HULIO 20mg 20mg / 0.4ml injection solution in pre-filled syringe medication leaflet

Hulio 20 mg solution for injection in pre-filled syringe

Each 0.4 ml single dose pre-filled syringe contains 20 mg of adalimumab.

Adalimumab is a recombinant human monoclonal antibody produced in Chinese hamster ovary cells.

Each pre-filled syringe contains 19.1 mg sorbitol (E420).

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear or slightly opalescent, colourless to pale brownish-yellow solution.

Hulio in combination with methotrexate is indicated for the treatment of active polyarticular juvenileidiopathic arthritis, in patients from the age of 2 years who have had an inadequate response to one ormore disease-modifying anti-rheumatic drugs (DMARDs). Hulio can be given as monotherapy in caseof intolerance to methotrexate or when continued treatment with methotrexate is inappropriate (for theefficacy in monotherapy see section 5.1). Adalimumab has not been studied in patients aged less than2 years.

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

Hulio is indicated for the treatment of severe chronic plaque psoriasis in children and adolescents from4 years of age who have had an inadequate response to or are inappropriate candidates for topicaltherapy and phototherapies.

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

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

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

Patients treated with Hulio should be given the patient reminder card.

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

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

Polyarticular juvenile idiopathic arthritis from 2 years of age

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

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

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

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

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

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

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

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

Table 2. Hulio 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.

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

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

Table 3. Hulio dose for paediatric patients with plaque psoriasis

Patient weight Dosing regimen15 kg to < 30 kg Initial dose of 20 mg, followed by 20 mg given every otherweek starting one week after the initial dose≥ 30 kg Initial dose of 40 mg, followed by 40 mg given every otherweek starting one week after the initial dose

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

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

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

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

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

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

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

Patient Induction dose Maintenanceweight dosestarting at week< 40 kg * 40 mg at week 0 and 20 mg at week 2 20 mg everyother week

In case there is a need for a more rapid response to therapy with theawareness that the risk for adverse events may be higher with use of thehigher 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 therapy with theawareness that the risk for adverse events may be higher with use of thehigher induction dose, the following dose may be used:

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

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

* < 40 kg: 20 mg every week

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

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

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

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

Paediatric uveitis

The recommended dose of Hulio for paediatric patients with uveitis from 2 years of age is based onbody weight (table 5). Hulio is administered via subcutaneous injection.

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

Table 5. Hulio dose for paediatric patients with uveitis

Patient weight Dosing regimen< 30 kg 20 mg every other week in combination withmethotrexate≥ 30 kg 40 mg every other week in combination withmethotrexate

When Hulio therapy is initiated, a loading dose of 40 mg for patients < 30 kg or 80 mg for patients≥ 30 kg may be administered one week prior to the start of maintenance therapy. No clinical data areavailable on the use of a Hulio 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 ayearly basis (see section 5.1).

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

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

Hulio is administered by subcutaneous injection. Full instructions for use are provided in the packageleaflet.

Hulio is available in other strengths and pharmaceutical forms.

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

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

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

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

Patients taking tumour necrosis factor (TNF)-antagonists are more susceptible to serious infections.

Impaired lung function may increase the risk for developing infections. Patients must therefore bemonitored closely for infections, including tuberculosis, before, during and after treatment withadalimumab. Because the elimination of adalimumab may take up to four months, monitoring shouldbe continued throughout this period.

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

Patients who develop a new infection while undergoing treatment with adalimumab should bemonitored closely and undergo a complete diagnostic evaluation. Administration of Hulio should bediscontinued if a patient develops a new serious infection or sepsis and appropriate antimicrobial orantifungal therapy should be initiated until the infection is controlled. Physicians should exercisecaution when considering the use of adalimumab in patients with a history of recurring infection orwith underlying conditions which may predispose patients to infections, including the use ofconcomitant immunosuppressive medicinal products.

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

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

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

Before initiation of therapy with Hulio, all patients must be evaluated for both active or inactive(“latent”) tuberculosis infection. This evaluation should include a detailed medical assessment ofpatient history of tuberculosis or possible previous exposure to people with active tuberculosis andprevious and/or current immunosuppressive therapy. Appropriate screening tests (i.e. tuberculin skintest and chest X-ray) should be performed in all patients (local recommendations may apply). It isrecommended that the conduct and results of these tests are recorded in the patient reminder card.

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

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

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

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

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

Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of Hulioin patients with several or significant risk factors for tuberculosis despite a negative test fortuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequatecourse of treatment cannot be confirmed.

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

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

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

For patients who develop the signs and symptoms such as fever, malaise, weight loss, sweats, cough,dyspnoea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitantshock an invasive fungal infection should be suspected and administration of Hulio should bepromptly discontinued. Diagnosis and administration of empiric antifungal therapy in these patientsshould be made in consultation with a physician with expertise in the care of patients with invasivefungal infections.

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

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

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

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

Hulio should be discontinued immediately and appropriate therapy initiated.

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

In the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies includinglymphoma have been observed among patients receiving a TNF-antagonist compared with controlpatients. However, the occurrence was rare. In the post marketing setting, cases of leukaemia havebeen reported in patients treated with a TNF-antagonist. There is an increased background risk forlymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active,inflammatory disease, which complicates the risk estimation. With the current knowledge, a possiblerisk for the development of lymphomas, leukaemia, and other malignancies in patients treated with a

TNF-antagonist cannot be excluded.

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age), includingadalimumab in the post marketing setting. Approximately half the cases were lymphomas. The othercases represented a variety of different malignancies and included rare malignancies usually associatedwith immunosuppression. A risk for the development of malignancies in children and adolescentstreated with TNF-antagonists cannot be excluded.

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

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

All patients, and in particular patients with a medical history of extensive immunosuppressant therapyor psoriasis patients with a history of psoralen + ultraviolet light A (PUVA) treatment should beexamined for the presence of non-melanoma skin cancer prior to and during treatment with Hulio.

Melanoma and Merkel cell carcinoma have also been reported in patients treated with TNF-antagonists including adalimumab (see section 4.8).

In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patientswith moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly inthe lung or head and neck, were reported in infliximab-treated patients compared with control patients.

All patients had a history of heavy smoking. Therefore, caution should be exercised when using any

TNF-antagonist in COPD patients, as well as in patients with increased risk for malignancy due toheavy smoking.

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

Rare reports of pancytopenia including aplastic anaemia have been reported with TNF-antagonists.

Adverse events of the haematologic system, including medically significant cytopenia (e.g.

thrombocytopenia, leukopenia) have been reported with adalimumab. All patients should be advised toseek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias(e.g. persistent fever, bruising, bleeding, pallor) while on adalimumab. Discontinuation of Huliotherapy should be considered in patients with confirmed significant haematologic abnormalities.

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

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

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

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

Treatment with Hulio 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 patientdevelops symptoms suggestive of a lupus-like syndrome following treatment with Hulio and ispositive for antibodies against double-stranded DNA, further treatment with Hulio should not be given(see section 4.8).

Concurrent administration of biologic DMARDS or TNF-antagonists

Serious infections were seen in clinical studies with concurrent use of anakinra and another

TNF-antagonist, etanercept, with no added clinical benefit compared to etanercept alone. Because ofthe nature of the adverse events seen with the combination of etanercept and anakinra therapy, similartoxicities may also result from the combination of anakinra and other TNF-antagonists. Therefore, thecombination of adalimumab and anakinra is not recommended. (see section 4.5).

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

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

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

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

See vaccinations above.

Sorbitol

This medicinal product contains sorbitol (E420). Patients with hereditary fructose intolerance (HFI)should not take/be given this medicinal product.

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.4 ml dose, i.e. essentially‘sodium-free’.

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

The combination of adalimumab and anakinra is not recommended (see section 4.4).

The combination of adalimumab and abatacept is not recommended (see section 4.4).

Women of child bearing potential

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

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

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

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

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

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

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

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

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

Consequently, adalimumab can be used during breastfeeding.

Preclinical data on fertility effects of adalimumab are not available.

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

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

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

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

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

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

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

The following list of adverse reactions is based on experience from clinical trials and onpostmarketing experience and are displayed by system organ class and frequency in table 6 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 not known (cannot be estimated from the available data). Within eachfrequency grouping, undesirable effects are presented in order of decreasing seriousness. The highestfrequency seen among the various indications has been included. An asterisk (*) appears in the System

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

Table 6: Undesirable effects

System organ class Frequency Adverse reaction

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

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

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

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

System organ class Frequency Adverse reaction

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

Rare Leukaemia1)

Not known Hepatosplenic T-cell lymphoma1),

Merkel cell carcinoma (neuroendocrinecarcinoma of the skin)1),

Kaposi’s sarcoma

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

Common Leucocytosis,thrombocytopenia

Uncommon Idiopathic thrombocytopenic purpura

Rare Pancytopenia

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

Uncommon Sarcoidosis1),vasculitis

Rare Anaphylaxis1)

Metabolism and nutrition Very common Lipids increaseddisorders

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

System organ class Frequency Adverse reaction

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

Nervous system Very common Headachedisorders*

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

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

System organ class Frequency Adverse reaction

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

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

Rare Pulmonary fibrosis1)

Gastrointestinal disorders Very common Abdominal pain,nausea and vomiting

Common GI haemorrhage,dyspepsia,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

System organ class Frequency Adverse reaction

Uncommon Night sweats,scar

Rare Erythema multiforme1),

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

Not known Worsening of symptoms of dermatomyositis1)

Musculoskeletal and Very common Musculoskeletal painconnective tissuedisorders

Common Muscle spasms (including blood creatinephosphokinase increased)

Uncommon Rhabdomyolysis,systemic lupus erythematosus

Rare Lupus-like syndrome1)

Renal and urinary Common Renal impairment,disorders haematuria

Uncommon Nocturia

Reproductive system 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 timeprolonged),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 -0.4 kg to 0.4 kg for placebo over a treatment period of 4-6 months. Weightincrease 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 andulcerative colitis. The mechanism behind this effect is unclear but could be associated with the anti-inflammatory effects of adalimumab.

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

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

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

The incidence of serious infections was 0.04 per patient year in adalimumab-treated patients and0.03 per patient year in placebo and active control-treated patients.

In controlled and open label adult and paediatric studies with adalimumab, serious infections(including fatal infections, which occurred rarely) have been reported, which include reports oftuberculosis (including miliary and extra-pulmonary locations) and invasive opportunistic infections(e.g. disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis,pneumocystis, candidiasis, aspergillosis and listeriosis). Most of the cases of tuberculosis occurredwithin the first eight months after initiation of therapy and may reflect recrudescence of latent disease.

No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient yearsduring adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathicarthritis and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatricpatients with an exposure of 498.1 patient years during adalimumab trials in paediatric patients with

Crohn’s disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0patient years during an adalimumab trial in paediatric patients with chronic plaque psoriasis. Nomalignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during anadalimumab 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 andnon-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per1 000 patient-years among 5 291 adalimumab-treated patients versus a rate of 6.3 (3.4, 11.8) per 1 000patient-years among 3 444 control patients (median duration of treatment was 4.0 months foradalimumab and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1 000 patient-years among adalimumab-treated patientsand 3.2 (1.3, 7.6) per 1 000 patient-years among control patients. Of these skin cancers, squamous cellcarcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1 000 patient-years amongadalimumab-treated patients and 0.6 (0.1, 4.5) per 1 000 patient-years among control patients. The rate(95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1 000 patient-years amongadalimumab-treated patients and 0.6 (0.1, 4.5) per 1 000 patient-years among control patients.

When combining controlled portions of these trials and ongoing and completed open label extensionstudies with a median duration of approximately 3.3 years including 6 427 patients and over 26 439patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanomaskin cancers is approximately 8.5 per 1 000 patient years. The observed rate of non-melanoma skincancers is approximately 9.6 per 1 000 patient years, and the observed rate of lymphomas isapproximately 1.3 per 1 000 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 000patient treatment years. The spontaneously reported rates for non-melanoma skin cancers andlymphomas are approximately 0.2 and 0.3 per 1 000 patient treatment years, respectively (see section4.4).

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

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

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

In controlled Phase 3 trials of adalimumab in patients with polyarticular juvenile idiopathic arthritiswho were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations≥ 3 x ULN occurred in 6.1% of adalimumab-treated patients and 1.3% of control-treated patients.

Most ALT elevations occurred with concomitant methotrexate use. No ALT elevations ≥ 3 x ULNoccurred in the Phase 3 trial of adalimumab in patients with polyarticular juvenile idiopathic arthritiswho were 2 to < 4 years.

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

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

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

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

In controlled trials of adalimumab (initial doses of 80 mg at week 0 followed by 40 mg every otherweek starting at week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5days and 105.0 days in adalimumab-treated and control-treated patients, respectively, ALT elevations≥ 3 x ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control-treated patients.

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

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

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

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

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

ATC code: L04AB04

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

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

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

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

After treatment with adalimumab, a rapid decrease in levels of acute phase reactants of inflammation(C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL-6) wasobserved, compared to baseline in patients with rheumatoid arthritis. Serum levels of matrixmetalloproteinases (MMP-1 and MMP-3) that produce tissue remodelling responsible for cartilagedestruction were also decreased after adalimumab administration. Patients treated with adalimumabusually experienced improvement in haematological signs of chronic inflammation.

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

Endoscopic studies in intestinal mucosa have shown evidence of mucosal healing in adalimumab-treated patients.

Adults with rheumatoid arthritis

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

RA study I evaluated 271 patients with moderately to severely active rheumatoid arthritis who were 18 years old, had failed therapy with at least one disease-modifying, anti rheumatic drug and hadinsufficient efficacy with methotrexate at doses of 12.5 to 25 mg (10 mg if methotrexate-intolerant)every week and whose methotrexate dose remained constant at 10 to 25 mg every week. Doses of 20,40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks.

RA study II evaluated 544 patients with moderately to severely active rheumatoid arthritis who were 18 years old and had failed therapy with at least one disease-modifying, anti-rheumatic drugs. Dosesof 20 or 40 mg of adalimumab were given by subcutaneous injection every other week with placeboon alternative weeks or every week for 26 weeks; placebo was given every week for the sameduration. No other disease-modifying anti-rheumatic drugs were allowed.

RA study III evaluated 619 patients with moderately to severely active rheumatoid arthritis who were 18 years old, and who had an ineffective response to methotrexate at doses of 12.5 to 25 mg or havebeen intolerant to 10 mg of methotrexate every week. There were three groups in this study. The firstreceived placebo injections every week for 52 weeks. The second received 20 mg of adalimumabevery week for 52 weeks. The third group received 40 mg of adalimumab every other week withplacebo injections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled inan open-label extension phase in which 40 mg of adalimumab/methotrexate (MTX) was administeredevery 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-rheumatic drug-naïve or to remain on their pre-existing rheumatologic therapy provided thattherapy was stable for a minimum of 28 days. These therapies include methotrexate, leflunomide,hydroxychloroquine, sulfasalazine and/or gold salts. Patients were randomised to 40 mg ofadalimumab or placebo every other week for 24 weeks.

RA study V evaluated 799 methotrexate-naïve, adult patients with moderate to severely active earlyrheumatoid arthritis (mean disease duration less than 9 months). This study evaluated the efficacy ofadalimumab 40 mg every other week/methotrexate combination therapy, adalimumab 40 mg everyother week monotherapy and methotrexate monotherapy in reducing the signs and symptoms and rateof progression of joint damage in rheumatoid arthritis for 104 weeks. Upon completion of the first 104weeks, 497 patients enrolled in an open-label extension phase in which 40 mg of adalimumab wasadministered every other week up to 10 years.

The primary end point in RA studies I, II and III and the secondary endpoint in RA study IV was thepercent of patients who achieved an American College of Rheumatology (ACR) 20 response atweek 24 or 26. The primary endpoint in RA study V was the percent of patients who achieved an ACR50 response at week 52. RA studies III and V had an additional primary endpoint at 52 weeks ofretardation of disease progression (as detected by X-ray results). RA study III also had a primaryendpoint of changes in quality of life.

The percent of adalimumab-treated patients achieving ACR 20, 50 and 70 responses was consistentacross RA studies I, II and III. The results for the 40 mg every other week dose are summarised intable 7.

Table 7: ACR responses in placebo-controlled trials (percent 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 andswollen joints, physician and patient assessment of disease activity and pain, disability index (HAQ)scores and CRP (mg/dl) values) improved at 24 or 26 weeks compared to placebo. In RA study III,these improvements were maintained throughout 52 weeks.

In the open-label extension for RA study III, most patients who were ACR responders maintainedresponse when followed for up to 10 years. Of 207 patients who were randomised to adalimumab40 mg every other week, 114 patients continued on adalimumab 40 mg every other week for 5 years.

Among those, 86 patients (75.4%) had ACR 20 responses; 72 patients (63.2%) had ACR 50 responses;and 41 patients (36%) had ACR 70 responses. Of 207 patients, 81 patients continued on adalimumab40 mg every other week for 10 years. Among those, 64 patients (79.0%) had ACR 20 responses; 56patients (69.1%) had ACR 50 responses; 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 50responses compared to placebo as early as one to two weeks after initiation of treatment.

In RA study V with early rheumatoid arthritis patients who were methotrexate naïve, combinationtherapy with adalimumab and methotrexate led to faster and significantly greater ACR responses thanmethotrexate monotherapy and adalimumab monotherapy at week 52 and responses were sustained atweek 104 (see table 8).

Table 8: ACR responses in RA study V (percent of patients)

Adalimumab

MTX Adalimumab

Response /MTX p-valuea p-valueb p-valuecn=257 n=274n=268

ACR 20

Week 62.6% 54.4% 72.8% 0.013 < 0.001 0.043

Week 56.0% 49.3% 69.4% 0.002 < 0.001 0.140

ACR 50

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

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

ACR 70

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

Week 28.4% 28.1% 46.6% < 0.001 < 0.001 0.864

a. p-value is from the pairwise comparison of methotrexate monotherapy and adalimumab/methotrexate combination therapy using the Mann-Whitney U test.

b. p-value is from the pairwise comparison of adalimumab monotherapy andadalimumab/methotrexate combination therapy using the Mann-Whitney U 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 forup to 10 years. Of 542 patients who were randomised to adalimumab 40 mg every other week, 170patients continued 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 70 responses.

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 methotrexatemonotherapy and 23.4% of patients receiving adalimumab monotherapy. Adalimumab/methotrexatecombination therapy was clinically and statistically superior to methotrexate (p < 0.001) andadalimumab monotherapy (p < 0.001) in achieving a low disease state in patients with recentlydiagnosed moderate to severe rheumatoid arthritis. The response for the two monotherapy arms wassimilar (p = 0.447). Of 342 subjects originally randomized to adalimumab monotherapy oradalimumab/methotrexate combination therapy who entered the open-label extension study, 171subjects completed 10 years of adalimumab treatment. Among those, 109 subjects (63.7%) werereported 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 aschange in modified Total Sharp Score (TSS) and its components, the erosion score and joint spacenarrowing score. adalimumab/methotrexate patients demonstrated significantly less radiographicprogression than patients receiving methotrexate alone at 6 and 12 months (see table 9).

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

Table 9: Radiographic mean changes over 12 months in RA study III

Placebo/MTXa Adalimumab/MTX Placebo/MTX- p-value40 mg every other Adalimumab/MTXweek (95% Confidence

Intervalb)

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 inmodified Total Sharp Score (see table 10).

Table 10: 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 andadalimumab/methotrexate combination therapy using the Mann-Whitney U testc p-value is from the pairwise comparison of adalimumab monotherapy and methotrexatemonotherapy using the Mann-Whitney U test

Following 52 weeks and 104 weeks of treatment, the percentage of patients without progression(change from baseline in modified Total Sharp Score  0.5) was significantly higher withadalimumab/methotrexate combination therapy (63.8% and 61.2% respectively) compared tomethotrexate monotherapy (37.4% and 33.5% respectively, p < 0.001) and adalimumab monotherapy(50.7%, p < 0.002 and 44.5%, p < 0.001 respectively).

In the open-label extension of RA study V, the mean change from baseline at Year 10 in the modified

Total Sharp Score was 10.8, 9.2 and 3.9 in patients originally randomized to methotrexatemonotherapy, adalimumab monotherapy and adalimumab/methotrexate combination therapy,respectively. The corresponding proportions of patients with no radiographic progression were 31.3%,23.7% and 36.7% respectively.

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

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

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

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

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

Adult plaque psoriasis

The safety and efficacy of adalimumab were studied in adult patients with chronic plaque psoriasis( 10% body surface area (BSA) involvement and PASI  12 or  10) who were candidates forsystemic therapy or phototherapy in randomised, double-blind studies. 73% of patients enrolled inpsoriasis studies I and II had received prior systemic therapy or phototherapy. The safety and efficacyof adalimumab were also studied in adult patients with moderate to severe chronic plaque psoriasiswith concomitant hand and/or foot psoriasis who were candidates for systemic therapy in arandomised double-blind study (psoriasis study III).

Psoriasis study I (REVEAL) evaluated 1 212 patients within three treatment periods. In period A,patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every otherweek starting one week after the initial dose. After 16 weeks of therapy, patients who achieved at leasta PASI 75 response (PASI score improvement of at least 75% relative to baseline), entered period Band received open-label 40 mg adalimumab every other week. Patients who maintained PASI 75response at week 33 and were originally randomised to active therapy in period A, were re-randomisedin period C to receive 40 mg adalimumab every other week or placebo for an additional 19 weeks.

Across all treatment groups, the mean baseline PASI score was 18.9 and the baseline Physician Global

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

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

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

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

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

In psoriasis studies I and II, a primary endpoint was the proportion of patients who achieved a PASI75 response from baseline at week 16 (see tables 11 and 12).

Table 11: 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 versus placebo

* every other week

Table 12: 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: 6 (11.3) 33 (30.0) 79 (73.1) a, b

Clear/minimala p < 0.001 adalimumab versus placebob p < 0.001 adalimumab versus methotrexatec p < 0.01 adalimumab versus placebod p < 0.05 adalimumab versus methotrexate

In psoriasis study I, 28% of patients who were PASI 75 responders and were re-randomised to placeboat week 33 compared to 5% continuing on adalimumab, p < 0.001, experienced “loss of adequateresponse” (PASI score after week 33 and on or before week 52 that resulted in a <PASI 50 responserelative to baseline with a minimum of a 6-point increase in PASI score relative to week 33). Of thepatients who lost adequate 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 weeksof re-treatment, respectively.

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

A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. During the withdrawal period, symptoms of psoriasis returned over time with amedian time to relapse (decline to PGA “moderate” or worse) of approximately 5 months. None ofthese patients experienced rebound during the withdrawal period. A total of 76.5% (218/285) ofpatients who entered the retreatment period had a response of PGA “clear” or “minimal” after16 weeks of retreatment, irrespective of whether they relapsed during withdrawal (69.1%[123/178]and 88.8% [95/107] for patients who relapsed and who did not relapse during the withdrawal period,respectively). A similar safety profile was observed during retreatment as before withdrawal.

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

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

Psoriasis study III (REACH) compared the efficacy and safety of adalimumab versus placebo in 72patients with moderate to severe chronic plaque psoriasis and hand and/or foot psoriasis. Patientsreceived an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one weekafter the initial dose) or placebo for 16 weeks. At week 16, a statistically significantly greaterproportion of patients who received adalimumab achieved PGA of 'clear' or 'almost clear' for the handsand/or feet compared to patients who received placebo (30.6% versus 4.3%, respectively [P = 0.014]).

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

Fingernail Psoriasis (PGA-F) and the Nail Psoriasis Severity Index (NAPSI) (see table 13).

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

Table 13: 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 3.4 46.6a 65.0

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

Percent Change in -7.8 -44.2 a -11.5 -56.2a -72.2

Total Fingernail

NAPSI (%)a p<0.001, adalimumab versus 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 over 1 500 patients with moderately toseverely active Crohn’s disease (Crohn’s Disease Activity Index (CDAI)  220 and  450) inrandomised, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates,corticosteroids, and/or immunomodulatory agents were permitted and 80% of patients continued toreceive at least one of these medicinal products.

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

Maintenance of clinical remission was evaluated in CD study III (CHARM). In CD Study III, 854patients received open-label 80 mg at week 0 and 40 mg at week 2. At week 4 patients wererandomised to 40 mg every other week, 40 mg every week, or placebo with a total study duration of56 weeks. Patients in clinical response (decrease in CDAI ≥ 70) at week 4 were stratified and analysedseparately from those not in clinical response at week 4. Corticosteroid taper was permitted afterweek 8.

CD study I and CD study II induction of remission and response rates are presented in table 14.

Table 14: Induction of clinical remission and response (percent of patients)

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

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 8and adverse events were more frequently noted in the 160/80 mg group.

In CD Study III, at week 4, 58% (499/854) of patients were in clinical response and were assessed inthe primary analysis. Of those in clinical response at week 4, 48% had been previously exposed toother TNF-antagonists. Maintenance of remission and response rates are presented in table 15. Clinicalremission results 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 15: Maintenance of clinical remission and response (percent of patients)

Placebo 40 mg 40 mgadalimumab 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 patientsresponded by week 12 compared to 30% of placebo maintenance patients. These results suggest thatsome patients who have not responded by week 4 benefit from continued maintenance therapy throughweek 12. Therapy continued beyond 12 weeks did not result in significantly more responses (seesection 4.2).

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

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

Adult uveitis

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

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

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

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

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

Results from both studies demonstrated statistically significant reduction of the risk of treatmentfailure in patients treated with adalimumab versus patients receiving placebo (see table 16). Bothstudies demonstrated an early and sustained effect of adalimumab on the treatment failure rate versusplacebo (see figure 1).

Table 16: Time to Treatment Failure in Studies UV I and UV II

Analysis N Failure Median time to HRa CI 95% P value b

Treatment N (%) failure (months) for HRa

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

Primary analysis (ITT)

Placebo 107 84 (78.5) 3.0 -- -- --

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

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

Primary analysis (ITT)

Placebo 111 61 (55.0) 8.3 -- -- --

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

Note: Treatment failure at or after week 6 (Study UV I), or at or after week 2 (Study UV II), wascounted as event. Drop outs due to reasons other than treatment failure were censored at the time ofdropping out.a HR of adalimumab versus 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 1: 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 wereobserved for each component of treatment failure. In study UV II, statistically significant differenceswere observed for visual acuity only, but the other components were numerically in favour ofadalimumab.

Of the 424 subjects included in the uncontrolled long-term extension of studies UV I and UV II, 60subjects were regarded ineligible (e.g. due to deviations or due to complications secondary to diabeticretinopathy, due to cataract surgery or vitrectomy) and were excluded from the primary analysis ofefficacy. Of the 364 remaining patients, 269 evaluable patients (74%) reached 78 weeks of open-labeladalimumab treatment. Based on the observed data approach, 216 (80.3%) were in quiescence (noactive inflammatory lesions, AC cell grade ≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose≤ 7.5 mg per day, and 178 (66.2%) were in steroid-free quiescence. BCVA was either improved ormaintained (< 5 letters deterioration) in 88.6% of the eyes at week 78. Data beyond week 78 weregenerally consistent with these results but the number of enrolled subjects declined after this time.

Overall, among the patients who discontinued the study, 18% discontinued due to adverse events, and8% due to insufficient response to adalimumab treatment.

TREATMENT FAILURE RATE (%) TREATMENT FAILURE RATE (%)

Patient reported outcomes regarding vision-related functioning were measured in both clinical studies,using the NEI VFQ-25. Adalimumab was numerically favoured for the majority of subscores withstatistically significant mean differences for general vision, ocular pain, near vision, mental health, andtotal score in study UV I, and for general vision and mental health in study UV II. Vision relatedeffects were not numerically in favour of adalimumab for colour vision in study UVI and for colourvision, peripheral vision and near vision in study UV II.

Formation of anti-adalimumab antibodies is associated with increased clearance and reduced efficacyof adalimumab. There is no apparent correlation between the presence of anti-adalimumab antibodiesand the occurrence of adverse events.

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

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

pJIA I

The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind,parallel − group study in 171 children (4-17 years old) with polyarticular JIA. In the open-label leadin phase (OL LI) patients were stratified into two groups, MTX (methotrexate)-treated or non-MTX-treated. Patients who were in the non-MTX stratum were either naïve to or had been withdrawn from

MTX at least two weeks prior to study adalimumab administration. Patients remained on stable dosesof non-steroidal anti-inflammatory drugs (NSAIDs) and or prednisone ( 0.2 mg/kg/day or 10 mg/daymaximum). In the OL LI phase all patients received 24 mg/m2 up to a maximum of 40 mgadalimumab 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 17.

Table 17: Distribution of patients by age and adalimumab dose received during the OL LIphase

Age group Number of patients at baseline Minimum, median andn (%) maximum dose4 to 7 years 31 (18.1) 10, 20 and 25 mg8 to 12 years 71 (41.5) 20, 25 and 40 mg13 to 17 years 69 (40.4) 25, 40 and 40 mg

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

Table 18: 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 Adalimumab/MTX Placebo/MTX Adalimumab Placebo32 weeks (N = 38) (N = 37) (N = 30) (N = 28)

Disease flares 36.8% (14/38) 64.9% (24/37)b 43.3% (13/30) 71.4%at 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 Pediatric ACR 30/50/70/90 responses weremaintained for up to six years in the OLE phase in patients who received adalimumab throughout thestudy. Over all 19 subjects, of which 11 of the baseline age group 4 to 12 and 8 of the baseline agegroup 13 to 17 years were treated 6 years or longer.

Overall responses were generally better and, fewer patients developed antibodies when treated withthe combination of adalimumab and MTX compared to adalimumab alone. Taking these results intoconsideration, adalimumab is recommended for use in combination with MTX and for use asmonotherapy in patients for whom MTX use is not appropriate (see section 4.2).

pJIA II

The safety and efficacy of adalimumab was assessed in an open-label, multicentre study in32 children (2 - < 4 years old or aged 4 and above weighing < 15 kg) with moderately to severelyactive polyarticular JIA. The patients received 24 mg/m2 body surface area (BSA) of adalimumab upto a maximum of 20 mg every other week as a single dose via SC injection for at least 24 weeks.

During the study, most subjects used concomitant MTX, with fewer reporting use of corticosteroidsor NSAIDs.

At week 12 and week 24, PedACR30 response was 93.5% and 90.0%, respectively, using the observeddata approach. 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 (Pediatric

ACR 30) at week 24 (n=27 out of 30 patients), the Pediatric ACR 30 responses were maintained for upto 60 weeks in the OLE phase in patients who received adalimumab throughout this time period.

Overall, 20 subjects were treated for 60 weeks or longer.

The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind studyin 46 paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients wererandomised to receive either 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of40 mg, or placebo every other week for 12 weeks. The double-blind period is followed by an open-label (OL) period during which patients received 24 mg/m2 BSA of adalimumab up to a maximum of40 mg every other week subcutaneously for up to an additional 192 weeks. The primary endpoint wasthe percent change from baseline to week 12 in the number of active joints with arthritis (swelling notdue to deformity or joints with loss of motion plus pain and/or tenderness), which was achieved withmean percent decrease of -62.6% (median percent change -88.9%) in patients in the adalimumabgroup compared to -11.6% (median percent change -50.0%) in patients in the placebo group.

Improvement in number of active joints with arthritis was maintained during the OL period throughweek 156 for the 26 of 31 (84%) patients in the adalimumab group who remained in the study.

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

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

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

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

Table 19: Paediatric plaque psoriasis efficacy results at 16 weeks

MTXa Adalimumab 0.8 mg/kg eow

N=37 N=38

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

PGA: Clear/minimalc 15 (40.5%) 23 (60.5%)a MTX = methotrexateb P=0.027, adalimumab 0.8 mg/kg versus MTXc P=0.083, adalimumab 0.8 mg/kg versus MTX

Patients who achieved PASI 75 and PGA clear or minimal were withdrawn from treatment for up to36 weeks and monitored for loss of disease control (i.e. a worsening of PGA by at least 2 grades).

Patients were then re-treated with adalimumab 0.8 mg/kg eow for an additional 16 weeks and responserates observed during retreatment were similar to the previous double-blind period: PASI 75 responseof 78.9% (15 of 19 subjects) and PGA clear or minimal of 52.6% (10 of 19 subjects).

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

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

All subjects received open-label induction therapy at a dose based on their baseline body weight:

160 mg at week 0 and 80 mg at week 2 for subjects ≥ 40 kg, and 80 mg and 40 mg, respectively, forsubjects < 40 kg.

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

Dose or Standard Dose maintenance regimens as shown in table 20.

Table 20: 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 pointsfrom baseline) rates are presented in table 21. Rates of discontinuation of corticosteroids orimmunomodulators are presented in table 22.

Table 21: 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 22: Paediatric CD Study - Discontinuation of corticosteroids or immunomodulatorsand 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 the investigator'sdiscretion if the subject met the clinical response criterion3 defined as a closure of all fistulas that were draining at baseline for at least 2 consecutive post-baseline visits

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

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

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

Paediatric uveitis

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

The primary endpoint was ‘time to treatment failure’. The criteria determining treatment failure wereworsening or sustained non-improvement in ocular inflammation, partial improvement withdevelopment of sustained ocular co-morbidities or worsening of ocular co-morbidities, non-permitteduse of concomitant medicinal products, and suspension of treatment for an extended period of time.

Adalimumab significantly delayed the time to treatment failure, as compared to placebo (see figure 2,

P < 0.0001 from log rank test).The median time to treatment failure was 24.1 weeks for subjectstreated with placebo, whereas the median time to treatment failure was not estimable for subjectstreated with adalimumab because less than one-half of these subjects experienced treatment failure.

Adalimumab significantly decreased the risk of treatment failure by 75% relative to placebo, as shownby the hazard ratio (HR = 0.25 [95% CI: 0.12, 0.49]).

Figure 2: Kaplan-Meier curves summarizing time to treatment failure in the paediatricuveitis study

TIME (WEEKS)

Treatment Placebo Adalimumab

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

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

CV) with concomitant methotrexate.

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

Following the administration of 24 mg/m2 (maximum of 40 mg) subcutaneously every other week topatients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state (values

PROBABILITY OF FAILING TREATMENTmeasured at week 24) serum adalimumab concentrations were 8.8 ± 6.6 μg/ml for adalimumabwithout concomitant methotrexate and 11.8 ± 4.3 μg/ml with concomitant methotrexate.

Following 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 paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was160/80 mg or 80/40 mg at weeks 0 and 2, respectively, dependent on a body weight cut-off of 40 kg.

At week 4, patients were randomised 1:1 to either the Standard Dose (40/20 mg eow) or Low Dose(20/10 mg eow) maintenance treatment groups based on their body weight. The mean (±SD) serumadalimumab trough concentrations achieved at week 4 were 15.7 ± 6.6 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 troughconcentrations at week 52 were 9.5 ± 5.6 g/ml for the Standard Dose group and 3.5 ± 2.2 g/ml forthe Low Dose group. The mean trough concentrations were maintained in patients who continued toreceive adalimumab treatment eow for 52 weeks. For patients who dose escalated from eow to weeklyregimen, the mean (±SD) serum concentrations of adalimumab at week 52 were 15.3 ± 11.4 μg/ml(40/20 mg, weekly) and 6.7 ± 3.5 μg/ml (20/10 mg, weekly).

Adalimumab exposure in paediatric uveitis patients was predicted using population pharmacokineticmodelling and simulation based on cross-indication pharmacokinetics in other paediatric patients(paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn’s disease, and enthesitis-relatedarthritis). No clinical exposure data are available on the use of a loading dose in children < 6 years.

The predicted exposures indicate that in the absence of methotrexate, a loading dose may lead to aninitial increase in systemic exposure.

Exposure-response relationship in paediatric population

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

Exposure-response relationships between adalimumab concentration and efficacy in paediatric patientswith severe chronic plaque psoriasis were established for PASI 75 and PGA clear or minimal,respectively. PASI 75 and PGA clear or minimal increased with increasing adalimumabconcentrations, both with a similar apparent EC50 of approximately 4.5 μg/ml (95% CI 0.4-47.6 and1.9-10.5, respectively).

After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumabwas slow, with peak serum concentrations being reached about 5 days after administration. Theaverage absolute bioavailability of adalimumab estimated from three studies following a single 40 mgsubcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg,concentrations were dose proportional. After doses of 0.5 mg/kg (~40 mg), clearances ranged from 11to 15 ml/hour, the distribution volume (Vss) ranged from 5 to 6 litres and the mean terminal phase half-life was approximately two weeks. Adalimumab concentrations in the synovial fluid from severalrheumatoid arthritis patients ranged from 31-96% of those in serum.

Following subcutaneous administration of 40 mg of adalimumab every other week in adult rheumatoidarthritis (RA) patients the mean steady-state trough concentrations were approximately 5 g/ml(without concomitant methotrexate) and 8 to 9 g/ml (with concomitant methotrexate), respectively.

The serum adalimumab trough levels at steady-state increased roughly proportionally with dosefollowing 20, 40 and 80 mg subcutaneous dosing every other week and every week.

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

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

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.

Population pharmacokinetic and pharmacokinetic/pharmacodynamic modelling and simulationpredicted comparable adalimumab exposure and efficacy in patients treated with 80 mg every otherweek when compared with 40 mg every week (including adult patients with RA, HS, UC, CD or Ps,patients with adolescent HS, and paediatric patients ≥ 40 kg with CD and UC).

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

Hepatic or renal impairment

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

Non-clinical data reveal no special hazard for humans based on studies of single dose toxicity,repeated dose toxicity, and genotoxicity.

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

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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 in the outer carton inorder to protect from light.

A single Hulio pre-filled syringe may be stored at temperatures up to a maximum of 25°C for a periodof up to 8 weeks. The pre-filled syringe must be protected from light, and discarded if not used withinthe 8-week period.

Hulio 20 mg solution for injection in single-use pre-filled syringe with an automatic needle guard. Thesyringe is made from cyclo olefin polymer plastic with a stopper (chlorobutyl rubber) and a needle(stainless steel) with a needle cap (butyl /diene blend polymer and polypropylene).

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

Biosimilar Collaborations Ireland Limited

Unit 35/36

Grange Parade,

Baldoyle Industrial Estate,

Dublin 13

DUBLIN

Ireland

D13 R20R

EU/1/18/1319/009

EU/1/18/1319/010

Date of first authorisation: 17 September 2018

Date of latest renewal: 03 August 2023

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

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