Humira 40 mg solution for injection in pre-filled syringe

Humira 40 mg solution for injection in pre-filled pen

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

Each 0.8 ml single dose pre-filled syringe contains 40 mg of adalimumab.

Each 0.8 ml single dose pre-filled pen contains 40 mg of adalimumab.

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 the full list of excipients, see section 6.1.

Clear solution for injection in pre-filled syringe.

Clear solution for injection in pre-filled pen

Clear solution for injection in single use vial.

Rheumatoid arthritis

Humira in combination with methotrexate, is indicated for:

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

• the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.

Humira can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

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

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 2 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 2 years.

Axial spondyloarthritis

Ankylosing spondylitis (AS)

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

Axial spondyloarthritis without radiographic evidence of AS

Humira is indicated for the treatment of adults with severe axial spondyloarthritis without radiographic evidence of AS but with objective signs of inflammation by elevated CRP and / or MRI, who have had an inadequate response to, or are intolerant to nonsteroidal anti-inflammatory drugs.

Psoriatic arthritis

Humira is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate. Humira has been shown to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease (see Section 5.1) and to improve physical function.

Psoriasis

Humira is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA.

Crohn's disease

Humira is indicated for treatment of moderately to severely active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies.

Paediatric Crohn's Disease

Humira is indicated for the treatment of severe active Crohn's disease in paediatric patients (6 to 17 years of age) who have had an inadequate response to conventional therapy including primary nutrition therapy, a corticosteroid, and an immunomodulator, or who are intolerant to or have contraindications for such therapies.

Ulcerative colitis

Humira is indicated for treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.

Posology

Humira treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which Humira is indicated. 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.

During treatment with Humira, other concomitant therapies (e.g., corticosteroids and/or immunomodulatory agents) should be optimised.

Rheumatoid arthritis

The recommended dose of Humira for adult patients with rheumatoid arthritis is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection. Methotrexate should be continued during treatment with Humira.

Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics can be continued during treatment with Humira. Regarding combination with disease modifying anti-rheumatic drugs other than methotrexate see sections 4.4 and 5.1.

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

Dose Interruption

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

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

Ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and psoriatic arthritis

The recommended dose of Humira for patients with ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and for patients with psoriatic arthritis is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection.

For all of the above indications, available data suggest that the 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.

Psoriasis

The recommended dose of Humira for adult patients is an initial dose of 80 mg administered subcutaneously, followed by 40 mg subcutaneously given every other week starting one week after the initial dose.

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

Crohn's disease

The recommended Humira induction dose regimen for adult patients with moderately to severely active Crohn's disease is 80 mg at Week 0 followed by 40 mg at Week 2. In case there is a need for a more rapid response to therapy, the regimen 160 mg at Week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days), 80 mg at Week 2, can be used with the awareness that the risk for adverse events is higher during induction.

After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection. Alternatively, if a patient has stopped Humira and signs and symptoms of disease recur, Humira may be re-administered. There is little experience from re-administration after more than 8 weeks since the previous dose.

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

Some patients who experience decrease in their response may benefit from an increase in dosing frequency to 40 mg Humira every week.

Some patients who have not responded by Week 4 may benefit from continued maintenance therapy through Week 12. Continued therapy should be carefully reconsidered in a patient not responding within this time period.

Ulcerative colitis

The recommended Humira induction dose regimen for adult patients with moderate to severe ulcerative colitis is 160 mg at Week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days) and 80 mg at Week 2. After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection.

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

Some patients who experience decrease in their response may benefit from an increase in dosing frequency to 40 mg Humira every week.

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

Elderly patients

No dose adjustment is required.

Impaired renal and/or hepatic function

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

Paediatric Population

Polyarticular Juvenile Idiopathis Arthritis

Polyarticular Juvenile Idiopathic Arthritis Age 2 to 12 years

The recommended dose of Humira for patients with polyarticular juvenile idiopathic arthritis, aged 2-12 years, is 24 mg/m² body surface area up to a maximum single dose of 20 mg adalimumab (for patients aged 2-<4) and up to a maximum single dose of 40 mg adalimumab (for patients aged 4-12) administered every other week via subcutaneous injection. The volume for injection is selected based on the patients' height and weight (Table 1). A 40 mg paediatric vial is available for patients who need to administer less than the full 40 mg dose.

Table 1. Humira Dose in Millilitres (ml) by Height and Weight of Children for Polyarticular Juvenile Idiopathic Arthritis

*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 prefilled 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.

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

Paediatric psoriasis

The safety and efficacy of Humira in children aged 4-17 years have not been established. No data are available. There is no relevant use of Humira in children aged <4 years in this indication.

Paediatric Crohn's disease

Paediatric Crohn's disease patients < 40 kg:

The recommended Humira induction dose regimen for paediatric subjects with severe Crohn's disease is 40 mg at Week 0 followed by 20 mg at Week 2. In case there is a need for a more rapid response to therapy, the regimen 80 mg at Week 0 (dose can be administered as two injections in one day), 40 mg at Week 2 can be used, with the awareness that the risk for adverse events may be higher with use of the higher induction dose.

After induction treatment, the recommended dose is 20 mg every other week via subcutaneous injection. Some subjects who experience insufficient response may benefit from an increase in dosing frequency to 20 mg Humira every week.

Paediatric Crohn's disease patients ≥ 40 kg:

The recommended Humira induction dose regimen for paediatric subjects with severe Crohn's disease is 80 mg at Week 0 followed by 40 mg at Week 2. In case there is a need for a more rapid response to therapy, the regimen 160 mg at Week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days), 80 mg at Week 2 can be used, with the awareness that the risk for adverse events may be higher with use of the higher induction dose.

After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection. Some subjects who experience insufficient response may benefit from an increase in dosing frequency to 40 mg Humira every 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 in this indication.

Paediatric ulcerative colitis

The safety and efficacy of Humira in children aged 4-17 years have not yet been established. No data are available. There is no relevant use of Humira in children aged <4 years in this indication.

Psoriatic arthritis and axial spondyloarthritis including ankylosing spondylitis.

There is no relevant use of Humira in the paediatric population in the indications, ankylosing spondylitis and psoriatric arthritis.

Method of administration

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

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

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).

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:

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 patient history of tuberculosis or possible previous exposure to people 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 and results of these tests are 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).

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 be consulted.

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 in patients with several or significant risk factors for tuberculosis despite a negative test for tuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.

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

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

Allergic reactions

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

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

In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in 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 thatpaediatric 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. Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for 5 months following the mother's last adalimumab injection during pregnancy.

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 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 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).

Concomitant administration of adalimumab with other biologic DMARDS (e.g, anakinra and abatacept) or other 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).

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 (3.5%) was higher than for those under 65 years of age (1.45%). Some of those had a fatal outcome. Particular attention regarding the risk for infection should be paid when treating the elderly.

Paediatric population

See Vaccinations above.

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 biologic DMARDS or TNF-antagonists”).

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

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 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 5 months following the mother's last adalimumab injection during pregnancy.

Lactation

Breast feeding

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.

Fertility

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 visual impairment may occur following administration of Humira (see Section 4.8).

Humira was studied in 8,152 patients in pivatol 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 ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, Crohn's disease, ulcerative colitis and psoriasis patients. The data in Table 2 is based on the pivotal controlled studies involving 5,312 patients receiving Humira and 3,133 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 5.7% for patients taking Humira and 6.2% for control treated patients.

Summary of the 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.

Paediatric population

Undesirable effects in paediatric patients

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

Tabulated list of adverse reactions

The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and is 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

Description of selected adverse reactions

Injection site reactions

In the pivotal controlled trials in adults and children, 13.6% of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.6% 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 in adults and children, the rate of infection was 1.51 per patient year in the Humira treated patients and 1.44 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, andurinary tract infection. Most patients continued on Humira after the infection resolved.

The incidence of serious infections was0.04 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 adult and paediatric 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 203 patients aged 2 to 17 years with an exposure of 605.3 patient years during Humira trials in juvenile idiopathic arthritis patients. In addition, no malignancies were observed in 192 paediatric patients with an exposure of 258.9 patient years during a Humira trial in paediatric patients with Crohn's disease.

During the controlled portions of pivotal Humira trials in adults of at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS, 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 6.8 (4.3, 10.8) per 1,000 patient-years among 4,622 Humira treated patients versus a rate of 5.9 (2.9, 11.8) per 1,000 patient-years among 2,828 control patients (median duration of treatment was 5.1 months for Humira and 4.0 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 9.8 (6.7, 14.4) per 1,000 patient-years among Humira-treated patients and 4.4 (2.0, 9.8) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.6 (1.3, 5.5) per 1,000 patient-years among Humira-treated patients and 0.7 (0.1, 5.2) 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, 5.9) 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 3.3 years including 5,611 patients and over 23,551 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 10.4 per 1,000 patient years, and the observed rate of lymphomas is approximately 1. 3 per 1,000 patient years.

In post-marketing experience from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 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.

Hepato-biliary events

In controlled Phase 3 trials of Humira in patients with rheumatoid arthritis and psoriatic arthritis with a control 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 plaque Psoriasis with a control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of Humira-treated patients and 1.8% of control-treated patients.

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.

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

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

Concurrent treatment with azathioprine/6-mercaptopurine

In adult Crohn's disease studies, higher incidences of malignant and serious infection-related adverse events were seen with the combination of Humira and azathioprine/6-mercaptopurine compared with Humira alone.

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 of 0.1-0.2 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 TNF was seen. Endoscopic studies in intestinal mucosa have shown evidence of mucosal healing in adalimumab treated patients.

Clinical efficacy and safety

Adults with Rheumatoid arthritis

Humira was evaluated in over 3000 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 10 years.

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 3.

Table 3

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 the open-label extension for RA study III, most patients who were ACR responders maintained response when followed for up to 10 years. Of 207 patients, 114 patients continued on Humira 40 mg every other week for 5 years. Among those, 86 patients (75.4%) had ACR 20 responses; 72 patients (63.2%) had ACR 50 responses; and 41 patients (36%) had ACR 70 responses. Of 207 patients, 81 patients continued on Humira 40 mg every other week for 10 years. Among those, 64 patients (79.0%) had ACR 20 responses; 56 patients (69.1%) had ACR 50 responses; and 43 patients (53.1%) had ACR 70 responses.

In RA study IV, the ACR 20 response of patients treated with 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 4).

Table 4

ACR Responses in RA Study V

(percent of patients)

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 6). Data from the open-label extension phase indicate that the reduction in rate of progression of structural damage is maintained for8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated with 40 mg Humira every other week were evaluated radiographically. Among those, 48 patients showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less. At 10 years, 79 of 207 patients originally treated with 40 mg Humira every other week were evaluated radiographically. Among those, 40 patients showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less.

Table 5

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 6).

Table 6

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

Polyarticular juvenile idiopathic arthritis (JIA)

The safety and efficacy of Humira was assessed in two studies (JIA I and II) in children with active polyarticular 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).

JIA 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 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 7.

Table 7.

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

Patients demonstrating a Pediatric 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 8

Ped ACR 30 Responses in the JIA study

^a Ped 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 Pediatric 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).

JIA II

The safety and efficacy of Humira was assessed in an open-label, multicenter 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 mg every other week as a single dose via SC injection for at least 24 weeks. During the study, most subjects used concomitant MTX, with fewer reporting use of corticosteroids or NSAIDs.

At Week 12 and Week 24, PedACR30 response was 93.5% and 90.0%, respectively, using the observed data approach. The proportions of subjects with PedACR50/70/90 at Week 12 and Week 24 were 90.3%/61.3%/38.7% and 83.3%/73.3%/36.7%, respectively. Amongst those who responded (Pediatric ACR 30) at Week 24 (n=27 out of 30 patients), the Pediatric ACR 30 responses were maintained for up to 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.

Axial Spondyloarthritis

Ankylosing spondylitis (AS)

Humira 40 mg every other week was assessed in 393 patients in two randomised, 24 week double − blind, placebo − controlled studies in patients with active ankylosing spondylitis (mean baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.3 in all groups) who have had an inadequate response to conventional therapy. Seventy-nine (20.1%) patients were treated concomitantly with disease modifying anti − rheumatic drugs, and 37 (9.4%) patients with glucocorticoids. The blinded period was followed by an open − label period during which patients received Humira 40 mg every other week subcutaneously for up to an additional 28 weeks. Subjects (n=215, 54.7%) who failed to achieve ASAS 20 at Weeks 12, or 16 or 20 received early escape open-label adalimumab 40 mg every other week subcutaneously and were subsequently treated as non-responders in the double-blind statistical analyses.

In the larger AS study I with 315 patients, results showed statistically significant improvement of the signs and symptoms of ankylosing spondylitis in patients treated with Humira compared to placebo. Significant response was first observed at Week 2 and maintained through 24 weeks (Table 9).

Table 9 –

Efficacy Responses in Placebo-Controlled AS Study – Study I

Reduction of Signs and Symptoms

***,** Statistically significant at p < 0.001, < 0.01 for all comparisons between Humira and placebo at Weeks 2, 12 and 24

^a ASsessments in Ankylosing Spondylitis

^b Bath Ankylosing Spondylitis Disease Activity Index

Humira treated patients had significantly greater improvement at Week 12 which was maintained through Week 24 in both the SF36 and Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL).

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

Axial spondyloarthritis without radiographic evidence of AS

Humira 40mg every other week was assessed in 185 patients in one randomized, 12 week double - blind, placebo - controlled study in patients with active non-radiographic axial spondyloarthitis (mean baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.4 for patients treated with Humira and 6.5 for those on placebo) who have had an inadequate response to or intolerance to ≥ 1 NSAIDs, or a contraindication for NSAIDs.

Thirty-three (18%) of patients were treated concomitantly with disease modifying anti-rheumatic drugs, and 145 (78%) patients with NSAIDs at baseline. The double-blind period was followed by an open-label period during which patients receive Humira 40 mg every other week subcutaneously for up to an additional 144 weeks. Week 12 results showed statistically significant improvement of the signs and symptoms of active non-radiographic axial spondyloarthritis in patients treated with Humira compared to placebo (Table 9).

Table 10

Efficacy Response in Placebo-Controlled Axial SpA Study - Reduction of signs and symptoms

^a ASAS = Assessments in Spondyloarthritis International Society

^a ASAS = Assessments in Spondyloarthritis International Society

^b Bath Ankylosing Spondylitis Disease Activity Index

***, **, * Statistically significant at p < 0.001, < 0.01, and

< 0.05, respectively, for all comparisons between Humira and placebo.

Health-related quality of life and physical function were assessed using the HAQ-S and the SF-36 questionnaires. Humira showed statistically significantly greater improvement in the HAQ-S total score and the SF-36 Physical Component Score (PCS) from baseline to week 12 compared to placebo.

Psoriatic arthritis

Humira, 40 mg every other week, was studied in patients with moderately to severely active psoriatic arthritis in two placebo-controlled studies, PsA studies I and II. PsA study I with 24 week duration, treated 313 adult patients who had an inadequate response to non-steroidal anti-inflammatory drug therapy and of these, approximately 50% were taking methotrexate. PsA study II with 12-week duration, treated 100 patients who had an inadequate response to DMARD therapy. Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg Humira was administered eow.

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

Table 11

ACR Response in Placebo-Controlled Psoriatic Arthritis Studies

(Percent of Patients)

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

* p < 0.05 for all comparisons between Humira and placebo

N/A not applicable

ACR responses in PsA study I were similar with and without concomitant methotrexate therapy.

ACR responses were maintained in the open-label extension study for up to 136 weeks.

Radiographic changes were assessed in the psoriatic arthritis studies. Radiographs of hands, wrists, and feet were obtained at baseline and Week 24 during the double-blind period when patients were on Humira or placebo and at Week 48 when all patients were on open-label Humira. A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e., not identical to the TSS used for rheumatoid arthritis), was used.

Humira treatment reduced the rate of progression of peripheral joint damage compared with placebo treatment as measured by change from baseline in mTSS (mean ± SD) 0.8 ± 2.5 in the placebo group (at Week 24) compared with 0.0 ± 1.9; (p< 0.001) in the Humira group (at Week 48).

In subjects treated with Humira with no radiographic progression from baseline to Week 48 (n=102), 84% continued to show no radiographic progression through 144 weeks of treatment.

Humira treated patients demonstrated statistically significant improvement in physical function as assessed by HAQ and Short Form Health Survey (SF 36) compared to placebo at Week 24. Improved physical function continued during the open label extension up to Week 136.

Psoriasis

The safety and efficacy of Humira were studied in adult patients with chronic plaque psoriasis (≥ 10% BSA involvement and Psoriasis Area and Severity Index (PASI) ≥ 12 or ≥ 10) who were candidates for systemic therapy or phototherapy in randomised, double-blind studies. 73% of patients enrolled in Psoriasis Studies I and II had received prior systemic therapy or phototherapy.

Psoriasis Study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A, patients received placebo or Humira at an initial dose of 80 mg followed by 40 mg every other week starting one week 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-label 40 mg Humira every other week. Patients who maintained ≥PASI 75 response at Week 33 and were originally 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 mean baseline PASI score was 18.9 and the baseline Physician's Global Assessment (PGA) score ranged from “moderate” (53% of subjects included) to “severe” (41%) to “very severe” (6%).

Psoriasis Study II (CHAMPION) compared the efficacy and safety of Humira versus methotrexate and placebo in 271 patients. Patients received placebo, an initial dose of MTX 7.5 mg and thereafter dose increases up to Week 12, with a maximum dose of 25 mg or an initial dose of 80 mg Humira followed by 40 mg every other week (starting one week after the initial dose) for 16 weeks. There are no data available comparing 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 treatment groups, the mean baseline PASI score was 19.7 and the baseline PGA score ranged from “mild” (<1%) to “moderate” (48%) to “severe” (46%) to “very severe” (6%).

Patients participating in all Phase 2 and Phase 3 psoriasis studies were eligible to enroll into an open-label extension 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 75 response from baseline at Week 16 (see Tables 12 and 13).

Table 13

Ps Study II (CHAMPION) Efficacy Results at 16 Weeks

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 to baseline with a minimum of a 6-point increase in PASI score relative to Week 33). Of the patients who lost adequate response after re-randomization to placebo who then enrolled into the open-label extension trial, 38% (25/66) and 55% (36/66) regained PASI 75 response after 12 and 24 weeks of re-treatment, respectively.

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

A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. During the withdrawal period, symptoms of psoriasis returned over time with a median time to relapse (decline to PGA “moderate” or worse) of approximately 5 months. None of these patients experienced rebound during the withdrawal period. A total of 76.5% (218/285) of patients who entered the retreatment period had a response of PGA “clear” or “minimal” after 16 weeks of retreatment, irrespective of whether they relapsed during withdrawal (69.1%[123/178] and 88.8% [95/107] for patients who relapsed and who did not relapse during the withdrawal period, respectively). A similar safety profile was observed during retreatment as before withdrawal.

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

In an open-label extension study, for patients who dose escalated from 40 mg every other week to 40 mg weekly due to a PASI response below 50% and were evaluated at 12 weeks after dose escalation, 93/349 (26.6%) of patients acheived PASI 75 response.

Crohn's disease

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/or immunomodulatory agents were permitted and 80% of patients continued to receive at least one of these medications.

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

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

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

In CD Study III, at Week 4, 58% (499/854) of patients were in clinical response and were assessed in the primary 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 remission results remained relatively constant irrespective of previous TNF-antagonist exposure.

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

Table 15

Maintenance of Clinical Remission and Response

(Percent of Patients)

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 who have not responded by Week 4 benefit from continued maintenance therapy through Week 12. Therapy continued beyond 12 Weeks did not result in significantly more responses (see section 4.2).

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

Quality of Life

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

Paediatric Crohn's disease

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

All subjects received open-label induction therapy at a dose based on their Baseline body weight: 160 mg at 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 randomized 1:1 based on their body weight at the time to either the Low Dose or Standard Dose maintenance regimens as shown in Table 16.

Efficacy Results

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 17. Rates of discontinuation of corticosteroids or immunomodulators are presented in Table 18.

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

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

Ulcerative Colitis

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

In Study UC-I, 390 TNF-antagonist naïve patients were randomised to receive either placebo at Weeks 0 and 2, 160 mg Humira at Week 0 followed by 80 mg at Week 2, or 80 mg Humira at Week 0 followed by 40 mg at Week 2. After Week 2, patients in both adalimumab arms received 40 mg eow. Clinical remission (defined as Mayo score ≤ 2 with no subscore > 1) was assessed at Week 8.

In study UC-II, 248 patients received 160 mg of Humira at Week 0, 80 mg at Week 2 and 40 mg eow thereafter, and 246 patients received placebo. Clinical results were assessed for induction of remission at Week 8 and for maintenance of remission at Week 52.

Subjects induced with 160/80 mg Humira achieved clinical remission versus placebo at Week 8 in statistically significantly greater percentages in study UC-I (18% vs. 9% respectively, p=0.031) and study UC-II (17% vs. 9% respectively, p=0.019). In study UC-II, among those treated with Humira who were in remission at Week 8, 21/41 (51%) were in remission at Week 52.

Results from the overall UC-II study population are shown in Table 19.

Table19

Response, Remission and Mucosal Healing in Study UC-II

(Percent of Patients)

Approximately 40% of patients in study UC-II had failed prior anti-TNF treatment with infliximab. The efficacy of adalimumab in those patients was reduced compared to that in anti-TNF naïve patients. Among patients who had failed prior anti-TNF treatment, Week 52 remission was achieved by 3% on placebo and 10% on adalimumab.

Patients from UC studies I and II had the option to roll over into an open-label long-term extension study. Patients, who lost response after one year of treatment or beyond, could benefit from an increase of dosing frequency to 40 mg weekly (see 4.2).

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.

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.

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.

In patients with psoriatic arthritis, anti-adalimumab antibodies were identified in 38/376 subjects (10%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 13.5% (24/178 subjects), compared to 7% (14 of 198 subjects) when adalimumab was used as add-on to methotrexate.

In patients with ankylosing spondylitis anti-adalimumab antibodies were identified in 17/204 subjects (8.3%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 16/185 (8.6%), compared to 1/19 (5.3%) when adalimumab was used as add-on to methotrexate.

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

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

In plaque psoriasis patients on long term adalimumab monotherapy who participated in a withdrawal and 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%).

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

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Humira in all subsets of the paediatric population 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 the studies with Humira in one or more subsets of the paediatric population ulcerative colitis, see section 4.2 for information on paediatric use.

Absorption and distribution

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.

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) who were 4 to 17 years the mean trough steady-state (values measured from Week 20 to 48) serum adalimumab concentration was 5.6 ± 5.6 µg/mL (102 %CV) Humira monotherapy and 10.9 ± 5.2 µg/mL (47.7% CV) with concomitant methotrexate.

In patients with JIA who were 2-<4 years old or aged 4 and above weighing <15 kg dosed with Humira 24 mg/m², the mean trough steady-state serum adalimumab concentrations was 6.0 ± 6.1 µg/ml (101% CV) Humira monotherapy and 7.9 ± 5.6 µg/ml (71.2% CV) with concomitant methotrexate.

In patients with psoriasis, the mean steady-state trough concentration was 5 μg/mL during adalimumab 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 Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 5.5 μg/ml during the induction period. A loading dose of 160 mg Humira on Week 0 followed by 80 mg Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 12 μg/ml during the induction period. Mean steady-state trough levels of approximately 7 μg/ml were observed in Crohn's disease patients who received a maintenance dose of 40 mg Humira every other week.

In paediatric subjects with moderate to severe CD, the open-label adalimumab induction dose was 160/80 mg or 80/40 mg at Weeks 0 and 2, respectively, dependent on a body weight cut-off of 40 kg. At Week 4, subjects were randomized 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) serum adalimumab trough concentrations achieved at Week 4 were 15.7±6.6 μg/mL for subjects ≥ 40 kg (160/80 mg) and 10.6±6.1 μg/mL for subjects < 40 kg (80/40 mg).

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

In patients with ulcerative colitis, a loading dose of 160 mg Humira on Week 0 followed by 80 mg Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 12 μg/ml during the induction period. Mean steady-state trough levels of approximately 8 μg/ml were observed in ulcerative colitis patients who received a maintenance dose of 40 mg Humira every other week.

Elimination

Population pharmacokinetic analyses with data from over 1,300 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.

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, 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 syringe in the outer carton in order to protect from light.

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

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

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

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

Humira 40 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 for patient use:

Packs of:

• 1 pre-filled syringe (0.8 ml sterile solution) with 1 alcohol pad in a blister.

• 2 pre-filled syringes (0.8 ml sterile solution), each with 1 alcohol pad, in a blister.

• 4 pre-filled syringes (0.8 ml sterile solution), each with 1 alcohol pad, in a blister.

• 6 pre-filled syringes (0.8 ml sterile solution), each with 1 alcohol pad, in a blister.

Not all pack sizes may be marketed.

Humira 40 mg solution for injection in single-use pre-filled pen for patient use containing a pre-filled syringe. The syringe inside the pen is made from type 1 glass with a plunger stopper (bromobutyl rubber) and a needle with a needle shield (thermoplastic elastomer).

Packs of:

• 1 pre-filled pen with 1 alcohol pad in a blister.

• 2 pre-filled pen, each with 1 alcohol pad, in a blister.

• 4 pre-filled pen, each with 1 alcohol pad, in a blister.

• 6 pre-filled pen, each with 1 alcohol pad, in a blister.

Not all pack sizes may be marketed.

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 medicinal product or waste material should be disposed of in accordance with local requirements.

AbbVie Ltd

Maidenhead

SL6 4XE

United Kingdom

EU/1/03/256/001

EU/1/03/256/002

EU/1/03/256/003

EU/1/03/256/004

EU/1/03/256/005

EU/1/03/256/007

EU/1/03/256/008

EU/1/03/256/009

EU/1/03/256/010

Date of first authorisation: 08 September 2003

Date of latest renewal: 08 September 2008

25 February 2013

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu