Abbott Laboratories Ireland Limited

Humira 40 mg/0.8 ml solution for injection for paediatric use.

Each 0.8 ml single dose vial contains 40 mg of adalimumab.

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

For a full list of excipients, see section 6.1.

Clear solution for injection.

Polyarticular juvenile idiopathic arthritis

Humira in combination with methotrexate is indicated for the treatment of active polyarticular juvenile idiopathic arthritis, in children and adolescents aged 4 to 17 years who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). Humira can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate (for the efficacy in monotherapy see section 5.1). Humira has not been studied in children aged less than 4 years.

Humira treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of polyarticular juvenile idiopathic arthritis. Patients treated with Humira should be given the special alert card.

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

Paediatric Population

Polyarticular Juvenile Idiopathic Arthritis

Humira has not been studied in children aged less than 4 years. Limited data are available for Humira treatment in paediatric patients with a weight below 15 kg.

Polyarticular Juvenile Idiopathic Arthritis Age 4 to 12 years

The recommended dose of Humira for patients with polyarticular juvenile idiopathic arthritis, aged 4 -12 years, is 24 mg/m² body surface area up to a maximum single dose of 40 mg adalimumab administered every other week via subcutaneous injection. The volume for injection is selected based on the patients' height and weight (Table 1).

*Maximum single dose is 40 mg (0.8 ml)

Polyarticular Juvenile Idiopathic Arthritis Age 13-17 years:

For adolescents aged 13-17 years, a dose of 40 mg is administered every other week regardless of body surface area.

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

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

Impaired renal and/or hepatic function

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

Hypersensitivity to the active substance or to any of the excipients.

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).

Infections

Patients taking TNF-antagonists are more susceptible to serious infections. Impaired lung function may increase 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 of adalimumab 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 or localized infections until infections are controlled. In patients who have been exposed to tuberculosis and patients who have travelled in areas of high risk of tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis, the risk and benefits of treatment with Humira should be considered prior to initiating therapy (see Other opportunistic infections).

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

Serious infections:

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

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

Tuberculosis:

There have been reports of tuberculosis in patients receiving Humira. It should be noted that in the majority of those reports, tuberculosis was extra-pulmonary, i.e. disseminated.

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 history of patients with a personal history of tuberculosis or possible previous exposure to patients with active tuberculosis and previous and/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 the conduct of these tests should be recorded in the patient alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.

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

If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be consulted. In all situations described below, the benefit/risk balance of therapy should be very carefully considered.

If inactive ('latent') tuberculosis is diagnosed, appropriate treatment for latent tuberculosis must be started with anti-tuberculosis prophylaxis therapy before the initiation of Humira, and in accordance with local recommendations.

In patients who have several or significant risk factors for tuberculosis and have a negative test for latent tuberculosis, anti-tuberculosis therapy should also be considered before the initiation of Humira.

Use of anti-tuberculosis therapy should also be considered before the initiation of Humira in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Some patients who have previously received treatment for latent or active tuberculosis have developed active tuberculosis while being treated with Humira.

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

Other opportunistic infections:

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 and this 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, dyspnea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant shock an invasive fungal infection should be suspected and administration of Humira should be promptly discontinued. Diagnosis and administration of empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the care of patients with invasive fungal infections.

Hepatitis B reactivation

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

Carriers of HBV who require treatment with Humira should be closely monitored for signs and symptoms of 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 HBV reactivation, Humira should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.

Neurological events

TNF-antagonists including Humira have been associated in rare instances with new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease including multiple sclerosis 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.

Allergic reactions

Serious allergic adverse reactions have not been reported with subcutaneous administration of Humira during clinical trials. Non-serious allergic reactions associated with Humira were uncommon during clinical trials. In postmarketing, serious allergic reactions including anaphylaxis have been reported very rarely following Humira administration. If an anaphylactic reaction or other serious allergic reaction occurs, administration of Humira should be discontinued immediately and appropriate therapy initiated.

The needle cover of the syringe contains natural rubber (latex). This may cause severe allergic reactions in patients sensitive to latex.

Immunosuppression

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

Malignancies and lymphoproliferative disorders

In the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies including lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare. In the post marketing setting, cases of leukemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukemia 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 of lymphomas, leukemia, and other malignancies in patients treated with a TNF-antagonist cannot be excluded.

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-antagonists (initiation of therapy 18 years of age), including adalimumab in the post marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. 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 with adalimumab. 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 on concomitant treatment with azathioprine or 6-mercaptopurine used for inflammatory bowel disease. The potential risk with the combination of azathioprine or 6-mercaptopurine and Humira should be carefully considered. A risk for the development of hepatosplenic T-cell lymphoma in patients treated with Humira cannot be excluded (see section 4.8).

No studies have been conducted that include patients with a history of malignancy or in whom treatment with Humira is continued following development of malignancy. Thus additional caution should be exercised 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 or psoriasis patients with a history of PUVA treatment should be examined for the presence of non-melanoma skin cancer prior to and during treatment with Humira.

In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung or head and neck, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist in COPD patients, as well as in patients with increased risk for malignancy due to heavy smoking.

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

Haematologic reactions

Rare reports of pancytopaenia including aplastic anaemia have been reported with TNF-antagonists. Adverse events of the haematologic system, including medically significant cytopoenia (e.g. thrombocytopaenia, leucopaenia) have been reported with Humira. All patients should be advised to seek immediate 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 be considered in patients with confirmed significant haematologic abnormalities.

Vaccinations

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

It is recommended that polyarticular juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating Humira therapy.

Patients on Humira may receive concurrent vaccinations, except for live vaccines.

Congestive heart failure

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

Autoimmune processes

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

Concurrent administration of TNF-antagonists and anakinra

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

Concurrent administration of TNF-antagonists and abatacept

Concurrent administration of TNF-antagonists and abatacept has been associated with an increased risk of infections including serious infections compared to TNF-antagonists alone, without increased clinical benefit. The combination of Humira and abatacept is not recommended. (See section 4.5).

Surgery

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 who requires surgery while on Humira should be closely monitored for infections, and appropriate actions should be taken. There is limited safety experience in patients undergoing arthroplasty while receiving Humira.

Small bowel obstruction

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

Elderly Population

The frequency of serious infections among HUMIRA treated subjects over 65 years of age (3.7%) was higher than for those under 65 years of age (1.4%). Some of those had a fatal outcome. Particular attention regarding the risk for infection should be paid when treating the elderly.

Humira has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis patients taking Humira as monotherapy and those taking concomitant methotrexate. Antibody formation was lower when Humira was given together with methotrexate in comparison with use as monotherapy. Administration of Humira without methotrexate resulted in increased formation of antibodies, 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 administration of TNF-antagonists and anakinra”).

The combination of Humira and abatacept is not recommended (see section 4.4 “Concurrent administration of TNF-antagonists and abatacept”).

Pregnancy

For Humira, limited clinical data on exposed pregnancies are available

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

Due to its inhibition of TNFα, adalimumab administered during pregnancy could affect normal immune responses in the newborn. Administration of adalimumab is not recommended during pregnancy. Women of childbearing potential are strongly recommended to use adequate contraception to prevent pregnancy and continue its use for at least five months after the last Humira treatment.

Adalimumab may cross the placenta into the serum of infants born to women treated with adalimumab during pregnancy. Consequently, these infants may be at increased risk for infection. Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for at least 5 months following the mother's last adalimumab injection during pregnancy.

Lactation

It is not known whether adalimumab is excreted in human milk or absorbed systemically after ingestion.

However, because human immunoglobulins are excreted in milk, women must not breast-feed for at least five months after the last Humira treatment.

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

Humira was studied in 7,552 patients in pivotal controlled and open label trials for up to 60 months or more. These trials included rheumatoid arthritis patients with short term and long standing disease, polyarticular juvenile idiopathic arthritis as well as psoriatic arthritis, ankylosing spondylitis, Crohn's disease and psoriasis patients. The data in Table 2 is based on the pivotal controlled Studies involving 5,029 patients receiving Humira and 3,035 patients receiving placebo or active comparator during the controlled period and spontaneous reporting.

The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies was 5.8% for patients taking Humira and 5.9% for control treated patients.

Summary of safety profile

The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract 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 the immune system and their use may affect the body's defense against infection and cancer.

Fatal and life-threating infections (including sepsis, opportunistic infections and TB), HBV reactivation and various maligancies (including leukaemia, lymphoma and HSTCL) have also been reported with use of Humira.

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

Undesirable effects in paediatric patients with polyarticular juvenile idiopathic arthritis

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

The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency (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) in Table 2 below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among the various indications has been included. An asterisk (*) appears in the SOC column if further information is found elsewhere in sections 4.3, 4.4 and 4.8.

Table 2

Undesirable Effects

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

** including open label extension studies

¹⁾ including spontaneous reporting data

Injection site reactions

In the pivotal controlled trials, 14% of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 8% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.

Infections

In the pivotal controlled trials, the rate of infection was 1.50 per patient year in the Humira treated patients and 1.42 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on Humira after the infection resolved.

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

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

Malignancies and lymphoproliferative disorders

No malignancies were observed in 171 patients with an exposure of 192.5 patient years during a Humira trial in juvenile idiopathic arthritis patients.

During the controlled portions of pivotal Humira trials of at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease and ulcerative colitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.1 (2.7, 10.0) per 1,000 patient-years among 4,527 Humira treated patients versus a rate of 5.2 (2.5, 11.0) per 1,000 patient-years among 2,730 control patients (median duration of treatment was 5.4 months for Humira and 4.0 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 9.5 (6.4, 14.1) per 1,000 patient-years among Humira-treated patients and 3.7 (1.6, 9.0) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 3.0 (1.5, 6.1) per 1,000 patient-years among Humira-treated patients and 0.7 (0.1, 5.3) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.8 (0.2, 3.0) per 1,000 patient-years among Humira-treated patients and 1.5 (0.4, 6.0) per 1,000 patient-years among control patients.

When combining controlled portions of these trials and ongoing and completed open label extension studies with a median duration of approximately 3.2 years including 5,331 patients and over 21,800 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.2 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 10.2 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1000 patient years.

In post-marketing experience from January 2003 to December 2009, predominantly in patients with rheumatoid arthritis, the reported rate of malignancies is approximately 2.6 per 1,000 patient treatment years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 0.3 per 1,000 patient treatment years, respectively (see section 4.4).

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

Autoantibodies

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 active control − treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at Week 24. Two patients out of 3,441 treated with Humira in all rheumatoid arthritis and psoriatic arthritis studies developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms.

Liver Enzyme Elevations

Rheumatoid arthritis clinical trials: in controlled rheumatoid arthritis clinical trials (RA studies I − IV), elevations of ALT were similar in patients receiving adalimumab or placebo. In patients with early rheumatoid arthritis (disease duration of less than 3 years) (RA study V), elevations of ALT were more common in the combination arm (Humira /methotrexate) compared to the methotrexate monotherapy arm or the Humira monotherapy arm. In the JIA trial the few transaminase elevations were small and similar in the placebo and adalimumab exposed patients, and mostly occurred in combination with methotrexate.

Psoriatic arthritis clinical trials: elevations in ALT were more common in psoriatic arthritis patients (PsA studies I - II) compared with patients in rheumatoid arthritis clinical studies.

In all rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis studies, patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved on continued treatment.

Psoriasis clinical trials: in controlled psoriasis clinical trials, elevations of ALT were similar in patients receiving adalimumab or placebo.

Crohn's disease and ulcerative colitis clinical trials: in controlled clinical trials, elevations of ALT were similar in patients receiving adalimumab or placebo.

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

Pharmacotherapeutic group: Selective immunosuppressive agents. ATC code: L04AB04

Mechanism of action

Adalimumab binds specifically to TNF and neutralizes the biological function of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors.

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC₅₀ of0.1-0.2 nM).

Pharmacodynamic effects

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) was observed, compared to baseline in patients with rheumatoid arthritis. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodelling responsible for cartilage destruction were also decreased after Humira administration. Patients treated with Humira usually experienced improvement in haematological signs of chronic inflammation.

A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic arthritis, Crohn's disease and ulcerative colitis after treatment with Humira. In patients with Crohn's disease, a reduction of the number of cells expressing inflammatory markers in the colon including a significant reduction of expression of TNFα was seen. Endoscopic studies in intestinal mucosa have shown evidence of mucosal healing in adalimumab treated patients.

Clinical trials

Polyarticular juvenile idiopathic arthritis (JIA)

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 in phase (OL LI) patients were stratified into two groups, MTX (methotrexate)-treated or non- MTX-treated. Patients who were in the non-MTX stratum were either naïve to or had been withdrawn from MTX at least two weeks prior to study drug administration. Patients remained on stable doses of 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 for 16 weeks. The distribution of patients by age and minimum, median and maximum dose received during the OL LI phase is presented in Table 3.

Table 3

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

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

Table 4

Paed ACR 30 Responses in the JIA study

^a Paed ACR 30/50/70 responses Week 48 significantly greater than those of placebo treated patients

^b p = 0.015

^c p = 0.031

Amongst those who responded at Week 16 (n=144), the Paediatric ACR 30/50/70/90 responses were maintained 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 to 17 years were treated 6 years or longer.

Overall responses were generally better and, fewer patients developed antibodies when treated with the combination 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 for whom MTX use is not appropriate (see section 4.2).

Adults with Rheumatoid arthritis

Humira was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. Some patients were treated for up to 60 months duration. The efficacy and safety of Humira for the treatment of rheumatoid arthritis were assessed in five randomised, double-blind and well-controlled studies.

RA study I evaluated 271 patients with moderately to severely active rheumatoid arthritis who were 18 years old, had failed therapy with at least one disease-modifying, anti rheumatic drug and had insufficient efficacy with methotrexate at doses of 12.5 to 25 mg (10 mg if methotrexate-intolerant) every week and whose methotrexate dose remained constant at 10 to 25 mg every week. Doses of 20, 40 or 80 mg of 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 of 20 or 40 mg of Humira were given by subcutaneous injection every other week with placebo on alternative weeks or every week for 26 weeks; placebo was given every week for the same duration. No other disease-modifying anti-rheumatic drugs were allowed.

RA study III evaluated 619 patients with moderately to severely active rheumatoid arthritis who were 18 years old, and who had an ineffective response to methotrexate at doses of 12.5 to 25 mg, or have been intolerant to 10 mg of methotrexate every week. There were three groups in this study. The first received placebo injections every week for 52 weeks. The second received 20 mg of Humira every week for 52 weeks. The third group received 40 mg of Humira every other week with placebo injections on alternate weeks. Thereafter, patients enrolled in an open-label extension phase in which 40 mg of Humira was administered every other week up to 60 months.

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

RA study V evaluated 799 methotrexate-naïve, adult patients with moderate to severely active early rheumatoid 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 week monotherapy and methotrexate monotherapy in reducing the signs and symptoms and rate of progression of joint damage in rheumatoid arthritis for 104 weeks.

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

ACR response

The percent of Humira-treated patients achieving ACR 20, 50 and 70 responses was consistent across RA studies I, II and III. The results for the 40 mg every other week dose are summarised in Table 5.

Table 5 ACR Responses in Placebo-Controlled Trials

(Percent of Patients)

^a RA study I at 24 weeks, RA study II at 26 weeks , and RA study III at 24 and 52 weeks

^b 40 mg Humira administered every other week

^c 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 swollen joints, physician and patient assessment of disease activity and pain, disability index (HAQ) scores and CRP (mg/dl) values) improved at 24 or 26 weeks compared to placebo. In RA study III, these improvements were maintained throughout 52 weeks. In addition, ACR response rates were maintained in the majority of patients followed in the open-label extension phase to Week 104. There were 114 out of 207 patients who continued on Humira 40 mg every other week for 60 months. Among those, 86, 72, and 41 patients had ACR 20/50/70 response, respectively at Month 60.

In RA study IV, the ACR 20 response of patients treated with Humira plus standard of care was statistically 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 responses compared to placebo as early as one to two weeks after initiation of treatment.

In RA study V with early rheumatoid arthritis patients who were methotrexate naïve, combination therapy with Humira and methotrexate led to faster and significantly greater ACR responses than methotrexate monotherapy and Humira monotherapy at Week 52 and responses were sustained at Week 104 (see Table 6).

Table 6 ACR Responses in RA Study V

(percent of patients)

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

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

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

At Week 52, 42.9% of patients who received Humira/methotrexate combination therapy achieved clinical remission (DAS28 < 2.6) compared to 20.6% of patients receiving methotrexate monotherapy and 23.4% of patients receiving Humira monotherapy. Humira/methotrexate combination therapy was clinically and statistically superior to methotrexate (p < 0.001) and Humira monotherapy (p < 0.001) in achieving 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).

Radiographic response

In RA study III, where Humira treated patients had a mean duration of rheumatoid arthritis of approximately 11 years, structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (TSS) and its components, the erosion score and joint space narrowing score. Humira/methotrexate patients demonstrated significantly less radiographic progression than patients receiving methotrexate alone at 6 and 12 months (see Table 7). Data from the open-label extension phase indicate that the reduction in rate of progression of structural damage is maintained for 60 months in a subset of patients. 113of 207 of patients originally treated with 40 mg Humira every other week were evaluated radiographically at 5 years. Among those, 66 patients showed no progression of structural damage defined by a change in the TSS of zero or less.

Table 7 Radiographic Mean Changes Over 12 Months in RA Study III

^amethotrexate

^b95% confidence intervals for the differences in change scores between methotrexate and Humira.

^cBased on rank analysis

^dJoint Space Narrowing

In RA study V, structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (see Table 8).

Table 8 Radiographic Mean Changes at Week 52 in RA Study V

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

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

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

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

Quality of life and physical function

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

In RA study III, improvement in physical function was maintained through Week 260 (60 months) of open-label treatment. Improvement in quality of life was measured up to Week 156 (36 months) and improvement was maintained through that time.

In RA study V, the improvement in the HAQ disability index and the physical component of the SF 36 showed greater improvement (p < 0.001) for Humira/methotrexate combination therapy versus methotrexate monotherapy and Humira monotherapy at Week 52, which was maintained through Week 104.

Immunogenicity

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

In patients with polyarticular juvenile idiopathic arthritis, adalimumab antibodies were identified in 27/171 subjects (15.8%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 22/86 (25.6%), compared to 5/85 (5.9%) when adalimumab was used as add-on to methotrexate.

Patients in RA Studies I, II and III were tested at multiple time points for anti-adalimumab antibodies during the 6 to 12 month period. In the pivotal trials, anti-adalimumab antibodies were identified in 58/1053 (5.5%) patients treated with adalimumab, compared to 2/370 (0.5%) on placebo. In patients not given concomitant methotrexate, the incidence was 12.4%, compared to 0.6% when adalimumab was used as add-on to methotrexate.

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

The European Medicines Agency has waived the obligation to submit the results of studies with Humira in all subsets of the paediatric population in Rheumatoid arthritis, Psoriatic arthritis and Ankylosing spondylitis (see section 4.2 for information on paediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies with Humira in one or more subsets of the paediatric population in Polyarticular juvenile idiopathic arthritis (see section 4.2 for information on paediatric use).

Following the administration of 24 mg/m² (up to a maximum of 40 mg) subcutaneously every other week to patients with polyarticular juvenile idiopathic arthritis (JIA) the mean trough steady-state (values measured from Week 20 to 48) serum adalimumab concentration was 5.6 ± 5.6 µg/ml (102%CV) Humira monotherapy and 10.9 ± 5.2 µg/ml (47.7% CV) with concomitant methotrexate

Adults

After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab was slow, with peak serum concentrations being reached about 5 days after administration. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous 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 to 15 ml/hour, the distribution volume (V_ss) ranged from 5 to 6 litres and the mean terminal phase half-life was approximately two weeks. Adalimumab concentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31-96% of those in serum.

Following subcutaneous administration of 40 mg of Humira every other week in adult rheumatoid arthritis (RA) patients the mean steady-state trough concentrations were approximately 5 μg/ml (without concomitant methotrexate) and 8 to 9 μg/ml (with concomitant methotrexate), respectively. The serum adalimumab trough levels at steady-state increased roughly proportionally with dose following 20, 40 and 80 mg subcutaneous dosing every other week and every week.

Population pharmacokinetic analyses with data from over 1300 RA patients revealed a trend toward higher apparent clearance of adalimumab with increasing body weight. After adjustment for weight differences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum levels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be lower in patients with measurable AAA. 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, repeated dose toxicity, and genotoxicity.

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

Mannitol

Citric acid monohydrate

Sodium citrate

Sodium dihydrogen phosphate dihydrate

Disodium phosphate dihydrate

Sodium chloride

Polysorbate 80

Sodium hydroxide

Water for injections.

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

24 months

Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial in the outer carton.

Humira 40 mg solution for injection in single-use vial (type I glass), fitted with rubber stoppers, aluminium crimps and flip-off seals.

1 Pack of 2 boxes each containing:

1 vial (0.8 ml sterile solution), 1 empty sterile injection syringe,1 needle, 1 vial adapter and 2 alcohol pads.

HUMIRA 40 mg solution for injection does not contain preservatives. Any unused product or waste material should be disposed of in accordance with local requirements.

Abbott Laboratories Ltd

Abbott House,

Vanwall Business Park

Vanwall Road

Maidenhead

Berkshire

SL6 4XE

United Kingdom

EU/1/03/256/001

Date of first authorisation: 8 September 2003

Date of latest renewal: 8 September 2008

4 April 2012