4.1. Therapeutic indications

Juvenile idiopathic arthritis

Polyarticular juvenile idiopathic arthritis

Yuflyma in combination with methotrexate is indicated for the treatment of active polyarticular juvenile idiopathic arthritis, in patients from the age of 2 years who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). Yuflyma 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). Adalimumab has not been studied in patients aged less than 2 years.

Enthesitis-related arthritis

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

Paediatric plaque psoriasis

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

Paediatric Crohn's disease

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

Paediatric uveitis

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

4.2. Posology and method of administration

Yuflyma treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which Yuflyma is indicated. Ophthalmologists are advised to consult with an appropriate specialist before initiation of treatment with Yuflyma (see section 4.4). Patients treated with Yuflyma should be given the Patient Reminder Card.

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

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

Posology

Paediatric population

Juvenile idiopathic arthritis

Polyarticular juvenile idiopathic arthritis from 2 years of age

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

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

Patient weight

Dosing regimen

10 kg to < 30 kg

20 mg every other week

≥ 30 kg

40 mg every other week

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

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

Yuflyma may be available in other presentations depending on the individual treatment needs.

Enthesitis-related arthritis

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

Table 2. Yuflyma dose for patients with enthesitis-related arthritis

Patient weight

Dosing regimen

15 kg to < 30 kg

20 mg every other week

≥ 30 kg

40 mg every other week

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

Yuflyma may be available in other presentations depending on the individual treatment needs.

Paediatric plaque psoriasis

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

Table 3. Yuflyma dose for paediatric patients with plaque psoriasis

Patient weight

Dosing regimen

15 kg to < 30 kg

Initial dose of 20 mg, followed by 20 mg given every other week starting one week after the initial dose

≥ 30 kg

Initial dose of 40 mg, followed by 40 mg given every other week starting one week after the initial dose

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

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

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

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

Yuflyma may be available in other presentations depending on the individual treatment needs.

Paediatric Crohn's disease

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

Table 4. Adalimumab dose for paediatric patients with crohn's disease

Patient weight

Induction dose

Maintenance dose starting at week 4

< 40 kg

• 40 mg at week 0 and 20 mg at week 2

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

• 80 mg at week 0 and 40 mg at week 2

20 mg every other week

≥ 40 kg

• 80 mg at week 0 and 40 mg at week 2

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

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

40 mg every other week

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

• < 40 kg: 20 mg every week

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

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

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

Yuflyma may be available in other presentations depending on the individual treatment needs.

Paediatric uveitis

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

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

Table 5. Yuflyma dose for paediatric patients with uveitis

Patient weight

Dosing regimen

< 30 kg

20 mg every other week in combination with methotrexate

≥ 30 kg

40 mg every other week in combination with methotrexate

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

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

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

Yuflyma may be available in other presentations depending on the individual treatment needs.

Renal and/or hepatic impairment

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

Method of administration

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

Yuflyma is available in other strengths and presentations.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

Traceability

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

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 Yuflyma. Because the elimination of adalimumab may take up to four months, monitoring should be continued throughout this period.

Treatment with Yuflyma should not be initiated in patients with active infections including chronic or localised 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 Yuflyma should be considered prior to initiating therapy (see Other opportunistic infections).

Patients who develop a new infection while undergoing treatment with Yuflyma should be monitored closely and undergo a complete diagnostic evaluation. Administration of Yuflyma 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 Yuflyma 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 adalimumab.

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

Before initiation of therapy with Yuflyma, all patients must be evaluated for both active or inactive (“latent”) tuberculosis infection. This evaluation should include a detailed medical assessment of 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 Reminder 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, Yuflyma therapy must not be initiated (see section 4.3).

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

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

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

Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of Yuflyma 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 adalimumab. Some patients who have been successfully treated for active tuberculosis have redeveloped tuberculosis while being treated with adalimumab.

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

Other opportunistic infections

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

For patients who develop the signs and symptoms such as fever, malaise, weight loss, sweats, cough, dyspnoea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant shock an invasive fungal infection should be suspected and administration of Yuflyma 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 adalimumab, 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 Yuflyma. 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 Yuflyma 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, Yuflyma should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.

Neurological events

TNF-antagonists including adalimumab 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 optic neuritis, and peripheral demyelinating disease, including Guillain- Barré syndrome. Prescribers should exercise caution in considering the use of Yuflyma in patients with pre- existing or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of Yuflyma should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders. Neurologic evaluation should be performed in patients with non-infectious intermediate uveitis prior to the initiation of Yuflyma therapy and regularly during treatment to assess for pre-existing or developing central demyelinating disorders.

Allergic reactions

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

Immunosuppression

In a study of 64 patients with rheumatoid arthritis that were treated with adalimumab, 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 leukaemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation. With the current knowledge, a possible risk for the development of lymphomas, leukaemia, and other malignancies in patients treated with a TNF-antagonist cannot be excluded.

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 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 adalimumab 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 Yuflyma should be carefully considered. A risk for the development of hepatosplenic T-cell lymphoma in patients treated with Yuflyma 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 adalimumab is continued following development of malignancy. Thus, additional caution should be exercised in considering Yuflyma treatment of these patients (see section 4.8).

All patients, and in particular patients with a medical history of extensive immunosuppressant therapy 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 Yuflyma. 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 pancytopenia including aplastic anaemia have been reported with TNF-antagonists. Adverse events of the haematologic system, including medically significant cytopenia (e.g. thrombocytopenia, leukopenia) have been reported with adalimumab. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor) while on Yuflyma. Discontinuation of Yuflyma therapy should be considered in 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 adalimumab.

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

Patients on Yuflyma may receive concurrent vaccinations, except for live vaccines. Administration of live vaccines (e.g., BCG vaccine) 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 adalimumab. Yuflyma should be used with caution in patients with mild heart failure (NYHA class I/II). Yuflyma is contraindicated in moderate to severe heart failure (see section 4.3). Treatment with Yuflyma must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.

Autoimmune processes

Treatment with Yuflyma may result in the formation of autoimmune antibodies. The impact of long-term treatment with adalimumab on the development of autoimmune diseases is unknown. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Yuflyma and is positive for antibodies against double-stranded DNA, further treatment with Yuflyma 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 adalimumab. The long half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Yuflyma should be closely monitored for infections, and appropriate actions should be taken. There is limited safety experience in patients undergoing arthroplasty while receiving adalimumab.

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 adalimumab does not worsen or cause strictures.

Elderly

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

Paediatric population

See Vaccinations above.

Sodium contents

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.2 ml dose, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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

The combination of adalimumab and anakinra is not recommended (see section 4.4 “Concurrent administration of biologic DMARDs or TNF-antagonists”).

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

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

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

In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn's disease (CD) treated with adalimumab at least during the first trimester and 120 women with RA or CD not treated with adalimumab were enrolled. The primary endpoint was the birth prevalence of major birth defects. The rate of pregnancies ending with at least one live born infant with a major birth defect was 6/69 (8.7%) in the adalimumab-treated women with RA and 5/74 (6.8%) in the untreated women with RA (unadjusted OR 1.31, 95% CI 0.38-4.52) and 16/152 (10.5%) in the adalimumab-treated women with CD and 3/32 (9.4%) in the untreated women with CD (unadjusted OR 1.14, 95% CI 0.31-4.16). The adjusted OR (accounting for baseline differences) was 1.10 (95% CI 0.45-2.73) with RA and CD combined. There were no distinct differences between adalimumab-treated and untreated women for the secondary endpoints spontaneous abortions, minor birth defects, preterm delivery, birth size and serious or opportunistic infections and no stillbirths or malignancies were reported. The interpretation of data may be impacted due to methodological limitations of the study, including small sample size and non-randomised design.

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

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

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

Breast-feeding

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

Fertility

Preclinical data on fertility effects of adalimumab are not available.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

Adalimumab was studied in 9,506 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, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS), psoriatic arthritis, Crohn's disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving adalimumab and 3,801 patients receiving placebo or active comparator during the controlled period.

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

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 adalimumab. TNF-antagonists, such as adalimumab affect the immune system and their use may affect the body's defence against infection and cancer.

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

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

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 are displayed by system organ class and frequency in Table 6 below: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among 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 6

Undesirable effects

System Organ Class

Frequency

Adverse Reaction

Infections and infestations*

Very common

Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral)

Common

Systemic infections (including sepsis, candidiasis and influenza), intestinal infections (including gastroenteritis viral), skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster), ear infections, oral infections (including herpes simplex, oral herpes and tooth infections), reproductive tract infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis), fungal infections, joint infections

Uncommon

Neurological infections (including viral meningitis), opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection), bacterial infections, eye infections, diverticulitis1)

Neoplasms benign, malignant and unspecified (including cysts and polyps)*

Common

Skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma), benign neoplasm

Uncommon

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

Rare

Leukaemia1)

Not known

Hepatosplenic T-cell lymphoma1)

Merkel cell carcinoma (neuroendocrine carcinoma of the skin)1), Kaposi's sarcoma

Blood and the lymphatic system disorders*

Very common

Leukopenia (including neutropenia and agranulocytosis), anaemia

Common

Leucocytosis, thrombocytopenia

Uncommon

Idiopathic thrombocytopenic purpura

Rare

Pancytopenia

Immune system disorders*

Common

Hypersensitivity, allergies (including seasonal allergy)

Uncommon

Sarcoidosis1), vasculitis

Rare

Anaphylaxis1)

Metabolism and nutrition disorders

Very common

Lipids increased

Common

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

Psychiatric disorders

Common

Mood alterations (including depression), anxiety, insomnia

Nervous system disorders*

Very common

Headache

Common

Paraesthesias (including hypoesthesia), migraine, nerve root compression

Uncommon

Cerebrovascular accident1), tremor, neuropathy

Rare

Multiple sclerosis, demyelinating disorders (e.g. optic neuritis, Guillain-Barré syndrome) 1)

Eye disorders

Common

Visual impairment, conjunctivitis, blepharitis, eye swelling

Uncommon

Diplopia

Ear and labyrinth disorders

Common

Vertigo

Uncommon

Deafness, tinnitus

Cardiac disorders*

Common

Tachycardia

Uncommon

Myocardial infarction1), arrhythmia, congestive heart failure

Rare

Cardiac arrest

Vascular disorders

Common

Hypertension, flushing, haematoma

Uncommon

Aortic aneurysm, vascular arterial occlusion, thrombophlebitis

Respiratory, thoracic and mediastinal disorders*

Common

Asthma, dyspnoea, cough

Uncommon

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

Rare

Pulmonary fibrosis1)

Gastrointestinal disorders

Very common

Abdominal pain, nausea and vomiting

Common

GI haemorrhage, dyspepsia, gastroesophageal reflux disease, sicca syndrome

Uncommon

Pancreatitis, dysphagia, face oedema

Rare

Intestinal perforation1)

Hepato-biliary disorders*

Very Common

Elevated liver enzymes

Uncommon

Cholecystitis and cholelithiasis, hepatic steatosis, bilirubin increased

Rare

Hepatitis reactivation of hepatitis B1) autoimmune hepatitis1)

Not known

Liver failure1)

Skin and subcutaneous tissue disorders

Very Common

Rash (including exfoliative rash)

Common

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

Uncommon

Night sweats, scar

Rare

Erythema multiforme1), Stevens-Johnson syndrome1), angioedema1), cutaneous vasculitis1) lichenoid skin reaction1)

Not known

Worsening of symptoms of dermatomyositis1)

Musculoskeletal and connective tissue disorders

Very common

Musculoskeletal pain

Common

Muscle spasms (including blood creatine phosphokinase increased)

Uncommon

Rhabdomyolysis, systemic lupus erythematosus

Rare

Lupus-like syndrome1)

Renal and urinary disorders

Common

Renal impairment, haematuria

Uncommon

Nocturia

Reproductive system and breast disorders

Uncommon

Erectile dysfunction

General disorders and administration site conditions*

Very Common

Injection site reaction (including injection site erythema)

Common

Chest pain, oedema, pyrexia1)

Uncommon

Inflammation

Investigations*

Common

Coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double stranded DNA antibody), blood lactate dehydrogenase increased

Not known

Weight increased2)

Injury, poisoning and procedural complications

Common

Impaired healing

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

** including open label extension studies

1) including spontaneous reporting data

2) The mean weight change from baseline for adalimumab ranged from 0.3 kg to 1.0 kg across adult indications compared to (minus) -0.4 kg to 0.4 kg for placebo over a treatment period of 4-6 months. Weight increase of 5-6 kg has also been observed in long-term extension studies with mean exposures of approximately 1-2 years without control group, particularly in patients with Crohn's disease and ulcerative colitis. The mechanism behind this effect is unclear but could be associated with the anti-inflammatory effect of adalimumab.

Uveitis

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

Description of selected adverse reactions

Injection site reactions

In the pivotal controlled trials in adults and children, 12.9% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.2% 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 adalimumab-treated patients and 1.46 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 adalimumab after the infection resolved.

The incidence of serious infections was 0.04 per patient year in adalimumab-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 adalimumab, 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 249 paediatric patients with an exposure of 655.6 patient years during adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric patients with an exposure of 498.1 patient years during adalimumab trials in paediatric patients with Crohn's disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during an adalimumab trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during an adalimumab trial in paediatric patients with uveitis.

During the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn's disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291 adalimumab-treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for adalimumab and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among adalimumab-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients.

When combining controlled portions of these trials and ongoing and completed open label extension studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 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 9.6 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 adalimumab and 8.1% of placebo and active control − treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at week 24. Two patients out of 3,441 treated with adalimumab in all rheumatoid arthritis and psoriatic arthritis 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 adalimumab 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 adalimumab-treated patients and 1.6% of control-treated patients.

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

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

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

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

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

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

Across all indications in clinical trials patients with raised ALT were asymptomatic and in most 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 adalimumab and azathioprine/6-mercaptopurine compared with adalimumab alone.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.