HUMIRA 20mg / 0.2ml injection solution in pre-filled syringe medication leaflet

Humira 20 mg solution for injection in pre-filled syringe

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

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

For the full list of excipients, see section 6.1.

Solution for injection. (injection)

Clear, colourless solution.

Humira 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). Humira 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). Humira has not been studied in patients aged less than 2 years.

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

Humira 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 topical therapyand phototherapies.

Humira 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.

Humira is indicated for the treatment of paediatric chronic non-infectious anterior uveitis in patients from2 years of age who have had an inadequate response to or are intolerant to conventional therapy, or inwhom conventional therapy is inappropriate.

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

Humira should be given the Patient Reminder Card.

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

During treatment with Humira, 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 Humira for patients with polyarticular juvenile idiopathic arthritis from 2 yearsof age is based on body weight (Table 1). Humira is administered every other week via subcutaneousinjection.

Table 1. Humira Dose for Patients with Polyarticular Juvenile Idiopathic Arthritis

Patient Weight Dosing Regimen10 kg to < 30 kg 20 mg every other week≥ 30 kg 40 mg every other week

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

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

Humira may be available in other strengths and/or presentations depending on the individual treatmentneeds.

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

Table 2. Humira 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

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

Humira may be available in other strengths and/or presentations depending on the individual treatmentneeds.

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

Table 3. Humira Dose for Paediatric Patients with Plaque Psoriasis

Patient Weight Dosing Regimen15 kg to < 30 kg Initial dose of 20 mg, followed by20 mg given every other weekstarting one week after the initialdose≥ 30 kg Initial dose of 40 mg, followed by40 mg given every other weekstarting one week after the initialdose

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

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

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

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

Humira may be available in other strengths and/or presentations depending on the individual treatmentneeds.

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

Table 4. Humira Dose for Paediatric Patients with Crohn’s disease

Patient Induction Dose Maintenance

Weight Dose

Starting at

Week 4< 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 dosage:

- < 40 kg: 20 mg every week

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

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

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

Humira may be available in other strengths and/or presentations depending on the individual treatmentneeds.

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

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

Table 5. Humira Dose for Paediatric Patients with Uveitis

Patient Weight Dosing Regimen< 30 kg 20 mg every other week incombination with methotrexate≥ 30 kg 40 mg every other week incombination with methotrexate

When Humira 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 Humira loading dose in children < 6 years of age (see section 5.2).

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

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

Humira may be available in other strengths and/or presentations depending on the individual treatmentneeds.

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

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

Humira is available in other strengths and presentations.

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

Active tuberculosis or other severe infections such as sepsis and opportunistic infections (see section 4.4).

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

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

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

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

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

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

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

Tuberculosis, including reactivation and new onset of tuberculosis, has been reported in patients receiving

Humira. Reports included cases of pulmonary and extra-pulmonary (i.e. disseminated) tuberculosis.

Before initiation of therapy with Humira, all patients must be evaluated for both active or inactive(“latent”) tuberculosis infection. This evaluation should include a detailed medical assessment of patienthistory of tuberculosis or possible previous exposure to people with active tuberculosis and previousand/or current immunosuppressive therapy. Appropriate screening tests (i.e. tuberculin skin test and chest

X-ray) should be performed in all patients (local recommendations may apply). It is recommended that theconduct and results of these tests are recorded in the Patient Reminder Card. Prescribers are reminded ofthe risk of false negative tuberculin skin test results, especially in patients who are severely ill orimmunocompromised.

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

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

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

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

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

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

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 or aftertherapy with Humira.

Opportunistic infections, including invasive fungal infections have been observed in patients receiving

Humira. These infections have not consistently been recognised in patients taking TNF-antagonists andthis has resulted in delays in appropriate treatment, sometimes resulting in fatal outcomes.

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

Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including Humira, who arechronic carriers of this virus (i.e. surface antigen positive). Some cases have had a fatal outcome. Patientsshould be tested for HBV infection before initiating treatment with Humira. For patients who test positivefor hepatitis B infection, consultation with a physician with expertise in the treatment of hepatitis B isrecommended.

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

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

TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBVreactivation, Humira should be stopped and effective anti-viral therapy with appropriate supportivetreatment should be initiated.

TNF-antagonists including Humira have been associated in rare instances with new onset or exacerbationof clinical symptoms and/or radiographic evidence of central nervous system demyelinating diseaseincluding multiple sclerosis and optic neuritis, and peripheral demyelinating disease, including Guillain-

Barré syndrome. Prescribers should exercise caution in considering the use of Humira in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of

Humira should be considered if any of these disorders develop. There is a known association betweenintermediate uveitis and central demyelinating disorders. Neurologic evaluation should be performed inpatients with non-infectious intermediate uveitis prior to the initiation of Humira therapy and regularlyduring treatment to assess for pre-existing or developing central demyelinating disorders.

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

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

In the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies includinglymphoma have been observed among patients receiving a TNF-antagonist compared with controlpatients. However, the occurrence was rare. In the post marketing setting, cases of leukaemia have beenreported in patients treated with a TNF-antagonist. There is an increased background risk for lymphomaand leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease,which complicates the risk estimation. With the current knowledge, a possible risk for the development oflymphomas, leukaemia, and other malignancies in patients treated with a TNF-antagonist cannot beexcluded.

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 other casesrepresented a variety of different malignancies and included rare malignancies usually associated withimmunosuppression. A risk for the development of malignancies in children and adolescents treated with

TNF-antagonists cannot be excluded.

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

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

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

All patients, and in particular patients with a medical history of extensive immunosuppressant therapy orpsoriasis patients with a history of PUVA treatment should be examined for the presence of non-melanoma skin cancer prior to and during treatment with Humira. Melanoma and Merkel cell carcinomahave 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 patients withmoderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lungor head and neck, were reported in infliximab-treated patients compared with control patients. All patientshad a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist in

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

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

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

Adverse events of the haematologic system, including medically significant cytopenia (e.g.thrombocytopenia, leukopenia) have been reported with Humira. All patients should be advised to seekimmediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g.persistent fever, bruising, bleeding, pallor) while on Humira. Discontinuation of Humira therapy should beconsidered 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 infection bylive vaccines in patients receiving Humira.

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

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

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

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

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

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

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

Humira.

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 Humira does not worsen or causestrictures.

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

See Vaccinations above.

Humira has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriaticarthritis patients taking Humira as monotherapy and those taking concomitant methotrexate. Antibodyformation was lower when Humira was given together with methotrexate in comparison with use asmonotherapy. Administration of Humira without methotrexate resulted in increased formation ofantibodies, increased clearance and reduced efficacy of adalimumab (see section 5.1).

The combination of Humira and anakinra is not recommended (see section 4.4 “Concurrent administrationof biologic DMARDS or TNF-antagonists”).

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

Women of childbearing potential should consider the use of adequate contraception to prevent pregnancyand continue its use for at least five months after the last Humira treatment.

A large number (approximately 2100) of prospectively collected pregnancies exposed to adalimumabresulting in live birth with known outcomes, including more than 1500 exposed during the first trimester,does not indicate an increase in the rate of malformation in the newborn.

In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn’s disease (CD)treated with adalimumab at least during the first trimester and 120 women with RA or CD not treated withadalimumab were enrolled. The primary endpoint was the birth prevalence of major birth defects. Therate of pregnancies ending with at least one live born infant with a major birth defect was 6/69 (8.7%) inthe 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). The adjusted OR(accounting for baseline differences) was 1.10 (95% CI 0.45-2.73) with RA and CD combined. There wereno distinct differences between adalimumab-treated and untreated women for the secondary endpointsspontaneous abortions, minor birth defects, preterm delivery, birth size and serious or opportunisticinfections and no stillbirths or malignancies were reported. The interpretation of data may be impacted dueto methodological limitations of the study, including small sample size and 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 normal immuneresponses in the newborn. Adalimumab should only be used during pregnancy if clearly needed.

Adalimumab may cross the placenta into the serum of infants born to women treated with adalimumabduring pregnancy. Consequently, these infants may be at increased risk for infection. Administration oflive vaccines (e.g., BCG vaccine) to infants exposed to adalimumab in utero is not recommended for5 months following the mother’s last adalimumab injection during pregnancy.

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

Humira can be used during breastfeeding.

Preclinical data on fertility effects of adalimumab are not available.

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

Humira was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months ormore. These trials included rheumatoid arthritis patients with short term and long standing disease,juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) aswell as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographicevidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativaand uveitis patients. The pivotal controlled studies involved 6,089 patients receiving Humira and 3,801patients receiving placebo or active comparator during the controlled period.

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

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

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

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

Serious haematological, neurological and autoimmune reactions have also been reported. These includerare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports oflupus, 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 on postmarketingexperience 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 each frequency grouping,undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among thevarious indications has been included. An asterisk (*) appears in the SOC column if further information isfound 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 lower andinfestations* upper respiratory tract infection, pneumonia,sinusitis, pharyngitis, nasopharyngitis andpneumonia herpes viral)

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

System Organ Class Frequency Adverse Reaction

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

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

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

Rare Leukaemia1)

Not known Hepatosplenic T-cell lymphoma1)

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

Kaposi’s sarcoma

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

Common Leucocytosis,thrombocytopenia

Uncommon Idiopathic thrombocytopenic purpura

Rare Pancytopenia

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

Uncommon Sarcoidosis1),vasculitis

Rare Anaphylaxis1)

Metabolism and nutrition Very common Lipids increased

System Organ Class Frequency Adverse Reactiondisorders

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

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

Nervous system disorders* Very common Headache

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

Uncommon Cerebrovascular accident1),tremor,neuropathy

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

Guillain-Barré syndrome) 1)

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

Uncommon Diplopia

Ear and labyrinth Common Vertigodisorders

Uncommon Deafness,tinnitus

Cardiac disorders* Common Tachycardia

Uncommon Myocardial infarction1),

System Organ Class Frequency Adverse Reactionarrhythmia,congestive heart failure

Rare Cardiac arrest

Vascular disorders Common Hypertension,flushing,haematoma

Uncommon Aortic aneurysm,vascular arterial occlusion,thrombophlebitis

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

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

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 Hepatitis

System Organ Class Frequency Adverse Reactionreactivation of hepatitis B1)autoimmune hepatitis1)

Not known Liver failure1)

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

Common Worsening or new onset of psoriasis(includingpalmoplantar pustular psoriasis)1),urticaria,bruising (including purpura),dermatitis (including eczema),onychoclasis,hyperhidrosis,alopecia1),pruritus

Uncommon Night sweats,scar

Rare Erythema multiforme1),

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

Not known Worsening of symptoms of dermatomyositis1)

Musculoskeletal and Very common Musculoskeletal painconnective tissue disorders

Common Muscle spasms (including blood creatinephosphokinase increased)

Uncommon Rhabdomyolysis,systemic lupus erythematosus

Rare Lupus-like syndrome1)

Renal and urinary Common Renal impairment,disorders haematuria

Uncommon Nocturia

Reproductive system and Uncommon Erectile dysfunctionbreast disorders

System Organ Class Frequency Adverse Reaction

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

Common Chest pain,oedema,pyrexia1)

Uncommon Inflammation

Investigations* Common Coagulation and bleeding disorders (includingactivated partial thromboplastin time prolonged),autoantibody test positive (including doublestranded DNA antibody),blood lactate dehydrogenase increased

Not known Weight increased2)

Injury, poisoning and Common Impaired healingprocedural complications

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

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

Weight increase of 5-6 kg has also been observed in long-term extension studies with mean exposures ofapproximately 1-2 years without control group, particularly in patients with Crohn’s disease and

Ulcerative colitis. The mechanism behind this effect is unclear but could be associated with theanti-inflammatory effect of adalimumab.

The safety profile for patients with uveitis treated with Humira every other week was consistent with theknown safety profile of Humira.

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

In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the

Humira treated patients and 1.46 per patient year in the placebo and active control-treated patients. Theinfections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Mostpatients continued on Humira after the infection resolved.

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

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

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

Humira trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis andenthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric patients with anexposure of 498.1 patient years during Humira trials in paediatric patients with Crohn’s disease. Nomalignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during a

Humira trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 60paediatric patients with an exposure of 58.4 patient years during a Humira trial in paediatric patients withuveitis.

During the controlled portions of pivotal Humira trials in adults of at least 12 weeks in duration in patientswith moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritiswithout radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’sdisease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer,were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291

Humira treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 controlpatients (median duration of treatment was 4.0 months for Humira and 3.8 months for control-treatedpatients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000patient-years among Humira-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among controlpatients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of2.7 (1.4, 5.4) per 1,000 patient-years among Humira-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) per1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years amongcontrol 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-melanoma skincancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers isapproximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per1,000 patient years.

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

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

Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis studies

I − V. In these trials, 11.9% of patients treated with Humira and 8.1% of placebo and activecontrol − treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at

Week 24. Two patients out of 3,441 treated with Humira in all rheumatoid arthritis and psoriatic arthritisstudies developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improvedfollowing discontinuation of therapy. No patients developed lupus nephritis or central nervous systemsymptoms.

In controlled Phase 3 trials of Humira in patients with rheumatoid arthritis and psoriatic arthritis with acontrol period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.7% of

Humira-treated patients and 1.6% of control-treated patients.

In controlled Phase 3 trials of Humira in patients with polyarticular juvenile idiopathic arthritis who were4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations ≥ 3 x ULN occurredin 6.1% of Humira-treated patients and 1.3% of control-treated patients. Most ALT elevations occurredwith concomitant methotrexate use. No ALT elevations ≥ 3 x ULN occurred in the Phase 3 trial of Humirain patients with polyarticular juvenile idiopathic arthritis who were 2 to < 4 years.

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

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

In controlled Phase 3 trials of Humira in patients with plaque psoriasis with a control period durationranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of Humira-treated patients and1.8% of control-treated patients.

No ALT elevations ≥ 3 x ULN occurred in the Phase 3 trial of Humira in paediatric patients with plaquepsoriasis.

In controlled trials of Humira (initial doses of 80 mg at Week 0 followed by 40 mg every other weekstarting at Week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 days and105.0 days in Humira-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULNoccurred in 2.4% of Humira-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, suchas 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 Humira and azathioprine/6-mercaptopurine compared with

Humira alone.

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

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

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

ATC code: L04AB04

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

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

After treatment with Humira, 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 Humira administration. Patients treated with Humira usuallyexperienced 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 with Humira. Inpatients with Crohn’s disease, a reduction of the number of cells expressing inflammatory markers in thecolon including a significant reduction of expression of TNFα was seen. Endoscopic studies in intestinalmucosa have shown evidence of mucosal healing in adalimumab treated patients.

Adults with rheumatoid arthritis

Humira was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. The efficacy andsafety of Humira were assessed in five randomised, double-blind and well-controlled studies. Somepatients 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) everyweek and whose methotrexate dose remained constant at 10 to 25 mg every week. Doses of 20, 40 or80 mg of Humira or placebo were given every other week for 24 weeks.

RA study II evaluated 544 patients with moderately to severely active rheumatoid arthritis who were 18 years old and had failed therapy with at least one disease-modifying, anti-rheumatic drugs. Doses of20 or 40 mg of Humira were given by subcutaneous injection every other week with placebo on alternativeweeks or every week for 26 weeks; placebo was given every week for the same duration. No otherdisease-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 Humira every weekfor 52 weeks. The third group received 40 mg of Humira every other week with placebo injections onalternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extensionphase in which 40 mg of Humira/MTX was administered every other week up to 10 years.

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

Humira 40 mg every other week/methotrexate combination therapy, Humira 40 mg every other weekmonotherapy and methotrexate monotherapy in reducing the signs and symptoms and rate of progressionof joint damage in rheumatoid arthritis for 104 weeks. Upon completion of the first 104 weeks, 497patients enrolled in an open-label extension phase in which 40 mg of Humira was administered everyother week up to 10 years.

The primary end point in RA studies I, II and III and the secondary endpoint in RA study IV was thepercent of patients who achieved an ACR 20 response at Week 24 or 26. The primary endpoint in RAstudy V was the percent of patients who achieved an ACR 50 response at Week 52. RA studies III and Vhad an additional primary endpoint at 52 weeks of retardation of disease progression (as detected by X-rayresults). RA study III also had a primary endpoint of changes in quality of life.

The percent of Humira-treated patients achieving ACR 20, 50 and 70 responses was consistent across RAstudies I, II and III. The results for the 40 mg every other week dose are summarised in Table 7.

Table 7

ACR Responses in Placebo-Controlled Trials(Percent of Patients)

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

Placebo/ Humirab/ MTXc Placebo Humirab Placebo/ Humirab/ MTXc

MTXc n=63 n=110 n=113 MTXc n=207n=60 n=200

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 Humira administered every other weekc MTX = methotrexate

**p < 0.01, Humira versus placebo

In RA studies I-IV, all individual components of the ACR response criteria (number of tender and swollenjoints, physician and patient assessment of disease activity and pain, disability index (HAQ) scores and

CRP (mg/dl) values) improved at 24 or 26 weeks compared to placebo. In RA study III, theseimprovements 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 Humira 40 mg everyother week, 114 patients continued on Humira 40 mg every other week for 5 years. Among those, 86patients (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 Humira 40 mg every other weekfor 10 years. Among those, 64 patients (79.0%) had ACR 20 responses; 56 patients (69.1%) had ACR 50responses; and 43 patients (53.1%) had ACR 70 responses.

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

In RA studies I-IV, Humira-treated patients achieved statistically significant ACR 20 and 50 responsescompared to placebo as early as one to two weeks after initiation of treatment.

In RA study V with early rheumatoid arthritis patients who were methotrexate naïve, combination therapywith Humira and methotrexate led to faster and significantly greater ACR responses than methotrexatemonotherapy and Humira monotherapy at Week 52 and responses were sustained at Week 104 (see Table8).

Table 8

ACR Responses in RA Study V(percent of patients)

MTX Humira Humira/MTX

Response p-valuea p-valueb p-valuecn=257 n=274 n=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 Humira/methotrexatecombination therapy using the Mann-Whitney U test.

b. p-value is from the pairwise comparison of Humira monotherapy and Humira/methotrexatecombination therapy using the Mann-Whitney U test

c. p-value is from the pairwise comparison of Humira monotherapy and methotrexate monotherapyusing the Mann-Whitney U test

In the open-label extension for RA study V, ACR response rates were maintained when followed for up to10 years. Of 542 patients who were randomised to Humira 40 mg every other week, 170 patientscontinued on Humira 40 mg every other week for 10 years. Among those, 154 patients (90.6%) had ACR20 responses; 127 patients (74.7%) had ACR 50 responses; and 102 patients (60.0%) had ACR 70responses.

At Week 52, 42.9% of patients who received Humira/methotrexate combination therapy achieved clinicalremission (DAS28 (CRP) < 2.6) compared to 20.6% of patients receiving methotrexate monotherapy and23.4% of patients receiving Humira monotherapy. Humira/methotrexate combination therapy wasclinically and statistically superior to methotrexate (p < 0.001) and Humira monotherapy (p < 0.001) inachieving a low disease state in patients with recently diagnosed moderate to severe rheumatoid arthritis.

The response for the two monotherapy arms was similar (p = 0.447). Of 342 subjects originallyrandomized to Humira monotherapy or Humira/methotrexate combination therapy who entered the open-label extension study, 171 subjects completed 10 years of Humira treatment. Among those, 109 subjects(63.7%) were reported to be in remission at 10 years.

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

Humira/methotrexate patients demonstrated significantly less radiographic progression than patientsreceiving 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 damage ismaintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated with40 mg Humira every other week were evaluated radiographically. Among those, 48 patients showed noprogression of structural damage defined by a change from baseline in the mTSS of 0.5 or less. At10 years, 79 of 207 patients originally treated with 40 mg Humira every other week were evaluatedradiographically. Among those, 40 patients showed no progression of structural damage defined by achange from baseline in the mTSS of 0.5 or less.

Table 9

Radiographic Mean Changes Over 12 Months in RA Study III

Placebo/ Humira/MTX Placebo/MTX- p-value

MTXa 40 mg every Humira/MTX (95%other week 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 Humira.cBased on rank analysisdJoint Space Narrowing

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

Total Sharp Score (see Table 10).

Table 10

Radiographic Mean Changes at Week 52 in RA Study V

MTX Humira Humira/MTXn=257 n=274 n=268(95% (95% (95% p-valuea p-valueb p-valuecconfidence confidence confidenceinterval) 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 and Humira/methotrexatecombination therapy using the Mann-Whitney U test.

b p-value is from the pairwise comparison of Humira monotherapy and Humira/methotrexatecombination therapy using the Mann-Whitney U testc p-value is from the pairwise comparison of Humira monotherapy and methotrexate monotherapyusing the Mann-Whitney U test

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

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

Total Sharp Score was 10.8, 9.2 and 3.9 in patients originally randomized to methotrexate monotherapy,

Humira monotherapy and Humira/methotrexate combination therapy, respectively. The correspondingproportions 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 apre-specified primary endpoint at Week 52 in RA study III. All doses/schedules of Humira in all fourstudies showed statistically significantly greater improvement in the disability index of the HAQ frombaseline to Month 6 compared to placebo and in RA study III the same was seen at Week 52. Results fromthe Short Form Health Survey (SF 36) for all doses/schedules of Humira in all four studies support thesefindings, with statistically significant physical component summary (PCS) scores, as well as statisticallysignificant pain and vitality domain scores for the 40 mg every other week dose. A statistically significantdecrease in fatigue as measured by functional assessment of chronic illness therapy (FACIT) scores wasseen in all three studies in which it was assessed (RA studies I, III, IV).

In RA study III, most subjects who achieved improvement in physical function and continued treatmentmaintained improvement through Week 520 (120 months) of open-label treatment. Improvement inquality of life was measured up to Week 156 (36 months) and improvement was maintained through thattime.

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 Humira/methotrexate combination therapy versusmethotrexate monotherapy and Humira monotherapy at Week 52, which was maintained through

Week 104. Among the 250 subjects who completed the open-label extension study, improvements inphysical function were maintained through 10 years of treatment.

Adult plaque psoriasis

The safety and efficacy of Humira were studied in adult patients with chronic plaque psoriasis ( 10%

BSA involvement and PASI  12 or  10) who were candidates for systemic therapy or phototherapy inrandomised, double-blind studies. 73% of patients enrolled in Psoriasis Studies I and II had received priorsystemic therapy or phototherapy. The safety and efficacy of Humira were also studied in adult patientswith moderate to severe chronic plaque psoriasis with concomitant hand and/or foot psoriasis who werecandidates for systemic therapy in a randomised double-blind study (Psoriasis Study III).

Psoriasis Study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A, patientsreceived placebo or Humira at an initial dose of 80 mg followed by 40 mg every other week starting oneweek after the initial dose. After 16 weeks of therapy, patients who achieved at least a PASI 75 response(PASI score improvement of at least 75% relative to baseline), entered period B and received open-label40 mg Humira every other week. Patients who maintained PASI 75 response at Week 33 and wereoriginally randomised to active therapy in Period A, were re-randomised in period C to receive 40 mg

Humira every other week or placebo for an additional 19 weeks. Across all treatment groups, the meanbaseline PASI score was 18.9 and the baseline PGA score ranged from “moderate” (53% of subjectsincluded) to “severe” (41%) to “very severe” (6%).

Psoriasis Study II (CHAMPION) compared the efficacy and safety of Humira versus methotrexate andplacebo in 271 patients. Patients received placebo, an initial dose of MTX 7.5 mg and thereafter doseincreases up to Week 12, with a maximum dose of 25 mg or an initial dose of 80 mg Humira followed by40 mg every other week (starting one week after the initial dose) for 16 weeks. There are no data availablecomparing Humira 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 treatmentgroups, the mean baseline PASI score was 19.7 and the baseline PGA score ranged from “mild” (<1%) to“moderate” (48%) to “severe” (46%) to “very severe” (6%).

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

In Psoriasis Studies I and II, a primary endpoint was the proportion of patients who achieved a PASI 75response from baseline at Week 16 (see Tables 11 and 12).

Table 11

Ps Study I (REVEAL) - Efficacy Results at 16 Weeks

Placebo Humira 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, Humira vs. Placebo

Table 12

Ps Study II (CHAMPION) Efficacy Results at 16 Weeks

Placebo MTX Humira 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 Humira vs. placebob p < 0.001 Humira vs. methotrexatec p < 0.01 Humira vs. placebod p < 0.05 Humira vs. methotrexate

In Psoriasis Study I, 28% of patients who were PASI 75 responders and were re-randomised to placebo at

Week 33 compared to 5% continuing on Humira, p < 0.001, experienced “loss of adequate response”(PASI score after Week 33 and on or before Week 52 that resulted in a <PASI 50 response relative tobaseline with a minimum of a 6-point increase in PASI score relative to Week 33). Of the patients wholost adequate response after re-randomisation to placebo who then enrolled into the open-label extensiontrial, 38% (25/66) and 55% (36/66) regained PASI 75 response after 12 and 24 weeks of re-treatment,respectively.

A total of 233 PASI 75 responders at Week 16 and Week 33 received continuous Humira therapy for52 weeks in Psoriasis Study I, and continued Humira in the open-label extension trial. PASI 75 and PGAof clear or minimal response rates in these patients were 74.7% and 59.0%, respectively, after anadditional 108 weeks of open-label therapy (total of 160 weeks). In an analysis in which all patients whodropped out of the study for adverse events or lack of efficacy, or who dose-escalated, were considerednon-responders, PASI 75 and PGA of clear or minimal response rates in these patients were 69.6% and55.7%, respectively, after an additional 108 weeks of open-label therapy (total of 160 weeks).

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

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

PASI 75 response at Week 12 and 24, respectively.

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

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

Humira treatment for an additional 26 weeks. Nail psoriasis assessments included the Modified Nail

Psoriasis Severity Index (mNAPSI), the Physician’s Global Assessment of Fingernail Psoriasis (PGA-F)and the Nail Psoriasis Severity Index (NAPSI) (see Table 13). Humira demonstrated a treatment benefit innail psoriasis patients with different extents of skin involvement (BSA≥10% (60% of patients) and

BSA<10% and ≥5% (40% of patients)).

Table 13

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

Endpoint Week 16 Week 26 Week 52

Placebo-Controlled Placebo-Controlled Open-label

Placebo Humira Placebo Humira Humira

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, Humira vs. placebo

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

The safety and efficacy of Humira were assessed in over 1500 patients with moderately to severely active

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

Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies, CD Study I(CLASSIC I) and CD Study II (GAIN). In CD Study I, 299 TNF-antagonist naive patients wererandomised to one of four treatment groups; placebo at Weeks 0 and 2, 160 mg Humira at Week 0 and80 mg at Week 2, 80 mg at Week 0 and 40 mg at Week 2, and 40 mg at Week 0 and 20 mg at Week 2. In

CD Study II, 325 patients who had lost response or were intolerant to infliximab were randomised toreceive either 160 mg Humira at Week 0 and 80 mg at Week 2 or placebo at Weeks 0 and 2. The primarynon-responders were excluded from the studies and therefore these patients were not further evaluated.

Maintenance of clinical remission was evaluated in CD study III (CHARM). In CD Study III, 854 patientsreceived open-label 80 mg at Week 0 and 40 mg at Week 2. At Week 4 patients were randomised to40 mg every other week, 40 mg every week, or placebo with a total study duration of 56 weeks. Patients inclinical response (decrease in CDAI ≥ 70) at Week 4 were stratified and analysed separately from thosenot in clinical response at Week 4. Corticosteroid taper was permitted after Week 8.

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

Table 14

Induction of Clinical Remission and Response(Percent of Patients)

CD Study I: Infliximab Naive CD Study II: Infliximab

Patients Experienced Patients

Placebo Humira Humira Placebo Humira

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

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

* p < 0.001

** p < 0.01

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

In CD Study III, at Week 4, 58% (499/854) of patients were in clinical response and were assessed in theprimary analysis. Of those in clinical response at Week 4, 48% had been previously exposed to other TNF-antagonists. Maintenance of remission and response rates are presented in Table 15. Clinical remissionresults remained relatively constant irrespective of previous TNF-antagonist exposure.

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

Table 15

Maintenance of Clinical Remission and Response(Percent of Patients)

Placebo 40 mg Humira 40 mg Humiraevery 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 Humira versus placebo pairwise comparisons of proportions

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

Among patients who were not in response at Week 4, 43% of Humira maintenance patients responded by

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

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

In CD Study I and CD Study II, statistically significant improvement in the disease-specific inflammatorybowel disease questionnaire (IBDQ) total score was achieved at Week 4 in patients randomised to Humira80/40 mg and 160/80 mg compared to placebo and was seen at Weeks 26 and 56 in CD Study III as wellamong the adalimumab treatment groups compared to the placebo group.

Adult Uveitis

The safety and efficacy of Humira were assessed in adult patients with non-infectious intermediate,posterior, and panuveitis, excluding patients with isolated anterior uveitis, in two randomised, double-masked, placebo-controlled studies (UV I and II). Patients received placebo or Humira at an initial dose of80 mg followed by 40 mg every other week starting one week after the initial dose. Concomitant stabledoses of one non-biologic immunosuppressant were permitted.

Study UV I evaluated 217 patients with active uveitis despite treatment with corticosteroids (oralprednisone at a dose of 10 to 60 mg/day). All patients received a 2-week standardised dose of prednisone60 mg/day at study entry followed by a mandatory taper schedule, with complete corticosteroiddiscontinuation by Week 15.

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

The primary efficacy endpoint in both studies was t́ime to treatment failure´. Treatment failure wasdefined by a multi-component outcome based on inflammatory chorioretinal and/or inflammatory retinalvascular lesions, anterior chamber (AC) cell grade, vitreous haze (VH) grade and best corrected visualacuity (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 Humira.

Clinical Response

Results from both studies demonstrated statistically significant reduction of the risk of treatment failure inpatients treated with Humira versus patients receiving placebo (See Table 16). Both studies demonstratedan early and sustained effect of Humira on the treatment failure rate versus placebo (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), was countedas event. Drop outs due to reasons other than treatment failure were censored at the time of dropping out.a HR of adalimumab vs placebo from proportional hazards regression with treatment as factor.b 2-sided P value from log rank test.c NE = not estimable. Fewer than half of at-risk subjects had an event.

Figure 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# = HUMIRA (Number of

Events/Number at Risk).

In Study UV I statistically significant differences in favour of adalimumab versus placebo were observedfor each component of treatment failure. In Study UV II, statistically significant differences were observedfor visual acuity only, but the other components were numerically in favour of adalimumab.

Of the 424 subjects included in the uncontrolled long-term extension of Studies UV I and UV II, 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 (no activeinflammatory lesions, AC cell grade ≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose ≤ 7.5 mgper day, and 178 (66.2%) were in steroid-free quiescence. BCVA was either improved or maintained (< 5letters deterioration) in 88.6% of the eyes at week 78. Data beyond Week 78 were generally consistent

TREATMENT FAILURE RATE (%) TREATMENT FAILURE RATE (%)with these results but the number of enrolled subjects declined after this time. Overall, among the patientswho discontinued the study, 18% discontinued due to adverse events, and 8% due to insufficient responseto adalimumab treatment.

Quality of Life

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

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

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

In patients with polyarticular juvenile idiopathic arthritis who were 4 to 17 years, anti-adalimumabantibodies were identified in 15.8% (27/171) of patients treated with adalimumab. In patients not givenconcomitant methotrexate, the incidence was 25.6% (22/86) compared to 5.9% (5/85) when adalimumabwas used as add-on to methotrexate. In patients with polyarticular juvenile idiopathic arthritis who were2 to < 4 years old or aged 4 and above weighing <15 kg, anti-adalimumab antibodies were identified in7% (1/15) of patients, and the one patient was receiving concomitant methotrexate.

In patients with enthesitis-related arthritis, anti-adalimumab antibodies were identified in 10.9% (5/46) ofpatients treated with adalimumab. In patients not given concomitant methotrexate, the incidence was13.6% (3/22), compared to 8.3% (2/24) when adalimumab was used as add-on to methotrexate.

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

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

In patients with paediatric psoriasis, anti-adalimumab antibodies were identified in 5/38 subjects (13%)treated with 0.8 mg/kg adalimumab monotherapy.

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

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

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

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

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

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

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

pJIA I

The safety and efficacy of Humira were assessed in a multicentre, randomised, double-blind,parallel − group study in 171 children (4-17 years old) with polyarticular JIA. In the open-label lead inphase (OL LI) patients were stratified into two groups, MTX (methotrexate)-treated or non-MTX-treated.

Patients who were in the non-MTX stratum were either naïve to or had been withdrawn from MTX atleast two weeks prior to study drug administration. Patients remained on stable doses of non-steroidalanti-inflammatory drugs (NSAIDs) and or prednisone ( 0.2 mg/kg/day or 10 mg/day maximum). In the

OL LI phase all patients received 24 mg/m2 up to a maximum of 40 mg Humira every other week for16 weeks. The distribution of patients by age and minimum, median and maximum dose received duringthe OL LI phase is presented in Table 17.

Table 17

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

Age Group Number of patients at Baseline Minimum, median and maximumn (%) 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 Paediatric ACR 30 response at Week 16 were eligible to be randomised into thedouble blind (DB) phase and received either Humira 24 mg/m2 up to a maximum of 40 mg, or placeboevery other week for an additional 32 weeks or until disease flare. Disease flare criteria were defined as aworsening of  30% from baseline in  3 of 6 Paediatric ACR core criteria,  2 active joints, andimprovement of  30% in no more than 1 of the 6 criteria. After 32 weeks or at disease flare, patientswere 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 32 weeks Humira /MTX Placebo/MTX Humira Placebo(N = 38) (N = 37) (N = 30) (N = 28)

Disease flares at 36.8% (14/38) 64.9% (24/37)b 43.3% (13/30) 71.4%the end of (20/28)c32 weeksa (n/N)

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

Amongst those who responded at Week 16 (n=144), the Paediatric ACR 30/50/70/90 responses weremaintained for up to six years in the OLE phase in patients who received Humira throughout the study.

Over all 19 subjects, of which 11 of the baseline age group 4 to 12 and 8 of the baseline age group 13 to17 years were treated 6 years or longer.

Overall responses were generally better and, fewer patients developed antibodies when treated with thecombination of Humira and MTX compared to Humira alone. Taking these results into consideration,

Humira is recommended for use in combination with MTX and for use as monotherapy in patients forwhom MTX use is not appropriate (see section 4.2).

pJIA II

The safety and efficacy of Humira was assessed in an open-label, multicentre study in 32 children(2 - < 4 years old or aged 4 and above weighing < 15 kg) with moderately to severely active polyarticular

JIA. The patients received 24 mg/m2 body surface area (BSA) of Humira up to a maximum of 20 mgevery other week as a single dose via SC injection for at least 24 weeks. During the study, most subjectsused concomitant MTX, with fewer reporting use of corticosteroids or NSAIDs.

At Week 12 and Week 24, PedACR30 response was 93.5% and 90.0%, respectively, using 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 (Paediatric

ACR 30) at Week 24 (n=27 out of 30 patients), the Paediatric ACR 30 responses were maintained for upto 60 weeks in the OLE phase in patients who received Humira throughout this time period. Overall,20 subjects were treated for 60 weeks or longer.

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

Baseline to Week 12 in the number of active joints with arthritis (swelling not due to deformity or jointswith loss of motion plus pain and/or tenderness), which was achieved with mean percent decrease of -62.6% (median percent change -88.9%) in patients in the Humira group compared to -11.6% (medianpercent change -50.0%) in patients in the placebo group. Improvement in number of active joints witharthritis was maintained during the OL period through Week 156 for the 26 of 31 (84%) patients in the

Humira group who remained in the study. Although not statistically significant, the majority of patientsdemonstrated clinical improvement in secondary endpoints such as number of sites of enthesitis, tenderjoint count (TJC), swollen joint count (SJC), Paediatric ACR 50 response, and Paediatric ACR 70response.

The efficacy of Humira was assessed in a randomised, double-blind, controlled study of 114 paediatricpatients from 4 years of age with severe chronic plaque psoriasis (as defined by a Physician’s Global

Assessment (PGA) ≥ 4 or > 20% BSA involvement or > 10% BSA involvement with very thick lesions or

Psoriasis Area and Severity Index (PASI) ≥ 20 or ≥ 10 with clinically relevant facial, genital, or hand/ footinvolvement) who were inadequately controlled with topical therapy and heliotherapy or phototherapy.

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

Table 19: Paediatric Plaque Psoriasis Efficacy Results at 16 Weeks

MTXa Humira 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, Humira 0.8 mg/kg versus MTXc P=0.083, Humira 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). Patientswere then re-treated with adalimumab 0.8 mg/kg eow for an additional 16 weeks and response ratesobserved during retreatment were similar to the previous double-blind period: PASI 75 response of 78.9%(15 of 19 subjects) and PGA clear or minimal of 52.6% (10 of 19 subjects).

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

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

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

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

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

Standard Dose maintenance regimens as shown in Table 20.

Table 20

Maintenance regimen

Patient Low dose Standard

Weight dose< 40 kg 10 mg eow 20 mg eow≥ 40 kg 20 mg eow 40 mg eow

The primary endpoint of the study was clinical remission at Week 26, defined as PCDAI score  10.

Clinical remission and clinical response (defined as reduction in PCDAI score of at least 15 points from

Baseline) rates are presented in Table 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 Immunomodulators and Fistula Remission

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

Discontinued corticosteroids N= 33 N=38

Week 26 84.8% 65.8% 0.066

Week 52 69.7% 60.5% 0.420

Discontinuation of Immunomodulators2 N=60 N=57

Week 52 30.0% 29.8% 0.983

Fistula remission3 N=15 N=21

Week 26 46.7% 38.1% 0.608

Week 52 40.0% 23.8% 0.3031 p value for Standard Dose versus Low Dose comparison.2 Immunosuppressant therapy could only be discontinued at or after Week 26 at theinvestigator's discretion if the subject met the clinical response criterion3 defined as a closure of all fistulas that were draining at Baseline for at least 2 consecutivepost-Baseline visits

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

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

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

The safety and efficacy of Humira was assessed in a randomized, double-masked, controlled study of 90paediatric patients from 2 to < 18 years of age with active JIA-associated noninfectious anterior uveitiswho were refractory to at least 12 weeks of methotrexate treatment. Patients received either placebo or20 mg adalimumab (if < 30 kg) or 40 mg adalimumab (if ≥ 30 kg) every other week in combination withtheir 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 with developmentof sustained ocular co-morbidities or worsening of ocular co-morbidities, non-permitted use ofconcomitant medications, and suspension of treatment for an extended period of time.

Clinical Response

Adalimumab significantly delayed the time to treatment failure, as compared to placebo (See Figure 2,

P < 0.0001 from log rank test).The median time to treatment failure was 24.1 weeks for subjects treatedwith placebo, whereas the median time to treatment failure was not estimable for subjects treated withadalimumab because less than one-half of these subjects experienced treatment failure. Adalimumabsignificantly decreased the risk of treatment failure by 75% relative to placebo, as shown by the hazardratio (HR = 0.25 [95% CI: 0.12, 0.49]).

Figure 2: Kaplan-Meier Curves Summarizing Time to Treatment Failure in the Paediatric Uveitis

Study

TIME (WEEKS)

Treatment Placebo Adalimumab

Note: P = Placebo (Number at Risk); H = HUMIRA (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) withconcomitant 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 concentrations was6.0 ± 6.1 µg/ml (101% CV) for adalimumab without concomitant methotrexate and 7.9 ± 5.6 µg/ml(71.2% CV) with concomitant methotrexate.

PROBABILITY OF FAILING TREATMENT

Following the administration of 24 mg/m2 (maximum of 40 mg) subcutaneously every other week topatients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state (valuesmeasured at Week 24) serum adalimumab concentrations were 8.8 ± 6.6 μg/ml for adalimumab withoutconcomitant 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 trough concentrationsat Week 52 were 9.5 ± 5.6 g/ml for the Standard Dose group and 3.5 ± 2.2 g/ml for the Low Dosegroup. The mean trough concentrations were maintained in patients who continued to receive adalimumabtreatment eow for 52 weeks. For patients who dose escalated from eow to weekly regimen, the mean(±SD) serum concentrations of adalimumab at Week 52 were 15.3 ± 11.4 μg/ml (40/20 mg, weekly) and6.7 ± 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. Thepredicted exposures indicate that in the absence of methotrexate, a loading dose may lead to an initialincrease 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-response relationshipwas established between plasma concentrations and PedACR 50 response. The apparent adalimumabplasma concentration that produces half the maximum probability of PedACR 50 response (EC50) was3 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 adalimumab concentrations,both with a similar apparent EC50 of approximately 4.5 μg/ml (95% CI 0.4-47.6 and 1.9-10.5,respectively).

After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab wasslow, with peak serum concentrations being reached about 5 days after administration. The averageabsolute bioavailability of adalimumab estimated from three studies following a single 40 mgsubcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg,concentrations were dose proportional. After doses of 0.5 mg/kg (~40 mg), clearances ranged from 11 to15 ml/hour, the distribution volume (Vss) ranged from 5 to 6 litres and the mean terminal phase half-lifewas approximately two weeks. Adalimumab concentrations in the synovial fluid from several rheumatoidarthritis 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 (withoutconcomitant methotrexate) and 8 to 9 g/ml (with concomitant methotrexate), respectively. The serumadalimumab trough levels at steady-state increased roughly proportionally with dose following 20, 40 and80 mg subcutaneous dosing every other week and every week.

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 Humira on Week 0 followed by 40 mg Humiraon Week 2 achieves serum adalimumab trough concentrations of approximately 5.5 g/ml during theinduction period. A loading dose of 160 mg Humira on Week 0 followed by 80 mg Humira on Week 2achieves serum adalimumab trough concentrations of approximately 12 g/ml during the induction period.

Mean steady-state trough levels of approximately 7 g/ml were observed in Crohn’s disease patients whoreceived a maintenance dose of 40 mg Humira 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 simulation predictedcomparable adalimumab exposure and efficacy in patients treated with 80 mg every other week whencompared with 40 mg every week (including adult patients with RA, HS, UC, CD or Ps, patients withadolescent HS, and paediatric patients ≥ 40 kg with CD).

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 serum levelsof free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be lower inpatients with measurable AAA.

Hepatic or renal impairment

Humira 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, repeateddose 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 of harmto the foetuses due to adalimumab. Neither carcinogenicity studies, nor a standard assessment of fertilityand postnatal toxicity, were performed with adalimumab due to the lack of appropriate models for anantibody with limited cross-reactivity to rodent TNF and to the development of neutralising antibodies inrodents.

Mannitol

Polysorbate 80

Water for injections

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

2 years

Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the pre-filled syringe in its outer carton in order toprotect from light.

A single Humira pre-filled syringe may be stored at temperatures up to a maximum of 25°C for a period ofup to 14 days. The syringe must be protected from light, and discarded if not used within the 14-dayperiod.

Humira 20 mg solution for injection in single-use pre-filled syringe (type I glass) with a plunger stopper(bromobutyl rubber) and a needle with a needle shield (thermoplastic elastomer).

Packs of:

- 2 pre-filled syringes (0.2 ml sterile solution), each with 1 alcohol pad, in a blister.

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

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/03/256/022

Date of first authorisation: 08 September 2003

Date of latest renewal: 08 September 2008

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

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