for patients with psoriatic arthritis is 40 mg adalimumab administeredevery 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 Yuflyma for adult patients is an initial dose of 80 mg administeredsubcutaneously, followed by 40 mg subcutaneously given every other week starting one week after theinitial dose.

Continued therapy beyond 16 weeks should be carefully reconsidered in a patient not responding within thistime period.

Beyond 16 weeks, patients with inadequate response to Yuflyma 40 mg every other week may benefit froman increase in dosage to 40 mg every week or 80 mg every other week. The benefits and risks of continued40 mg weekly or 80 mg every other week therapy should be carefully reconsidered in a patient with aninadequate response after the increase in dosage (see section 5.1). If adequate response is achieved with40 mg every week or 80 mg every other week, the dosage may subsequently be reduced to 40 mg every otherweek.

The recommended Yuflyma dose regimen for adult patients with hidradenitis suppurativa (HS) is 160 mginitially at day 1 (given as four 40 mg injections in one day or as two 40 mg injections per day for twoconsecutive days), followed by 80 mg two weeks later at day 15 (given as two 40 mg injections in one day).

Two weeks later (day 29) continue with a dose of 40 mg every week or 80 mg every other week (given astwo 40 mg injections in one day). Antibiotics may be continued during treatment with Yuflyma if necessary.

It is recommended that the patient should use a topical antiseptic wash on their HS lesions on a daily basisduring treatment with Yuflyma.

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

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

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

The recommended Yuflyma induction dose regimen for adult patients with moderately to severely active

Crohn’s disease is 80 mg at week 0 followed by 40 mg at week 2. In case there is a need for a more rapidresponse to therapy, the regimen 160 mg at week 0 (given as four 40 mg injections in one day or as two40 mg injections per day for two consecutive days), followed by 80 mg at week 2 (given as 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 subcutaneous injection.

Alternatively, if a patient has stopped Yuflyma and signs and symptoms of disease recur, Yuflyma may bere-administered. There is little experience from re-administration after more than 8 weeks since the previousdose.

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

Some patients who experience decrease in their response to Yuflyma 40 mg every other week may benefitfrom an increase in dosage to 40 mg Yuflyma every week or 80 mg every other week.

Some patients who have not responded by week 4 may benefit from continued maintenance therapy throughweek 12. Continued therapy should be carefully reconsidered in a patient not responding within this timeperiod.

The recommended Yuflyma induction dose regimen for adult patients with moderate to severe ulcerativecolitis is 160 mg at week 0 (given as four 40 mg injections in one day or as two 40 mg injections per day fortwo consecutive days) and 80 mg at week 2 (given as two 40 mg injections in one day). After inductiontreatment, 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 Yuflyma 40 mg every other week may benefitfrom an increase in dosage to 40 mg Yuflyma every week or 80 mg every other week.

Available data suggest that clinical response is usually achieved within 2-8 weeks of treatment. Yuflymatherapy should not be continued in patients failing to respond within this time period.

The recommended dose of Yuflyma for adult patients with uveitis is an initial dose of 80 mg, followed by40 mg given every other week starting one week after the initial dose. There is limited experience in theinitiation of treatment with adalimumab alone. Treatment with Yuflyma can be initiated in combination withcorticosteroids and/or with other non-biologic immunomodulatory agents. Concomitant corticosteroids maybe tapered in accordance with clinical practice starting two weeks after initiating treatment with Yuflyma.

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

No dose adjustment is required.

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

Polyarticular juvenile idiopathic arthritis from 2 years of age

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

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

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

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

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

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

Table 2. Yuflyma 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.

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

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

Table 3. Yuflyma dose for paediatric patients with plaque psoriasis

Patient weight Dosing regimen

Initial dose of 20 mg,followed by 20 mg given15 kg to < 30 kgevery other week starting oneweek after the initial dose

Initial dose of 40 mg,followed by 40 mg given≥ 30 kgevery other week starting oneweek after the initial dose

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

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

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

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

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

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

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

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

Yuflyma.

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

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

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

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

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

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

Patient Maintenance dose

Induction doseweight 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 with 20 mg every otherthe awareness that the risk for adverse events may be higher with weekuse of the higher induction dose, the following dose may be 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 therapywith the awareness that the risk for adverse events may behigher with use of the higher induction dose, the followingdose may be used:

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

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

* < 40 kg: 20 mg every week

* ≥ 40 kg: 40 mg every week or 80 mg every other week

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

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

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

Table 5. Yuflyma dose for paediatric patients with ulcerative colitis

Patient weight Induction dosestarting at week 4*< 40 kg * 80 mg at week 0 (given as two 40 mg * 40 mg every other weekinjections in one day) and

* 40 mg at week 2 (given as one 40 mginjection)≥ 40 kg * 160 mg at week 0 (given as four 40 mg * 80 mg every other weekinjections in one day or two 40 mg injectionsper day for two consecutive days) and

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

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

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

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

Paediatric uveitis

The recommended dose of Yuflyma for paediatric patients with uveitis from 2 years of age is based on bodyweight (Table 6). Yuflyma is administered via subcutaneous injection.

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

Table 6. Yuflyma dose for paediatric patients with uveitis

Patient weight Dosing regimen20 mg every other week in< 30 kg combination withmethotrexate40 mg every other week in≥ 30 kg combination withmethotrexate

When Yuflyma therapy is initiated, a loading dose of 40 mg for patients < 30 kg or 80 mg for patients ≥ 30kg may be administered one week prior to the start of maintenance therapy. No clinical data are available onthe use of an adalimumab loading dose in children < 6 years of age (see section 5.2).

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

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

Yuflyma is administered by subcutaneous injection.

Full instructions for use are provided in the package leaflet.

Yuflyma is available in other strengths and presentations.

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 (NYHA class III/IV) (see section 4.4).

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

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

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

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

Serious infections, including sepsis, due to bacterial, mycobacterial, invasive fungal, parasitic, viral, or otheropportunistic infections such as listeriosis, legionellosis and pneumocystis have been reported in patientsreceiving adalimumab.

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

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

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

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

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

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

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

Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of Yuflyma inpatients with several or significant risk factors for tuberculosis despite a negative test for tuberculosis and inpatients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannotbe confirmed.

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

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

Yuflyma.

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

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

Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including adalimumab, whoare chronic carriers of this virus (i.e. surface antigen positive). Some cases have had a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with Yuflyma. For patients who testpositive for hepatitis B infection, consultation with a physician with expertise in the treatment of hepatitis Bis recommended.

Carriers of HBV who require treatment with Yuflyma should be closely monitored for signs and symptomsof active HBV infection throughout therapy and for several months following termination of therapy.

Adequate data from treating patients who are carriers of HBV with anti-viral therapy in conjunction with

TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBVreactivation, Yuflyma should be stopped and effective anti-viral therapy with appropriate supportivetreatment 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 system demyelinatingdisease including multiple sclerosis and optic neuritis, and peripheral demyelinating disease, including

Guillain- Barré syndrome. Prescribers should exercise caution in considering the use of Yuflyma in patientswith pre- existing or recent-onset central or peripheral nervous system demyelinating disorders;discontinuation of Yuflyma should be considered if any of these disorders develop. There is a knownassociation between intermediate uveitis and central demyelinating disorders. Neurologic evaluation shouldbe performed in patients with non-infectious intermediate uveitis prior to the initiation of Yuflyma therapyand regularly during treatment to assess for pre-existing or developing central demyelinating disorders.

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

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

In the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies includinglymphoma have been observed among patients receiving a TNF-antagonist compared with control patients.

However, the occurrence was rare. In the post marketing setting, cases of leukaemia have been reported inpatients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukaemiain rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicatesthe risk estimation. With the current knowledge, a possible risk for the development of lymphomas,leukaemia, and other malignancies in patients treated with a TNF-antagonist cannot be excluded.

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

Rare postmarketing cases of hepatosplenic T-cell lymphoma have been identified in patients treated withadalimumab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal.

Some of these hepatosplenic T-cell lymphomas with adalimumab have occurred in young adult patients onconcomitant treatment with azathioprine or 6-mercaptopurine used for inflammatory bowel disease. Thepotential risk with the combination of azathioprine or 6-mercaptopurine and Yuflyma should be carefullyconsidered. A risk for the development of hepatosplenic T-cell lymphoma in patients treated with Yuflymacannot be excluded (see section 4.8).

No studies have been conducted that include patients with a history of malignancy or in whom treatmentwith adalimumab is continued following development of malignancy. Thus, additional caution should beexercised in considering Yuflyma treatment of these patients (see section 4.8).

All patients, and in particular patients with a medical history of extensive immunosuppressant therapy orpsoriasis patients with a history of PUVA treatment should be examined for the presence of non- melanomaskin cancer prior to and during treatment with Yuflyma. Melanoma and Merkel cell carcinoma have alsobeen reported in patients treated with TNF-antagonists including adalimumab (see section 4.8).

In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patients withmoderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lungor head and neck, were reported in infliximab-treated patients compared with control patients. All patientshad a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist in

COPD patients, as well as in patients with increased risk for malignancy due to heavy smoking.

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

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

Similar antibody responses to the standard 23-valent pneumococcal vaccine and the influenza trivalent virusvaccination were observed in a study in 226 adult subjects with rheumatoid arthritis who were treated withadalimumab or placebo. No data are available on the secondary transmission of infection by live vaccines inpatients 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 Yuflyma therapy.

Patients on Yuflyma may receive concurrent vaccinations, except for live vaccines. Administration of livevaccines (e.g., BCG vaccine) to infants exposed to adalimumab in utero is not recommended for 5 monthsfollowing the mother’s last adalimumab injection during pregnancy.

In a clinical trial with another TNF-antagonist worsening congestive heart failure and increased mortalitydue to congestive heart failure have been observed. Cases of worsening congestive heart failure have alsobeen reported in patients receiving adalimumab. Yuflyma should be used with caution in patients with mildheart failure (NYHA class I/II). Yuflyma is contraindicated in moderate to severe heart failure (see section4.3). Treatment with Yuflyma must be discontinued in patients who develop new or worsening symptoms ofcongestive heart failure.

Treatment with Yuflyma may result in the formation of autoimmune antibodies. The impact of long-termtreatment with adalimumab on the development of autoimmune diseases is unknown. If a patient developssymptoms suggestive of a lupus-like syndrome following treatment with Yuflyma and is positive forantibodies against double-stranded DNA, further treatment with Yuflyma should not be given (see section4.8).

Serious infections were seen in clinical studies with concurrent use of anakinra and another TNF-antagonist,etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverseevents seen with the combination of etanercept and anakinra therapy, similar toxicities may also result fromthe combination of anakinra and other TNF-antagonists. Therefore, the combination of adalimumab andanakinra is not recommended (see section 4.5).

Concomitant administration of adalimumab with other biologic DMARDs (e.g, anakinra and abatacept) orother TNF-antagonists is not recommended based upon the possible increased risk for infections, includingserious infections and other potential pharmacological interactions (see section 4.5).

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

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

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

See Vaccinations above.

Sodium contents

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.4 ml dose, that is to sayessentially ‘sodium-free’.

Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriaticarthritis patients taking adalimumab as monotherapy and those taking concomitant methotrexate. Antibodyformation was lower when adalimumab was given together with methotrexate in comparison with use asmonotherapy. Administration of adalimumab without methotrexate resulted in increased formation ofantibodies, increased clearance and reduced efficacy of 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 prevent pregnancyand continue its use for at least five months after the last Yuflyma treatment.

A large number (approximately 2,100) of prospectively collected pregnancies exposed to adalimumabresulting in live birth with known outcomes, including more than 1,500 exposed during the 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) treatedwith adalimumab at least during the first trimester and 120 women with RA or CD not treated withadalimumab were enrolled. The primary endpoint was the birth prevalence of major birth defects. The rateof pregnancies ending with at least one live born infant with a major birth defect was 6/69 (8.7%) in theadalimumab-treated women with RA and 5/74 (6.8%) in the untreated women with RA (unadjusted OR1.31, 95% CI 0.38-4.52) and 16/152 (10.5%) in the adalimumab-treated women with CD and 3/32 (9.4%) inthe untreated women with CD (unadjusted OR 1.14, 95% CI 0.31-4.16). The adjusted OR (accounting forbaseline differences) was 1.10 (95% CI 0.45-2.73) with RA and CD combined. There were no distinctdifferences between adalimumab-treated and untreated women for the secondary endpoints spontaneousabortions, minor birth defects, preterm delivery, birth size and serious or opportunistic infections and nostillbirths or malignancies were reported. The interpretation of data may be impacted due to methodologicallimitations of the study, including small sample size and non-randomised design.

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

Due to its inhibition of TNF, adalimumab administered during pregnancy could affect normal immuneresponses in the newborn. Adalimumab should only be used during pregnancy if clearly needed.

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

Limited information from the published literature indicates that adalimumab is excreted in breast milk atvery low concentrations with the presence of adalimumab in human milk at concentrations of 0.1% to 1% ofthe maternal serum level. Given orally, immunoglobulin G proteins undergo intestinal proteolysis and havepoor bioavailability. No effects on the breastfed newborns/infants are anticipated. Consequently, Yuflymacan be used during breastfeeding.

Preclinical data on fertility effects of adalimumab are not available.

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

Adalimumab was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months ormore. These trials included rheumatoid arthritis patients with short term and long standing disease, juvenileidiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axialspondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS),psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients.

The pivotal controlled studies involved 6,089 patients receiving adalimumab and 3,801 patients receivingplacebo or active comparator during the controlled period.

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

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

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

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

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

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

The following list of adverse reactions is based on experience from clinical trials and on postmarketingexperience and are displayed by system organ class and frequency in Table 7 below: very common ( 1/10);common ( 1/100 to < 1/10); uncommon ( 1/1,000 to < 1/100); rare ( 1/10,000 to < 1/1,000); and notknown (cannot be estimated from the available data). Within each frequency grouping, undesirable effectsare presented in order of decreasing seriousness. The highest frequency seen among the various indicationshas been included. An asterisk (*) appears in the SOC column if further information is found elsewhere insections pct. 4.3, pct. 4.4 and 4.8.

Table 7

Undesirable effects

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, candidiasisand 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),

System Organ Class Frequency Adverse Reactionfungal 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 unspecified basal cell carcinoma and squamous cell(including cysts and carcinoma),polyps)* benign neoplasm

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 lymphatic Very common Leukopenia (including neutropenia andsystem disorders* agranulocytosis),anaemia

Common Leucocytosis,thrombocytopenia

Uncommon Idiopathic thrombocytopenic purpura

Rare Pancytopenia

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

System Organ Class Frequency Adverse Reaction

Uncommon Sarcoidosis1),vasculitis

Rare Anaphylaxis1)

Metabolism and nutrition Very common Lipids increaseddisorders

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

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

Nervous system disorders* Very common Headache

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

Uncommon Cerebrovascular accident1),tremor,neuropathy

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

Guillain-Barré syndrome) 1)

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

System Organ Class Frequency Adverse Reaction

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 and Common Asthma,mediastinal disorders* dyspnoea,cough

Uncommon Pulmonary embolism1),interstitial lung disease,chronic obstructive pulmonary disease,pneumonitis,pleural effusion1)1)

Rare Pulmonary fibrosis

Gastrointestinal disorders Very common Abdominal pain,nausea and vomiting

Common GI haemorrhage,

System Organ Class Frequency Adverse Reactiondyspepsia,gastroesophageal reflux disease,sicca syndrome

Uncommon Pancreatitis,dysphagia,face oedema

Rare Intestinal perforation1)

Hepato-biliary disorders* Very Common Elevated liver enzymes

Uncommon Cholecystitis and cholelithiasis,hepatic steatosis,bilirubin increased

Rare Hepatitisreactivation 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)

System Organ Class Frequency Adverse Reaction

Not known Worsening of symptoms of dermatomyositis1)

Musculoskeletal and Very common Musculoskeletal painconnective tissue disorders

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 and Uncommon Erectile dysfunctionbreast disorders

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 healingprocedural complications

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

** including open label extension studies1) including spontaneous reporting data2) The mean weight change from baseline for adalimumab ranged from 0.3 kg to 1.0 kg across adultindications compared to (minus) -0.4 kg to 0.4 kg for placebo over a treatment period of 4-6 months.

Weight increase of 5-6 kg has also been observed in long-term extension studies with mean exposures ofapproximately 1-2 years without control group, particularly in patients with Crohn’s disease and ulcerativecolitis. The mechanism behind this effect is unclear but could be associated with the anti-inflammatoryeffect of adalimumab.

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

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

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

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

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

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

No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years duringadalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis andenthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric patients with anexposure of 498.1 patient years during adalimumab trials in paediatric patients with Crohn’s disease. Nomalignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during anadalimumab trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 93paediatric patients with an exposure of 65.3 patient years during an adalimumab trial in paediatric patientswith ulcerative colitis. No malignancies were observed in 60 paediatric patients with an exposure of 58.4patient years during an adalimumab trial in paediatric patients with uveitis.

During the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in duration inpatients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axialspondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitissuppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000patient-years among 5,291 adalimumab-treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for adalimumab and 3.8months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was8.8 (6.0, 13.0) per 1,000 patient-years among adalimumab-treated patients and 3.2 (1.3, 7.6) per 1,000patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates(95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among adalimumab-treated patients and0.6 (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 trials and ongoing and completed open label extension studieswith a median duration of approximately 3.3 years including 6,427 patients and over 26,439 patient-years oftherapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers isapproximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers isapproximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per1,000 patient years.

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

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

Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis studies I− V. In these trials, 11.9% of patients treated with adalimumab and 8.1% of placebo and active control −treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at week 24.

Two patients out of 3,441 treated with adalimumab in all rheumatoid arthritis and psoriatic arthritis studiesdeveloped clinical signs suggestive of new-onset lupus-like syndrome. The patients improved followingdiscontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms.

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

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

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

In the Phase 3 trial of adalimumab in patients with paediatric Crohn’s disease which evaluated efficacy andsafety of two body weight adjusted maintenance dose regimens following body weight adjusted inductiontherapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of patients ofwhom 4 were receiving concomitant immunosuppressants at baseline.

In controlled Phase 3 trials of adalimumab in patients with plaque psoriasis with a control period durationranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumab-treated patientsand 1.8% of control-treated patients.

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

In controlled trials of adalimumab (initial doses of 160 mg at week 0 and 80 mg at week 2, followed by40 mg every week starting at week 4), in patients with hidradenitis suppurativa with a control periodduration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of adalimumab-treatedpatients and 0.6% of control-treated patients.

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

In the controlled Phase 3 trial of adalimumab in patients with paediatric ulcerative colitis (N=93) whichevaluated efficacy and safety of a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week(N=31) and a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every week (n=32), following bodyweight adjusted induction dosing of 2.4 mg/kg (maximum of 160 mg) at week 0 and week 1, 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 ULNoccurred in 1.1% (1/93) of patients.

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

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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

Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNF-α) inhibitors. ATCcode: L04AB04

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

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

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

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changesin the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1with 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 adalimumab usuallyexperienced improvement in haematological signs of chronic inflammation.

A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic arthritis,

Crohn’s disease, ulcerative colitis and hidradenitis suppurativa after treatment with adalimumab. In patientswith Crohn’s disease, a reduction of the number of cells expressing inflammatory markers in the colonincluding a significant reduction of expression of TNFα was seen. Endoscopic studies in intestinal mucosahave shown evidence of mucosal healing in adalimumab-treated patients.

Adalimumab was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. The efficacy andsafety of adalimumab were assessed in five randomised, double-blind and well-controlled studies. Somepatients were treated for up to 120 months duration. Injection site pain of adalimumab 40 mg/0.4 ml wasassessed in two randomised, active control, single-blind, two-period crossover studies.

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) everyweek and whose methotrexate dose remained constant at 10 to 25 mg every week. Doses of 20, 40 or80 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. Doses of 20or 40 mg of adalimumab were given by subcutaneous injection every other week with placebo on alternativeweeks or every week for 26 weeks; placebo was given every week for the same duration. No other disease-modifying anti-rheumatic drugs were allowed.

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

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

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 every otherweek monotherapy and methotrexate monotherapy in reducing the signs and symptoms and rate ofprogression of joint damage in rheumatoid arthritis for 104 weeks. Upon completion of the first 104 weeks,497 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administeredevery other week up to 10 years.

RA studies VI and VII each evaluated 60 patients with moderately to severely active rheumatoid arthritiswho were ≥ 18 years old. Enrolled patients were either current users of adalimumab 40 mg/0.8 ml and ratedtheir average injection site pain as at least 3 cm (on a 0-10 cm VAS) or were biologic-naïve subjects whowere starting adalimumab 40 mg/0.8 ml. Patients were randomised to receive a single dose of adalimumab40 mg/0.8 ml or adalimumab 40 mg/0.4 ml, followed by a single injection of the opposite treatment at theirnext dose.

The primary end point in RA studies I, II and III and the secondary endpoint in RA study IV was thepercentage of patients who achieved an ACR 20 response at week 24 or 26. The primary endpoint in RAstudy V was the percentage of patients who achieved an ACR 50 response at week 52. RA studies III and Vhad an additional primary endpoint at 52 weeks of retardation of disease progression (as detected by X-rayresults). RA study III also had a primary endpoint of changes in quality of life. The primary endpoint in RAstudies VI and VII was injection site pain immediately after injection as measured by a 0-10 cm VAS.

The percentage of adalimumab-treated patients achieving ACR 20, 50 and 70 responses was consistentacross RA studies I, II and III. The results for the 40 mg every other week dose are summarised in Table 8.

Table 8

ACR responses in placebo-controlled trials(percentage of patients)

Response RA Study Ia** RA Study IIa** RA Study IIIa**

Placebo/ Adalimumabb/ Placebo Adalimumabb Placebo/ Adalimumabb/

MTXc MTXc n=110 n=113 MTXc MTXcn=60 n=63 n=200 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%

ACR 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 and swollenjoints, physician and patient assessment of disease activity and pain, disability index (HAQ) scores and CRP(mg/dl) values) improved at 24 or 26 weeks compared to placebo. In RA study III, these improvements weremaintained throughout 52 weeks.

In the open-label extension for RA study III, most patients who were ACR responders maintained responsewhen followed for up to 10 years. Of 207 patients who were randomised to adalimumab 40 mg every otherweek, 114 patients continued on adalimumab 40 mg every other week for 5 years. Among those, 86 patients(75.4%) had ACR 20 responses; 72 patients (63.2%) had ACR 50 responses; and 41 patients (36%) had

ACR 70 responses. Of 207 patients, 81 patients continued on adalimumab 40 mg every other week for 10years. Among those, 64 patients (79.0%) had ACR 20 responses; 56 patients (69.1%) had ACR 50responses; and 43 patients (53.1%) had ACR 70 responses.

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

In RA studies I-IV, adalimumab-treated patients achieved statistically significant ACR 20 and 50 responsescompared 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 therapywith adalimumab and methotrexate led to faster and significantly greater ACR responses than methotrexatemonotherapy and adalimumab monotherapy at week 52 and responses were sustained at week 104 (see

Table 9).

Table 9

ACR responses in RA Study V(percentage of patients)

Adalimumab

MTX Adalimumab

Response /MTX p-valuea p-valueb p-valuecn=257 n=274n=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 0.864

a. 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 and adalimumab/methotrexate combination therapy using the Mann-Whitney U test

c. p-value is from the pairwise comparison of adalimumab monotherapy and methotrexatemonotherapy using the Mann-Whitney U test

In the open-label extension for RA study V, ACR response rates were maintained when followed for up to10 years. Of 542 patients who were randomised to adalimumab 40 mg every other week, 170 patientscontinued on adalimumab 40 mg every other week for 10 years. Among those, 154 patients (90.6%) had

ACR 20 responses; 127 patients (74.7%) had ACR 50 responses; and 102 patients (60.0%) had ACR 70responses.

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

In RA study III, where adalimumab-treated patients had a mean duration of rheumatoid arthritis ofapproximately 11 years, structural joint damage was assessed radiographically and expressed as change inmodified Total Sharp Score (TSS) and its components, the erosion score and joint space narrowing score.

Adalimumab/methotrexate patients demonstrated significantly less radiographic progression than patientsreceiving methotrexate alone at 6 and 12 months (see Table 10).

In the open-label extension of RA Study III, the reduction in rate of progression of structural damage ismaintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated with40 mg adalimumab every other week were evaluated radiographically. Among those, 48 patients showed noprogression of structural damage defined by a change from baseline in the mTSS of 0.5 or less. At 10 years,79 of 207 patients originally treated with 40 mg adalimumab every other week were evaluatedradiographically. Among those, 40 patients showed no progression of structural damage defined by a changefrom baseline in the mTSS of 0.5 or less.

Table 10

Radiographic mean changes over 12 months in RA Study III

Placebo/ Adalimumab/MTX Placebo/MTX- p-value

MTXa 40 mg every other adalimumab/MTXweek (95% confidenceintervalb)

Total Sharp Score 2.7 0.1 2.6 (1.4, 3.8) < 0.001c

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

JSNd score 1.0 0.1 0.9 (0.3, 1.4) 0.002amethotrexateb95% confidence intervals for the differences in change scores between methotrexate and adalimumab.cBased on rank analysisdJoint Space Narrowing

In RA study V, structural joint damage was assessed radiographically and expressed as change in modified

Total Sharp Score (see Table 11).

Table 11

Radiographic mean changes at week 52 in RA Study V

Adalimumab

MTX Adalimumab/MTXn=257 n=274n=268(95% (95% p-valuea p-valueb p-valuec(95%confidence confidenceconfidenceinterval) interval)interval)

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

Score

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

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

Following 52 weeks and 104 weeks of treatment, the percentage of patients without progression (changefrom baseline in modified Total Sharp Score  0.5) was significantly higher with adalimumab/methotrexatecombination therapy (63.8% and 61.2% respectively) compared to methotrexate monotherapy (37.4% and33.5% respectively, p < 0.001) and adalimumab monotherapy (50.7%, p < 0.002 and 44.5%, p < 0.001respectively).

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

Health-related quality of life and physical function were assessed using the disability index of the Health

Assessment Questionnaire (HAQ) in the four original adequate and well-controlled trials, which was a pre-specified primary endpoint at week 52 in RA study III. All doses/schedules of adalimumab in all four studiesshowed statistically significantly greater improvement in the disability index of the HAQ frombaseline to Month 6 compared to placebo and in RA study III the same was seen at week 52. Results fromthe Short Form Health Survey (SF 36) for all doses/schedules of adalimumab in all four studies supportthese findings, with statistically significant physical component summary (PCS) scores, as well asstatistically significant pain and vitality domain scores for the 40 mg every other week dose. A statisticallysignificant decrease in fatigue as measured by functional assessment of chronic illness therapy (FACIT)scores was seen in all three studies in which it was assessed (RA studies I, III, IV).

In RA study III, most subjects who achieved improvement in physical function and continued treatmentmaintained improvement through week 520 (120 months) of open-label treatment. Improvement in qualityof life was measured up to week 156 (36 months) and improvement was 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 week104. Among the 250 subjects who completed the open-label extension study, improvements in physicalfunction were maintained through 10 years of treatment.

Injection site pain

For the pooled crossover RA studies VI and VII, a statistically significant difference for injection site painimmediately after dosing was observed between adalimumab 40 mg/0.8 ml and adalimumab 40 mg/0.4 ml(mean VAS of 3.7 cm versus 1.2 cm, scale of 0-10 cm, P < 0.001). This represented an 84% medianreduction in injection site pain.

Adalimumab 40 mg every other week was assessed in 393 patients in two randomised, 24 week double −blind, placebo − controlled studies in patients with active ankylosing spondylitis (mean baseline score ofdisease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.3 in all groups) whohave had an inadequate response to conventional therapy. Seventy-nine (20.1%) patients were treatedconcomitantly with disease modifying anti − rheumatic drugs, and 37 (9.4%) patients with glucocorticoids.

The blinded period was followed by an open − label period during which patients received adalimumab40 mg every other week subcutaneously for up to an additional 28 weeks. Subjects (n=215, 54.7%) whofailed to achieve ASAS 20 at weeks 12, or 16 or 20 received early escape open-label adalimumab 40 mgevery other week subcutaneously and were subsequently treated as non-responders in the double-blindstatistical analyses.

In the larger AS study I with 315 patients, results showed statistically significant improvement of the signsand symptoms of ankylosing spondylitis in patients treated with adalimumab compared to placebo.

Significant response was first observed at week 2 and maintained through 24 weeks (Table 12).

Table 12

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

Response Placebo Adalimumab

N=107 N=208

ASASa 20

Week 2 16% 42%***

Week 12 21% 58%***

Week 24 19% 51%***

ASAS 50

Week 2 3% 16%***

Week 12 10% 38%***

Week 24 11% 35%***

ASAS 70

Week 2 0% 7%**

Week 12 5% 23%***

Week 24 8% 24%***

BASDAIb 50

Week 2 4% 20%***

Week 12 16% 45%***

Week 24 15% 42%***

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

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

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

The safety and efficacy of adalimumab were assessed in two randomised, double-blind placebo controlledstudies in patients with non-radiographic axial spondyloarthritis (nr-axSpA). Study nr-axSpA I evaluatedpatients with active nr-axSpA. Study nr-axSpA II was a treatment withdrawal study in active nr-axSpApatients who achieved remission during open-label treatment with adalimumab.

Study nr-axSpA I

In Study nr-axSpA I, adalimumab 40 mg every other week was assessed in 185 patients in a randomised, 12week double - blind, placebo - controlled study in patients with active nr-axSpA (mean baseline score ofdisease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.4 for patientstreated with adalimumab and 6.5 for those on placebo) who have had an inadequate response to orintolerance to  1 NSAIDs, or a contraindication for NSAIDs.

Thirty-three (18%) patients were treated concomitantly with disease modifying anti-rheumatic drugs, and146 (79%) patients with NSAIDs at baseline. The double-blind period was followed by an open-label periodduring which patients receive adalimumab 40 mg every other week subcutaneously for up to an additional144 weeks. Week 12 results showed statistically significant improvement of the signs and symptoms ofactive nr-axSpA in patients treated with adalimumab compared to placebo (Table 13).

Table 13

Efficacy response in placebo-controlled Study nr-axSpA I

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

ASASa 40 15% 36%***

ASAS 20 31% 52%**

ASAS 5/6 6% 31%***

ASAS Partial Remission 5% 16%*

BASDAIb 50 15% 35%**

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

ASDAS Inactive Disease 4% 24%***hs-CRPd,f,g -0.3 -4.7***

SPARCCh MRI Sacroiliac Jointsd,i -0.6 -3.2**

SPARCC MRI Spined,j -0.2 -1.8**a 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 comparisons betweenadalimumab and placebo.

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

Inhibition of inflammation

Significant improvement of signs of inflammation as measured by hs-CRP and MRI of both Sacroiliac Jointsand 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-S totalscore and the SF-36 Physical Component Score (PCS) from baseline to week 12 compared to placebo.

Improvement in health-related quality of life and physical function was maintained during the open-labelextension 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 enrolled into theopen-label period of Study nr-axSpA II during which they received adalimumab 40 mg eow for 28 weeks.

These patients also had objective evidence of inflammation in the sacroiliac joints or spine on MRI orelevated hs-CRP. Patients who achieved sustained remission for at least 12 weeks (N=305) (ASDAS < 1.3 atweeks 16, 20, 24, and 28) during the open-label period were then randomised to receive either continuedtreatment 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 duration 68 weeks). Subjects who flared during the double-blindperiod were allowed adalimumab 40 mg eow rescue therapy for at least 12 weeks.

The primary efficacy endpoint was the proportion of patients with no flare by week 68 of the study. Flarewas defined as ASDAS ≥ 2.1 at two consecutive visits four weeks apart. A greater proportion of patients onadalimumab had no disease flare during the double-blind period, when compared with those 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 completed 12 weeks ofrescue therapy with adalimumab, out of which 37 (56.9%) had regained remission (ASDAS < 1.3) after12 weeks of restarting the open-label treatment.

By week 68, patients receiving continuous adalimumab treatment showed statistically significant greaterimprovement of the signs and symptoms of active nr-axSpA as compared to patients allocated to treatmentwithdrawal 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 II

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

ASASa,b 20 47.1% 70.4%***

ASASa,b 40 45.8% 65.8%***

ASASa Partial Remission 26.8% 42.1%**

ASDASc Inactive Disease 33.3% 57.2%***

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

***, ** 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 active psoriaticarthritis in two placebo-controlled studies, PsA studies I and II. PsA study I with 24 week duration, treated313 adult patients who had an inadequate response to non-steroidal anti-inflammatory drug therapy and ofthese, approximately 50% were taking methotrexate. PsA study II with 12-week duration, treated 100patients who had an inadequate response to DMARD therapy. Upon completion of both studies, 383 patientsenrolled in an open-label extension study, in which 40 mg adalimumab was administered every other week(eow).

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

Table 15

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

PsA Study I PsA Study II

Placebo Adalimumab Placebo Adalimumab

Response

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. ACRresponses 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 feetwere obtained at baseline and week 24 during the double-blind period when patients were on adalimumab orplacebo and at week 48 when all patients were on open-label adalimumab. A modified Total Sharp Score(mTSS), which included distal interphalangeal joints (i.e. not identical to the TSS used for rheumatoidarthritis), was used.

Adalimumab treatment reduced the rate of progression of peripheral joint damage compared with placebotreatment as measured by change from baseline in mTSS (mean ± SD) 0.8 ± 2.5 in the placebo group (atweek 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 function asassessed by HAQ and Short Form Health Survey (SF 36) compared to placebo at week 24. Improvedphysical 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 were candidates forsystemic therapy or phototherapy in randomised, double-blind studies. 73% of patients enrolled in Psoriasis

Studies I and II had received prior systemic therapy or phototherapy. The safety and efficacy of adalimumabwere also studied in adult patients with moderate to severe chronic plaque psoriasis with concomitant handand/or foot psoriasis who were candidates for systemic therapy in a randomised double- blind study(Psoriasis Study III).

Psoriasis Study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A, patientsreceived placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting oneweek after the initial dose. After 16 weeks of therapy, patients who achieved at least a PASI 75 response(PASI score improvement of at least 75% relative to baseline), entered period B and received open-label40 mg adalimumab every other week. Patients who maintained PASI 75 response at week 33 and wereoriginally randomised to active therapy in Period A, were re-randomised in period C to receive 40 mgadalimumab every other week or placebo for an additional 19 weeks. Across all treatment groups, the meanbaseline PASI score was 18.9 and the baseline Physician’s Global Assessment (PGA) score ranged from“moderate” (53% of subjects included) to “severe” (41%) to “very severe” (6%).

Psoriasis Study II (CHAMPION) compared the efficacy and safety of adalimumab versus methotrexate andplacebo in 271 patients. Patients received placebo, an initial dose of MTX 7.5 mg and thereafter doseincreases up to week 12, with a maximum dose of 25 mg or an initial dose of 80 mg adalimumab followedby 40 mg every other week (starting one week after the initial dose) for 16 weeks. There are no dataavailable comparing adalimumab and MTX beyond 16 weeks of therapy. Patients receiving MTX whoachieved a PASI 50 response at week 8 and/or 12 did not receive further dose increases. Across alltreatment groups, the mean baseline PASI score was 19.7 and the baseline PGA score ranged from “mild” (<1%) to “moderate” (48%) to “severe” (46%) to “very severe” (6%).

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

In Psoriasis Studies I and II, a primary endpoint was the proportion of patients who achieved a PASI 75response from baseline at week 16 (see Tables 16 and 17).

Table 16

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

Placebo Adalimumab 40 mg eow

N=398 N=814n (%) 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 weeks

Placebo MTX Adalimumab 40 mg eow

N=53 N=110 N=108n (%) n (%) 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: Clear/minimal 6 (11.3) 33 (30.0) 79 (73.1) a, ba p < 0.001 adalimumab vs. placebob p < 0.001 adalimumab vs. methotrexatec p < 0.01 adalimumab vs. placebod p < 0.05 adalimumab vs. methotrexate

In Psoriasis Study I, 28% of patients who were PASI 75 responders and were re-randomised to placebo atweek 33 compared to 5% continuing on adalimumab, p < 0.001, experienced “loss of adequate response”(PASI score after week 33 and on or before week 52 that resulted in a < PASI 50 response relative tobaseline with a minimum of a 6-point increase in PASI score relative to week 33). Of the patients who lostadequate response after re-randomisation to placebo who then enrolled into the open-label extension trial,38% (25/66) and 55% (36/66) regained PASI 75 response 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 therapy for52 weeks in Psoriasis Study I, and continued adalimumab in the open-label extension trial. PASI 75 and

PGA of clear or minimal response rates in these patients were 74.7% and 59.0%, respectively, after anadditional 108 weeks of open-label therapy (total of 160 weeks). In an analysis in which all patients whodropped 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 patients were 69.6% and 55.7%,respectively, after an additional 108 weeks of open-label therapy (total of 160 weeks).

A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-labelextension study. During the withdrawal period, symptoms of psoriasis returned over time with a median timeto relapse (decline to PGA “moderate” or worse) of approximately 5 months. None of these patientsexperienced rebound during the withdrawal period. A total of 76.5% (218/285) of patients who entered theretreatment period had a response of PGA “clear” or “minimal” after 16 weeks of retreatment, irrespectiveof whether they relapsed during withdrawal (69.1%[123/178] and 88.8% [95/107] for patients who relapsedand who did not relapse during the withdrawal period, respectively). A similar safety profile was observedduring 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 thephysical and mental component summary scores of the SF-36 were also significant compared to placebo.

In an open-label extension study, for patients who dose escalated from 40 mg every other week to 40 mgweekly due to a PASI response below 50%, 26.4% (92/349) and 37.8% (132/349) of patients achieved PASI75 response at week 12 and 24, respectively.

Psoriasis Study III (REACH) compared the efficacy and safety of adalimumab versus placebo in 72 patientswith moderate to severe chronic plaque psoriasis and hand and/or foot psoriasis. Patients received an initialdose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) orplacebo for 16 weeks. At week 16, a statistically significantly greater proportion of patients who receivedadalimumab achieved PGA of 'clear' or 'almost clear' for the hands and/or feet compared to patients whoreceived placebo (30.6% versus 4.3%, respectively [P = 0.014]).

Psoriasis Study IV compared efficacy and safety of adalimumab versus placebo in 217 adult patients withmoderate to severe nail psoriasis. Patients received an initial dose of 80 mg adalimumab followed by 40 mgevery other week (starting one week after the initial dose) or placebo for 26 weeks followed by open-labeladalimumab treatment for an additional 26 weeks. Nail psoriasis assessments included the Modified Nail

Psoriasis Severity Index (mNAPSI), the Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) andthe Nail Psoriasis Severity Index (NAPSI) (see Table 18). Adalimumab demonstrated a treatment benefit innail psoriasis patients with different extents of skin involvement (BSA ≥ 10% (60% of patients) and BSA<10% and ≥ 5% (40% of patients)).

Table 18

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

Endpoint Week 16 Week 26 Week 52

Placebo-Controlled Placebo-Controlled Open-label

Placebo adalimumab Placebo adalimumab adalimumab

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

N=109 N=109 N=80≥ mNAPSI 75 (%) 2.9 26.0a a3.4 46.6 65.0

PGA-F clear/minimal and 2.9 29.7a6.9 48.9a61.3≥ 2-grade improvement

P(%er)c entage Change in -7.8 -44.2 a -11.5 -56.2a

- 72.2

Total

Fa pin <ge 0r.n0a0il1 ,N aAdaPlSimI (u%m)a b vs. placebo

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

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

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

Study HS-II (PIONEER II) evaluated 326 patients with 2 treatment periods. In Period A, patients receivedplacebo or adalimumab at an initial dose of 160 mg at week 0 and 80 mg at week 2 and 40 mg every weekstarting at week 4 to week 11. 19.3% of patients had continued baseline oral antibiotic therapy 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, adalimumab 40 mg every other week,or placebo from week 12 to week 35). Patients who had been randomised to placebo in Period A wereassigned to receive placebo in Period B.

Patients participating in Studies HS-I and HS-II were eligible to enrol into an open-label extension study inwhich adalimumab 40mg was administered every week. Mean exposure in all adalimumab population was762 days. Throughout all 3 studies patients used topical antiseptic wash daily.

Clinical Response

Reduction of inflammatory lesions and prevention of worsening of abscesses and draining fistulas wasassessed using Hidradenitis Suppurativa Clinical Response (HiSCR; at least a 50% reduction in total abscessand inflammatory nodule count with no increase in abscess count and no increase in draining fistula countrelative to Baseline). Reduction in HS-related skin pain was assessed using a Numeric Rating Scale inpatients who entered the study with an initial baseline score of 3 or greater on a 11 point scale.

At week 12, a significantly higher proportion of patients treated with adalimumab versus placebo achieved

HiSCR. At week 12, a significantly higher proportion of patients in Study HS-II experienced a clinicallyrelevant decrease in HS-related skin pain (see Table 19). Patients treated with adalimumab had significantlyreduced risk of disease flare during the initial 12 weeks of treatment.

Table 19

Efficacy results at 12 weeks, HS Studies I and II

HS Study I HS Study II

Placebo Adalimumab Placebo Adalimumab40 mg Weekly 40 mg Weekly

Hidradenitis Suppurativa N = 154 N = 153 N=163 N=163

Clinical Response (HiSCR)a 40 (26.0%) 64 (41.8%) * 45 (27.6%) 96 (58.9%) ***≥ 30% Reduction in Skin N = 109 N = 122 N=111 N=105

Painb 27 (24.8%) 34 (27.9%) 23 (20.7%) 48 (45.7%) ***

* P < 0.05, ***P < 0.001, adalimumab versus placeboa Among all randomised 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 of abscesses anddraining fistulas. Approximately twice the proportion of patients in the placebo group in the first 12 weeksof Studies HS-I and HS-II, compared with those in the adalimumab group experienced worsening ofabscesses (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-specifichealth-related quality of life, as measured by the Dermatology Life Quality Index (DLQI; Studies HS-I and

HS-II), patient global satisfaction with medication treatment as measured by the Treatment Satisfaction

Questionnaire - medication (TSQM; Studies HS-I and HS-II), and physical health as measured by thephysical component summary score of the SF-36 (Study HS-I).

In patients with at least a partial response to adalimumab 40 mg weekly at week 12, the HiSCR rate at week36 was higher in patients who continued weekly adalimumab than in patients in whom dosing frequency wasreduced to every other week, or in whom treatment was withdrawn (see Table 20).

Table 20

Proportion of patientsa achieving HiSCRb at weeks 24 and 36 after treatment reassignment fromweekly adalimumab at week 12

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

N = 73 N = 70 N = 70

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

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

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

Among patients whose adalimumab treatment was withdrawn at week 12 in Studies HS-I and HS-II, the

HiSCR rate 12 weeks after re-introduction of adalimumab 40 mg weekly returned to levels similar to thatobserved before withdrawal (56.0 %).

The safety and efficacy of adalimumab were assessed in over 1500 patients with moderately to severelyactive Crohn’s disease (Crohn’s Disease Activity Index (CDAI)  220 and  450) in randomised, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/orimmunomodulatory agents were permitted and 80% of patients continued to receive at least one of thesemedications.

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 were randomisedto one of four treatment groups; placebo at weeks 0 and 2, 160 mg adalimumab at week 0 and 80 mg at week2, 80 mg at week 0 and 40 mg at week 2, and 40 mg at week 0 and 20 mg at week 2. In CD Study II, 325patients who had lost response or were intolerant to infliximab were randomised to receive either 160 mgadalimumab at week 0 and 80 mg at week 2 or placebo at weeks 0 and 2. The primary non-responders wereexcluded from the studies and therefore these patients were not further evaluated.

Maintenance of clinical remission was evaluated in CD study III (CHARM). In CD Study III, 854 patientsreceived open-label 80 mg at week 0 and 40 mg at week 2. At week 4 patients were randomised to 40 mgevery other week, 40 mg every week, or placebo with a total study duration of 56 weeks. Patients in clinicalresponse (decrease in CDAI ≥ 70) at week 4 were stratified and analysed separately from those not inclinical response at week 4. Corticosteroid taper was permitted 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(percentage of patients)

CD Study I: CD Study II:

infliximab naive patients infliximab experiencedpatients

Placebo Adalimumab Adalimumab Placebo Adalimumab

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

N = 75 N=76 N=159

Week 4

Clinical remission 12% 24% 36%* 7% 21%*

Clinical response 24% 37% 49%** 25% 38%**(CR-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 andadverse events were more frequently noted in the 160/80 mg group.

In CD Study III, at week 4, 58% (499/854) of patients were in clinical response and were assessed in theprimary analysis. Of those in clinical response at week 4, 48% had been previously exposed to other TNF-antagonists. Maintenance of remission and response rates are presented in Table 22. Clinical remissionresults remained relatively constant irrespective of previous TNF-antagonist exposure.

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

Table 22

Maintenance of clinical remission and response(percentage of patients)

Placebo 40 mg 40 mg

Adalimumab Adalimumabevery other week every week

Week 26 N=170 N=172 N=157

Clinical remission 17% 40%* 47%*

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

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

Week 56 N=170 N=172 N=157

Clinical 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 patients respondedby week 12 compared to 30% of placebo maintenance patients. These results suggest that some patients whohave not responded by week 4 benefit from continued maintenance therapy through week 12. Therapycontinued beyond 12 weeks did not result in significantly more responses (see section 4.2).

117/276 patients from CD study I and 272/777 patients from CD studies II and III were followed through atleast 3 years of open-label adalimumab therapy. 88 and 189 patients, respectively, continued to be inclinical remission. Clinical response (CR-100) was maintained in 102 and 233 patients, respectively.

In CD Study I and CD Study II, statistically significant improvement in the disease-specific inflammatorybowel disease questionnaire (IBDQ) total score was achieved at week 4 in patients randomised toadalimumab 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 the placebo group.

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

In study UC-I, 390 TNF-antagonist naïve patients were randomised to receive either placebo at weeks 0 and2, 160 mg adalimumab at week 0 followed by 80 mg at week 2, or 80 mg adalimumab at week 0 followed by40 mg at week 2. After week 2, patients in both adalimumab arms received 40 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 mg eowthereafter, and 246 patients received placebo. Clinical results were assessed for induction of remission atweek 8 and for maintenance of remission at week 52.

Patients induced with 160/80 mg adalimumab achieved clinical remission versus placebo at week 8 instatistically significantly greater percentages in study UC-I (18% vs. 9% respectively, p=0.031) and study

UC-II (17% vs. 9% respectively, p=0.019). In study UC-II, among those treated with adalimumab who werein 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(percentage of patients)

Placebo Adalimumab 40 mg eow

Week 52 N=246 N=248clinical response 18 % 30 %*clinical remission 9 % 17 %*mucosal healing 15 % 25 %*steroid-free remission for ≥ 90 daysa6 % 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 inthe rectal bleeding subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1;

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

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

Of those patients who had a response at week 8, 47% were in response, 29% were in remission, 41% hadmucosal 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. Theefficacy of adalimumab in those patients was reduced compared to that in anti-TNF naïve patients. Amongpatients who had failed prior anti-TNF treatment, week 52 remission was achieved by 3% on placebo and10% on adalimumab.

Patients from studies UC-I and UC-II had the option to roll over into an open-label long-term extensionstudy (UC III). Following 3 years of adalimumab therapy, 75% (301/402) continued to be in clinicalremission 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. The number ofall cause hospitalisations in the adalimumab treatment group was 0.18 per patient year vs. 0.26 per patientyear in the placebo group and the corresponding figures for UC-related hospitalisations were 0.12 per patientyear 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-infectious intermediate,posterior, and panuveitis, excluding patients with isolated anterior uveitis, in two randomised, double-masked, placebo-controlled studies (UV I and II). Patients received placebo or adalimumab at an initial doseof 80 mg followed by 40 mg every other week starting one week after the initial dose. Concomitant stabledoses of one non-biologic immunosuppressant were permitted.

Study UV I evaluated 217 patients with active uveitis despite treatment with corticosteroids (oral prednisoneat a dose of 10 to 60 mg/day). All patients received a 2-week standardised dose of prednisone 60 mg/day atstudy entry followed by a mandatory taper schedule, with complete corticosteroid discontinuation by week15.

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

The primary efficacy endpoint in both studies was ‘time to treatment failure’. Treatment failure was definedby a multi-component outcome based on inflammatory chorioretinal and/or inflammatory retinal vascularlesions, anterior chamber (AC) cell grade, vitreous haze (VH) grade and best corrected visual acuity(BCVA).

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

Clinical Response

Results from both studies demonstrated statistically significant reduction of the risk of treatment failure inpatients treated with adalimumab versus patients receiving placebo (see Table 24). Both studiesdemonstrated an early and sustained effect of adalimumab on the treatment failure rate versus placebo (see

Figure 2).

Table 24

Time to treatment failure in Studies UV I and UV II

Median

Analysis time to CI 95% P Valueb

N Failure N (%) HRatreatment failure for HRa(months)time 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) NEc 0.57 0.39, 0.84 0.004

Note: Treatment failure at or after Week 6 (Study UV I), or at or after Week 2 (Study UV II), was countedas event. Drop outs due to reasons other than treatment failure were censored at the time of dropping 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)

TIME (MONTHS)

Study UV I Treatment Placebo Adalimumab

TIME (MONTHS)

Study UV II Treatment Placebo Adalimumab

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 were observed foreach component of treatment failure. In Study UV II, statistically significant differences were observed forvisual acuity only, but the other components were numerically in favour of adalimumab.

Of the 424 subjects included in the uncontrolled long-term extension of Studies UV I and UV II, 60 subjectswere regarded ineligible (e.g. due to deviations or due to complications secondary to diabetic retinopathy,due to cataract surgery or vitrectomy) and were excluded from the primary analysis of efficacy. Of the 364remaining patients, 269 evaluable patients (74%) reached 78 weeks of open-label adalimumab treatment.

Based on the observed data approach, 216 (80.3%) were in quiescence (no active inflammatory lesions, ACcell grade ≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose ≤ 7.5 mg per day, and 178 (66.2%)were in steroid-free quiescence. BCVA was either improved or maintained (< 5 letters deterioration) in88.6% of the eyes at week 78. Data beyond week 78 were generally consistent with these results but the

TREATMENT FAILURE RATE (%) TREATMENT FAILURE RATE (%)number of enrolled subjects declined after this time. Overall, among the patients who discontinued the study,18% discontinued due to adverse events, and 8% due to insufficient response to adalimumab treatment.

Quality of Life

Patient reported outcomes regarding vision-related functioning were measured in both clinical studies, usingthe NEI VFQ-25. Adalimumab was numerically favoured for the majority of subscores with statisticallysignificant mean differences for general vision, ocular pain, near vision, mental health, and total score in

Study UV I, and for general vision and mental health in Study UV II. Vision related effects were notnumerically in favour of adalimumab for colour vision in Study UVI and for colour vision, peripheral visionand near vision in Study UV II.

Formation of anti-adalimumab antibodies is associated with increased clearance and reduced efficacy ofadalimumab. There is no apparent correlation between the presence of anti-adalimumab antibodies and theoccurrence of adverse events.

Patients in rheumatoid arthritis studies I, II and III were tested at multiple time points for anti-adalimumabantibodies during the 6 to 12 month period. In the pivotal trials, anti-adalimumab antibodies wereidentified in 5.5% (58/1053) of patients treated with adalimumab, compared to 0.5% (2/370) on placebo.

In patients not given concomitant methotrexate, the incidence was 12.4%, compared to 0.6% whenadalimumab was used as add-on to methotrexate.

In patients with Crohn’s disease, anti-adalimumab antibodies were identified in 7/269 subjects (2.6%) andin 19/487 subjects (3.9%) with ulcerative colitis.

In adult patients with psoriasis, anti-adalimumab antibodies were identified in 77/920 subjects (8.4%)treated with adalimumab monotherapy.

In adult plaque psoriasis patients on long term adalimumab monotherapy who participated in a withdrawaland retreatment study, the rate of antibodies to adalimumab after retreatment (11 of 482 subjects, 2.3%)was similar to the rate observed prior to withdrawal (11 of 590 subjects, 1.9%).

In patients with moderate to severe hidradenitis suppurativa, anti-adalimumab antibodies were identified in10/99 subjects (10.1%) treated with adalimumab.

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

In adult patients with non-infectious uveitis, anti-adalimumab antibodies were identified in 4.8% (12/249) ofpatients treated with adalimumab.

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

Because immunogenicity analyses are product-specific, comparison of antibody rates with those from otherproducts is not appropriate.

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

pJIA I

The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind, parallel −group study in 171 children (4-17 years old) with polyarticular JIA. In the open-label lead in phase (OL LI)patients were stratified into two groups, MTX (methotrexate)-treated or non-MTX-treated. Patients whowere in the non-MTX stratum were either naïve to or had been withdrawn from MTX at least two weeksprior to study drug administration. Patients remained on stable doses of NSAIDs and or prednisone ( 0.2mg/kg/day or 10 mg/day maximum). In the OL LI phase all patients received 24 mg/m2 up to a maximum of40 mg adalimumab every other week for 16 weeks. The distribution of patients by age and minimum,median and maximum dose received during the OL LI phase is presented in Table 25.

Table 25

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

Age group Number of patients at baseline Minimum, median andn (%) maximum4 to 7 years 31 (18.1) d10os, e2 0 and 25 mg8 to 12 years 71 (41.5) 20, 25 and 40 mg13 to 17 years 69 (40.4) 25, 40 and 40 mg

Patients demonstrating a Paediatric ACR 30 response at week 16 were eligible to be randomised into thedouble blind (DB) phase and received either adalimumab 24 mg/m2 up to a maximum of 40 mg, or placeboevery other week for an additional 32 weeks or until disease flare. Disease flare criteria were defined as aworsening of  30% from baseline in  3 of 6 Paediatric ACR core criteria,  2 active joints, andimprovement of  30% in no more than 1 of the 6 criteria. After 32 weeks or at disease flare, patients wereeligible to enrol into the open label extension phase.

Table 26

Ped ACR 30 responses in the JIA study

Stratum MTX Without MTX

Phase

OL-LI 16 weeks

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

Efficacy Outcomes

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

Disease flares at 36.8% (14/38) 64.9% (24/37)b 43.3% (13/30) 71.4%the end of (20/28)c32 weeksa (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 responses weremaintained for up to six years in the OLE phase in patients who received adalimumab throughout the study.

Over all 19 subjects, of which 11 of the baseline age group 4 to 12 and 8 of the baseline age group 13 to 17years were treated 6 years or longer.

Overall responses were generally better and, fewer patients developed antibodies when treated with thecombination of adalimumab and MTX compared to adalimumab alone. Taking these results intoconsideration, Yuflyma is recommended for use in combination with MTX and for use as monotherapy inpatients 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. Thepatients received 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of 20 mg every otherweek as a single dose via SC injection for at least 24 weeks. During the study, most subjects usedconcomitant MTX, with fewer reporting use of corticosteroids or NSAIDs.

At week 12 and week 24, PedACR30 response was 93.5% and 90.0%, respectively, using the observed dataapproach. The proportions of subjects with PedACR50/70/90 at week 12 and week 24 were90.3%/61.3%/38.7% and 83.3%/73.3%/36.7%, respectively. Amongst those who responded (Paediatric ACR30) at week 24 (n=27 out of 30 patients), the Paediatric ACR 30 responses were maintained for up to 60weeks in the OLE phase in patients who received adalimumab throughout this time period. Overall, 20subjects were treated for 60 weeks or longer.

The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind study in 46paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients were randomised toreceive either 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of 40 mg, or placeboevery other week for 12 weeks. The double-blind period is followed by an open-label (OL) period duringwhich patients received 24 mg/m2 BSA of adalimumab up to a maximum of 40 mg every other weeksubcutaneously for up to an additional 192 weeks. The primary endpoint was the percentage change from

Baseline to week 12 in the number of active joints with arthritis (swelling not due to deformity or joints withloss of motion plus pain and/or tenderness), which was achieved with mean percentage decrease of - 62.6%(median percentage change -88.9%) in patients in the adalimumab group compared to -11.6% (medianpercentage change -50.0%) in patients in the placebo group. Improvement in number of active joints witharthritis was maintained during the OL period through week 156 for the 26 of 31 (84%) patients in theadalimumab group who remained in the study. Although not statistically significant, the majority of patientsdemonstrated clinical improvement in secondary endpoints such as number of sites of enthesitis, tender jointcount (TJC), swollen joint count (SJC), Paediatric ACR 50 response, and Paediatric ACR 70 response.

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

Patients received adalimumab 0.8 mg/kg eow (up to 40 mg), 0.4 mg/kg eow (up to 20 mg), or methotrexate0.1- 0.4 mg/kg weekly (up to 25 mg). At week 16, more patients randomised to adalimumab 0.8 mg/kg hadpositive efficacy responses (e.g., PASI 75) than those randomised to 0.4 mg/kg eow or MTX.

Table 27

Paediatric plaque psoriasis efficacy results at 16 weeks

MTXa

Adalimumab 0.8 mg/kg eow

N=37 N=38

PASI 75b12 (32.4%) 22 (57.9%)

PGA: Clear/minimalc15 (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 to 36weeks and monitored for loss of disease control (i.e. a worsening of PGA by at least 2 grades). Patientswere then re-treated with adalimumab 0.8 mg/kg eow for an additional 16 weeks and response ratesobserved during retreatment were similar to the previous double-blind period: PASI 75 response of 78.9%(15 of 19 subjects) and PGA clear or minimal of 52.6% (10 of 19 subjects).

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

Adolescent hidradenitis suppurativa

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

Adalimumab was assessed in a multicentre, randomised, double-blind clinical trial designed to evaluate theefficacy and safety of induction and maintenance treatment with doses dependent on body weight (< 40 kgor ≥ 40 kg) in 192 paediatric subjects between the ages of 6 and 17 (inclusive) years, with moderate tosevere Crohn ś disease (CD) defined as Paediatric Crohn's Disease Activity Index (PCDAI) score > 30.

Subjects had to have failed conventional therapy (including a corticosteroid and/or an immunomodulator)for CD. Subjects may also have previously lost response or been intolerant to infliximab.

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

At week 4, subjects were randomised 1:1 based on their body weight at the time to either the Low Dose or

Standard Dose maintenance regimens as shown in Table 28.

Table 28

Maintenance regimen

Patient Weight Low dose Standard 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 points from

Baseline) rates are presented in Table 29. Rates of discontinuation of corticosteroids or immunomodulatorsare presented in Table 30.

Table 29

Paediatric CD Study

PCDAI clinical remission and response

Standard Dose Low Dose P value*40/20 mg eow 20/10 mg eow

N = 93 N = 95

Week 26

Clinical remission 38.7% 28.4% 0.075

Clinical response 59.1% 48.4% 0.073

Week 52

Clinical remission 33.3% 23.2% 0.100

Clinical response 41.9% 28.4% 0.038

* p value for Standard Dose versus Low Dose comparison.

Table 30

Paediatric CD Studydiscontinuation of corticosteroids or immunomodulators and fistula remission

Standard dose Low dose P value140/20 mg eow 20/10 mg eow

Discontinued corticosteroids N= 33 N=38

Week 26 84.8% 65.8% 0.066

Week 52 69.7% 60.5% 0.420

Discontinuation of immunomodulators2 N=60 N=57

Week 52 30.0% 29.8% 0.983

Fistula remission3 N=15 N=21

Week 26 46.7% 38.1% 0.608

Week 52 40.0% 23.8% 0.3031 p value for Standard dose versus Low dose comparison.2 Immunosuppressant therapy could only be discontinued at or after week 26 at theinvestigator's discretion if the subject met the clinical response criterion3 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 andheight velocity were observed for both treatment groups.

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

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

PCDAI.

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

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

At week 8, 62 patients who demonstrated clinical response per Partial Mayo Score (PMS; defined as adecrease in PMS ≥ 2 points and ≥ 30% from Baseline) were randomised equally to receive double-blindmaintenance treatment with adalimumab at a dose of 0.6 mg/kg (maximum of 40 mg) every week (ew), or amaintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week (eow). Prior to an amendment to thestudy design, 12 additional patients who demonstrated clinical response per PMS were randomised toreceive 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 week8), at least 2 points (for patients with pms of 3 to 4 at week 8), or at least 1 point (for patients with pms of 5to 6 at week 8).

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

Efficacy Results

The co-primary endpoints of the study were clinical remission per PMS (defined as PMS ≤ 2 and noindividual subscore > 1) at week 8, and clinical remission per FMS (Full Mayo Score) (defined as a Mayo

Score ≤ 2 and no individual subscore > 1) at week 52 in patients who achieved clinical response per PMS atweek 8.

Clinical remission rates per PMS at week 8 for patients in each of the adalimumab double-blind inductiongroups are presented in Table 31.

Table 31: Clinical remission per PMS at 8 weeks

Adalimumaba Adalimumabb, cmaximum 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, and 1.2mg/kg (maximum of 80 mg) at week 2b Adalimumab 2.4 mg/kg (maximum of 160 mg) at week 0 and week 1, and 1.2mg/kg (maximum of 80 mg) at week 2c Not including open-label Induction dose of adalimumab 2.4 mg/kg (maximum of 160 mg) atweek 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 the endpoint

At week 52, clinical remission per FMS in week 8 responders, clinical response per FMS (defined as adecrease in Mayo Score ≥ 3 points and ≥ 30% from Baseline) in week 8 responders, mucosal healing per

FMS (defined as an Mayo endoscopy score ≤ 1) in week 8 responders, clinical remission per FMS in Week8 remitters, and the proportion of subjects in corticosteroid-free remission per FMS in Week 8 responderswere assessed in patients who received adalimumab at the double-blind maximum 40 mg eow (0.6 mg/kg)and maximum 40 mg ew (0.6 mg/kg) maintenance doses (Table 32).

Table 32: Efficacy results at 52 weeks

Adalimumaba Adalimumabbmaximum of 40 mg eow maximum of 40 mg ew

N=31 N=31

Clinical remission in week 8 PMS9/31 (29.0%) 14/31 (45.2%)responders

Clinical response in week 8 PMS19/31 (61.3%) 21/31 (67.7%)responders

Mucosal healing in week 8 PMS12/31 (38.7%) 16/31 (51.6%)responders

Clinical remission in week 8 PMS9/21 (42.9%) 10/22 (45.5%)remitters

Corticosteroid-free remission in week 84/13 (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 randomised to receive re-induction ormaintenance treatment were considered non-responders for week 52 endpoints

Additional exploratory efficacy endpoints included clinical response per the Paediatric Ulcerative Colitis

Activity Index (PUCAI) (defined as a decrease in PUCAI ≥ 20 points from Baseline) and clinical remissionper PUCAI (defined as PUCAI < 10) at week 8 and week 52 (Table 33).

Table 33: Exploratory endpoints results per PUCAI

Week 8

Adalimumaba Adalimumabb,cmaximum of 160 mg at maximum of 160 mg at weekweek 0/placebo at week 1 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

Adalimumabd Adalimumabemaximum 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, and 1.2mg/kg (maximum of 80 mg) at week 2b Adalimumab 2.4 mg/kg (maximum of 160 mg) at week 0 and week 1, and 1.2mg/kg (maximum of 80 mg) at week 2c Not including open-label induction dose of adalimumab 2.4 mg/kg (maximum of 160 mg) atweek 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 the endpoints

Note 3: Patients with missing values at week 52 or who were randomised to receive re-inductionor maintenance treatment were considered non-responders for week 52 endpoints

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

Clinically meaningful improvements from Baseline were observed in IMPACT III and the caregiver Work

Productivity and Activity Impairment (WPAI) scores for the groups treated with adalimumab.

Clinically meaningful increases (improvement) from Baseline in height velocity were observed for thegroups treated with adalimumab, and clinically meaningful increases (improvement) from Baseline in Body

Mass Index were observed for subjects on the high maintenance dose of maximum 40 mg (0.6 mg/kg) ew.

Paediatric uveitis

The safety and efficacy of adalimumab was assessed in a randomised, double-masked, controlled study of 90paediatric patients from 2 to < 18 years of age with active JIA-associated noninfectious anterior uveitis whowere refractory to at least 12 weeks of methotrexate treatment. Patients received either placebo or 20 mgadalimumab (if < 30 kg) or 40 mg adalimumab (if ≥ 30 kg) every other week in combination with theirbaseline 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 with development ofsustained ocular co-morbidities or worsening of ocular co-morbidities, non-permitted use of concomitantmedications, 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 for subjects treated withplacebo, whereas the median time to treatment failure was not estimable for subjects treated withadalimumab because less than one-half of these subjects experienced treatment failure. Adalimumabsignificantly decreased the risk of treatment failure by 75% relative to placebo, as shown by the hazard ratio(HR = 0.25 [95% CI: 0.12, 0.49]).

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

TIME (WEEKS)

Treatment Placebo Adalimumab

Note: P = Placebo (Number at Risk); A = Adalimumab (Number at Risk).

After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab wasslow, with peak serum concentrations being reached about 5 days after administration. The average absolutebioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was64%. After single intravenous doses ranging from 0.25 to 10 mg/kg, concentrations were dose proportional.

After doses of 0.5 mg/kg (~40 mg), clearances ranged from 11 to 15 ml/hour, the distribution volume (Vss)ranged from 5 to 6 litres and the mean terminal phase half-life was approximately two weeks. Adalimumabconcentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31-96% of thosein serum.

Following subcutaneous administration of 40 mg of adalimumab every other week in adult rheumatoidarthritis (RA) patients the mean steady-state trough concentrations were approximately 5 g/ml (withoutconcomitant methotrexate) and 8 to 9 g/ml (with concomitant methotrexate), respectively. The serumadalimumab trough levels at steady-state increased roughly proportionally with dose following 20, 40 and80 mg subcutaneous dosing every other week and every week.

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

PROBABILITY OF FAILING TREATMENT

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

Following the administration of 24 mg/m2 (maximum of 40 mg) subcutaneously every other week to patientswith enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state (values measured atweek 24) serum adalimumab concentrations were 8.8 ± 6.6 μg/ml for adalimumab without concomitantmethotrexate 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 68was 8.0 ± 4.6 g/ml.

In adult patients with psoriasis, the mean steady-state trough concentration was 5 g/ml during adalimumab40 mg every other week monotherapy treatment.

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

In adult patients with hidradenitis suppurativa, a dose of 160 mg adalimumab on week 0 followed by 80 mgon week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 μg/ml at week 2 andweek 4. The mean steady-state trough concentration at week 12 through week 36 were approximately 8 to10 μg/ml during adalimumab 40 mg every week treatment.

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

In patients with Crohn’s disease, the loading dose of 80 mg adalimumab on week 0 followed by 40 mgadalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 5.5 g/mlduring the induction period. A loading dose of 160 mg adalimumab on week 0 followed by 80 mgadalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 12 g/mlduring the induction period. Mean steady-state trough levels of approximately 7 g/ml were observed in

Crohn’s disease patients who received a maintenance dose of 40 mg adalimumab every other week.

In paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was160/80 mg or 80/40 mg at weeks 0 and 2, respectively, dependent on a body weight cut-off of 40 kg. Atweek 4, patients were randomised 1:1 to either the Standard Dose (40/20 mg eow) or Low Dose (20/10 mgeow) maintenance treatment groups based on their body weight. The mean (±SD) serum adalimumab troughconcentrations achieved at week 4 were 15.7 ± 6.6 g/ml for patients ≥ 40 kg (160/80 mg) and 10.6 ± 6.1g/ml for patients < 40 kg (80/40 mg).

For patients who stayed on their randomised therapy, the mean (±SD) adalimumab trough concentrations atweek 52 were 9.5 ± 5.6 g/ml for the Standard Dose group and 3.5 ± 2.2 g/ml for the Low Dose group.

The mean trough concentrations were maintained in patients who continued to receive adalimumabtreatment eow for 52 weeks. For patients who dose escalated from eow to weekly regimen, the mean (±SD)serum concentrations of adalimumab at week 52 were 15.3 ± 11.4 μg/ml (40/20 mg, weekly) and 6.7 ± 3.5μg/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 g/mlduring the induction period. Mean steady-state trough levels of approximately 8 g/ml were observed inulcerative 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 of 40 mg)every other week to paediatric patients with ulcerative colitis, the mean trough steady-state serumadalimumab concentration was 5.01 ± 3.28 µg/ml at week 52. For patients who received 0.6 mg/kg(maximum of 40 mg) every week, the mean (±SD) trough steady-state serum adalimumab concentration was15.7 ± 5.60 μg/ml at week 52.

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

Adalimumab exposure in paediatric uveitis patients was predicted using population pharmacokineticmodelling and simulation based on cross-indication pharmacokinetics in other paediatric patients (paediatricpsoriasis, juvenile idiopathic arthritis, paediatric Crohn’s disease, and enthesitis-related arthritis). No clinicalexposure data are available on the use of a loading dose in children < 6 years. The predicted exposuresindicate that in the absence of methotrexate, a loading dose may lead to an initial increase in systemicexposure.

Population pharmacokinetic and pharmacokinetic/pharmacodynamic modelling and simulation predictedcomparable adalimumab exposure and efficacy in patients treated with 80 mg every other week whencompared with 40 mg every week (including adult patients with RA, HS, UC, CD or Ps, patients withadolescent HS, and paediatric patients ≥ 40 kg with CD and UC).

Exposure-response relationship in paediatric population

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

Exposure-response relationships between adalimumab concentration and efficacy in paediatric patients withsevere chronic plaque psoriasis were established for PASI 75 and PGA clear or minimal, respectively. PASI75 and PGA clear or minimal increased with increasing adalimumab concentrations, both with a similarapparent EC50 of approximately 4.5 μg/ml (95% CI 0.4-47.6 and 1.9-10.5, respectively).

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

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

Acetic acid

Sodium acetate trihydrate

Glycine

Polysorbate 80

Water for injections

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

3 years

Store in a refrigerator (2°C - 8°C). Do not freeze.

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

A single Yuflyma pre-filled syringe or pre-filled pen may be stored at temperatures up to a maximum of25°C for a period of up to 31 days. The pre-filled syringe or pre-filled pen must be protected from light, anddiscarded if not used within the 31-day period.

Yuflyma 40 mg solution for injection in pre-filled syringe

Solution for injection in a pre-filled syringe (type I glass) with a plunger stopper (bromobutyl rubber) and aneedle with a needle shield (thermoplastic elastomer).

Packs of:

* 1 pre-filled syringe (0.4 ml sterile solution) with 2 alcohol pads.

* 2 pre-filled syringes (0.4 ml sterile solution), each with 1 alcohol pad.

* 4 pre-filled syringes (0.4 ml sterile solution), each with 1 alcohol pad.

* 6 pre-filled syringes (0.4 ml sterile solution), each with 1 alcohol pad.

Yuflyma 40 mg solution for injection in pre-filled syringe with needle guard

The syringe is made from type I glass with a plunger stopper (bromobutyl rubber) and a needle with a needleshield (thermoplastic elastomer).

Packs of:

* 1 pre-filled syringe with needle guard (0.4 ml sterile solution) with 2 alcohol pads.

* 2 pre-filled syringes with needle guard (0.4 ml sterile solution), each with 1 alcohol pad.

* 4 pre-filled syringes with needle guard (0.4 ml sterile solution), each with 1 alcohol pad.

* 6 pre-filled syringes with needle guard (0.4 ml sterile solution), each with 1 alcohol pad.

Yuflyma 40 mg solution for injection in pre-filled pen

Solution for injection in a pre-filled pen for patient use containing a pre-filled syringe. The syringe inside thepen is made from type 1 glass with a plunger stopper (bromobutyl rubber) and a needle with a needle shield(thermoplastic elastomer).

Packs of:

* 1 pre-filled pen (0.4 ml sterile solution), with 2 alcohol pads.

* 2 pre-filled pens (0.4 ml sterile solution), each with 1 alcohol pad.

* 4 pre-filled pens (0.4 ml sterile solution), each with 1 alcohol pad.

* 6 pre-filled pens (0.4 ml sterile solution), each with 1 alcohol pad.

Not all presentations or pack sizes may be marketed.

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

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

Yuflyma 40 mg solution for injection in pre-filled syringe

EU/1/20/1513/001

EU/1/20/1513/002

EU/1/20/1513/003

EU/1/20/1513/004

Yuflyma 40 mg solution for injection in pre-filled syringe with needle guard

EU/1/20/1513/005

EU/1/20/1513/006

EU/1/20/1513/007

EU/1/20/1513/008

Yuflyma 40 mg solution for injection in pre-filled pen

EU/1/20/1513/009

EU/1/20/1513/010

EU/1/20/1513/011

EU/1/20/1513/012

Date of first authorisation: 11 February 2021

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

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