Cyltezo

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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This medicinal product is subject to additional monitoring. This will allow quick identification of new 
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See 
section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Cyltezo 40 mg solution for injection in pre-filled syringe
Cyltezo 40 mg solution for injection in pre-filled pen

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Cyltezo 40 mg solution for injection in pre-filled syringe
Each 0.8 mL single dose pre-filled syringe contains 40 mg of adalimumab. 

Cyltezo 40 mg solution for injection in pre-filled pen
Each 0.8 mL single dose pre-filled pen contains 40 mg of adalimumab. 

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection (injection).

Clear to slightly opalescent solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Rheumatoid arthritis
Cyltezo 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. 

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

Cyltezo reduces the rate of progression of joint damage as measured by X-ray and improves physical 
function, when given in combination with methotrexate.

Juvenile idiopathic arthritis

Polyarticular juvenile idiopathic arthritis 

Adalimumab 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). Adalimumab can be given as monotherapy in case of 

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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

Adalimumab 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).

Axial spondyloarthritis

Ankylosing spondylitis (AS)

Cyltezo 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 

Cyltezo 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

Cyltezo 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. Adalimumab 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

Cyltezo is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who are 
candidates for systemic therapy.

Paediatric plaque psoriasis

Cyltezo 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.

Hidradenitis suppurativa (HS)

Cyltezo is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) in 
adults and adolescents from 12 years of age with an inadequate response to conventional systemic HS 
therapy (see sections 5.1 and 5.2).

Crohn’s disease

Cyltezo 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

Cyltezo 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 

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nutrition therapy and a corticosteroid and/or an immunomodulator, or who are intolerant to or have 
contraindications for such therapies.

Ulcerative colitis

Cyltezo 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.

Uveitis

Cyltezo is indicated for the treatment of non-infectious intermediate, posterior and panuveitis in adult
patients who have had an inadequate response to corticosteroids, in patients in need of corticosteroid-sparing,
or in whom corticosteroid treatment is inappropriate.

Paediatric Uveitis

Cyltezo 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

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

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

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

Posology

Rheumatoid arthritis

The recommended dose of Cyltezo 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 Cyltezo.

Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics can be continued during 
treatment with Cyltezo. 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 to Cyltezo 40 mg every other
week may benefit from an increase in dosage to 40 mg adalimumab every week or 80 mg every other week.

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

Dose interruption

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

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Available data suggest that re-introduction of adalimumab 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 Cyltezo 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. 

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

Psoriasis

The recommended dose of Cyltezo 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. 

Beyond 16 weeks, patients with inadequate response to Cyltezo 40 mg every other week may benefit from an 
increase in dosage to 40 mg every week or 80 mg every other week. The benefits and risks of continued 
40 mg weekly or 80 mg every other week therapy should be carefully reconsidered in a patient with an 
inadequate response after the increase in dosage (see section 5.1). If adequate response is achieved with 
40 mg every week or 80 mg every other week, the dosage may subsequently be reduced to 40 mg every other 
week.

Hidradenitis suppurativa

The recommended Cyltezo dose regimen for adult patients with hidradenitis suppurativa (HS) is 160 mg
initially at Day 1 (given as four 40 mg injections in one day or as two 40 mg injections per day for two 
consecutive days), followed by 80 mg two weeks later at Day 15 (given as two 40 mg injections in one day). 
Two weeks later (Day 29) continue with a dose of 40 mg every week or 80 mg every other week (given as 
two 40 mg injections in one day). Antibiotics may be continued during treatment with Cyltezo if necessary. 
It is recommended that the patient should use a topical antiseptic wash on their HS lesions on a daily basis 
during treatment with Cyltezo.

Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no improvement 
within this time period.

Should treatment be interrupted, Cyltezo 40 mg every week or 80 mg every other week may be re-introduced 
(see section 5.1).

The benefit and risk of continued long-term treatment should be periodically evaluated (see section 5.1).

Crohn’s disease

The recommended Cyltezo 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 (given as four 40 mg injections in one day or as two 
40 mg injections per day for two consecutive days), 80 mg at week 2 (given as two 40 mg injections in one 
day), 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 Cyltezo and signs and symptoms of disease recur, Cyltezo may be re-
administered. There is little experience from re-administration after more than 8 weeks since the previous 
dose.

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

Some patients who experience decrease in their response to Cyltezo 40 mg every other week may benefit 
from an increase in dosage to 40 mg Cyltezo every week or 80 mg every other 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 Cyltezo induction dose regimen for adult patients with moderate to severe ulcerative 
colitis is 160 mg at week 0 (given as four 40 mg injections in one day or as two 40 mg injections per day for 
two consecutive days) and 80 mg at week 2 (given as two 40 mg injections in one day). 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 to Cyltezo 40 mg every other week may benefit 
from an increase in dosage to 40 mg Cyltezo every week or 80 mg every other week.

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

Uveitis

The recommended dose of Cyltezo for adult patients with uveitis is an initial dose of 80 mg, followed by 
40 mg given every other week starting one week after the initial dose. There is limited experience in the 
initiation of treatment with adalimumab alone. Treatment with Cyltezo can be initiated in combination with 
corticosteroids and/or with other non-biologic immunomodulatory agents. Concomitant corticosteroids may 
be tapered in accordance with clinical practice starting two weeks after initiating treatment with Cyltezo.

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

Special populations

Elderly 

No dose adjustment is required.

Renal and/or hepatic impairment

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

Paediatric population

Cyltezo is only available as 40 mg pre-filled syringe/pre-filled pen. Thus, it is not possible to administer 
Cyltezo to paediatric patients that require less than a full 40 mg dose. If an alternate dose is required, other 
adalimumab products offering such an option should be used.Me
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Juvenile idiopathic arthritis

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

Table 1: Cyltezo dose for patients with polyarticular juvenile idiopathic arthritis

Patient Weight Dosing Regimen

10 kg to < 30 kg -

≥ 30 kg 40 mg every other week

- Not applicable. Cyltezo is only available as 40 mg pre-filled syringe/pre-filled pen.

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.

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

Table 2: Cyltezo dose for patients with enthesitis-related arthritis

Patient Weight Dosing Regimen

15 kg to < 30 kg -

≥ 30 kg 40 mg every other week

- Not applicable. Cyltezo is only available as 40 mg pre-filled syringe/pre-filled pen.

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

Paediatric plaque psoriasis 

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

Table 3: Cyltezo dose for paediatric patients with plaque psoriasis

Patient Weight Dosing Regimen

15 kg to < 30 kg -

≥ 30 kg Initial dose of 40 mg, followed by 
40 mg given every other week starting 

one week after the initial dose

- Not applicable. Cyltezo is only available as 40 mg pre-filled syringe/pre-filled pen.

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

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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. 

Adolescent hidradenitis suppurativa (from 12 years of age, weighing at least 30 kg)

There are no clinical trials with adalimumab in adolescent patients with HS. The posology of adalimumab in
these patients has been determined from pharmacokinetic modelling and simulation (see section 5.2).

The recommended Cyltezo dose is 80 mg at week 0 followed by 40 mg every other week starting at week 1 
via subcutaneous injection.

In adolescent patients with inadequate response to Cyltezo 40 mg every other week, an increase in dosage to 
40 mg every week or 80 mg every other week may be considered.

Antibiotics may be continued during treatment with Cyltezo if necessary. It is recommended that the patient 
should use a topical antiseptic wash on their HS lesions on a daily basis during treatment with Cyltezo.

Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no improvement 
within this time period.

Should treatment be interrupted, Cyltezo may be re-introduced as appropriate.

The benefit and risk of continued long-term treatment should be periodically evaluated (see adult data in 
section 5.1)

There is no relevant use of adalimumab in children aged less than 12 years in this indication.

Paediatric Crohn's disease 

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

Table 4: Cyltezo dose for paediatric patients with Crohn’s disease

Patient 
Weight

Induction Dose Maintenance 
Dose 

Starting at 
Week 4

< 40 kg - -

≥ 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

- Not applicable. Cyltezo is only available as 40 mg pre-filled syringe/pre-filled pen.

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Patients who experience insufficient response may benefit from an increase in dosage:
 < 40 kg: Not applicable. Cyltezo is only available as 40 mg pre-filled syringe/pre-filled pen.
 ≥ 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.

Paediatric Uveitis

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

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

Table 5: Cyltezo dose for paediatric patients with uveitis

Patient Weight Dosing Regimen

< 30 kg -

≥ 30 kg 40 mg every other week in
combination with methotrexate

- Not applicable. Cyltezo is only available as 40 mg pre-filled syringe/pre-filled pen.

When adalimumab 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).

Paediatric ulcerative colitis

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

Psoriatic arthritis and axial spondyloarthritis including ankylosing spondylitis

There is no relevant use of adalimumab in the paediatric population for the indications of ankylosing 
spondylitis and psoriatic arthritis. 

Method of administration

Cyltezo is administered by subcutaneous injection. Full instructions for use are provided in the package 
leaflet. 
A paediatric presentation is not available for patients who need to administer less than the full 40 mg dose.

A 40 mg pre-filled syringe/pre-filled pen is available for patients to administer a full 40 mg dose.

4.3 Contraindications

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

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

Treatment with Cyltezo 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 Cyltezo should be considered 
prior to initiating therapy (see Other opportunistic infections). 

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

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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 Cyltezo, and in accordance with local recommendations. 

Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of Cyltezo 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 
Cyltezo.

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 Cyltezo 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 Cyltezo. 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 Cyltezo 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, 
Cyltezo 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 Cyltezo in patients 
with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders; 
discontinuation of Cyltezo should be considered if any of these disorders develop. There is a known 
association between intermediate uveitis and central demyelinating disorders. Neurologic evaluation should 

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be performed in patients with non-infectious intermediate uveitis prior to the initiation of Cyltezo 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 Cyltezo should be discontinued 
immediately and appropriate therapy initiated.

Dry natural rubber / latex sensitivity

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

Immunosuppression

In a study of 64 patients with rheumatoid arthritis that were treated with 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 Cyltezo should be carefully 
considered. A risk for the development of hepatosplenic T-cell lymphoma in patients treated with Cyltezo
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 Cyltezo 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 Cyltezo. Melanoma and Merkel cell carcinoma have also been 
reported in patients treated with TNF-antagonists including adalimumab (see section 4.8). 

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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 Cyltezo. Discontinuation of Cyltezo 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 adalimumab therapy. 

Patients on Cyltezo 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. Cyltezo should be used with caution in patients with mild 
heart failure (NYHA class I/II). Cyltezo is contraindicated in moderate to severe heart failure (see section 
4.3). Treatment with Cyltezo must be discontinued in patients who develop new or worsening symptoms of 
congestive heart failure. 

Autoimmune processes

Treatment with Cyltezo may result in the formation of autoimmune antibodies. The impact of long-term 
treatment with Cyltezo on the development of autoimmune diseases is unknown. If a patient develops 
symptoms suggestive of a lupus-like syndrome following treatment with Cyltezo and is positive for 
antibodies against double-stranded DNA, further treatment with Cyltezo 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 

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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 Cyltezo 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.

Excipients with known effects

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8 mL dose, i.e. 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 Cyltezo and anakinra is not recommended (see section 4.4 “Concurrent administration of 
biologic DMARDS or TNF-antagonists”).

The combination of Cyltezo 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 child bearing 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 Cyltezo treatment.

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Pregnancy

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

In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn’s disease (CD) treated 
with adalimumab at least during the first trimester and 120 women with RA or CD not treated 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-randomized design.

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

Due to its inhibition of 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 Cyltezo in utero is not recommended for 5 months 
following the mother’s last Cyltezo 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, 
Cyltezo 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

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

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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. They 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.

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Table 6: Undesirable Effects

System Organ Class Frequency Adverse Reaction

Infections and 
infestations*

Very common

Common

Uncommon 

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

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

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 

Uncommon 

Rare 

Not known 

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

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

Leukaemia1)

Hepatosplenic T-cell lymphoma1)

Merkel cell carcinoma (neuroendocrine 
carcinoma of the skin)1)Me

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System Organ Class Frequency Adverse Reaction

Blood and the 
lymphatic system 
disorders* 

Very common 

Common 

Uncommon 

Rare 

Leukopenia (including neutropenia and 
agranulocytosis), 
anaemia 

Leukocytosis, 
thrombocytopenia 

Idiopathic thrombocytopenic purpura 

Pancytopenia 

Immune system 
disorders* 

Common 

Uncommon 

Rare 

Hypersensitivity, 
allergies (including seasonal allergy) 

Sarcoidosis1), 
vasculitis 

Anaphylaxis1)

Metabolism and 
nutrition disorders 

Very common 

Common 

Lipids increased 

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

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

Nervous system 
disorders* 

Very common 

Common

Uncommon 

Rare 

Headache 

Paraesthesias (including hypoaesthesia), 
migraine, 
nerve root compression 

Cerebrovascular accident1), 
tremor, 
neuropathy 

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

Eye disorders Common 

Uncommon 

Visual impairment, 
conjunctivitis, 
blepharitis, 
eye swelling 

Diplopia 

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System Organ Class Frequency Adverse Reaction

Ear and labyrinth 
disorders 

Common 

Uncommon 

Vertigo 

Deafness, 
tinnitus 

Cardiac disorders* Common 

Uncommon 

Rare 

Tachycardia 

Myocardial infarction1), 
arrhythmia,
congestive heart failure 

Cardiac arrest 

Vascular disorders Common 

Uncommon 

Hypertension, 
flushing, 
haematoma 

Aortic aneurysm, 
vascular arterial occlusion, 
thrombophlebitis 

Respiratory, thoracic 
and mediastinal 
disorders* 

Common 

Uncommon

Rare

Asthma, 
dyspnoea, 
cough 

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

Pulmonary fibrosis1)

Gastrointestinal 
disorders 

Very common 

Common 

Uncommon 

Rare 

Abdominal pain, 
nausea and vomiting 

GI haemorrhage, 
dyspepsia, 
gastroesophageal reflux disease, 
sicca syndrome 

Pancreatitis, 
dysphagia, 
face oedema

Intestinal perforation1)

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System Organ Class Frequency Adverse Reaction

Hepato-biliary 
disorders* 

Very Common 

Uncommon 

Rare 

Not known 

Elevated liver enzymes 

Cholecystitis and cholelithiasis, 
hepatic steatosis, 
bilirubin increased 

Hepatitis 
reactivation of hepatitis B1)

autoimmune hepatitis1)

Liver failure1)

Skin and subcutaneous 
tissue disorders 

Very common 

Common

Uncommon 

Rare 

Not known 

Rash (including exfoliative rash) 

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

Night sweats, 
scar 

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

Worsening of symptoms of dermatomyositis1)

Musculoskeletal and 
connective tissue 
disorders 

Very common 

Common

Uncommon

Rare 

Musculoskeletal pain 

Muscle spasms (including blood creatine 
phosphokinase increased) 

Rhabdomyolysis, 
systemic lupus erythematosus 

Lupus-like syndrome1)

Renal and urinary 
disorders 

Common 

Uncommon 

Renal impairment, 
haematuria 

Nocturia 

Reproductive system 
and breast disorders 

Uncommon Erectile dysfunction 

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System Organ Class Frequency Adverse Reaction

General disorders and 
administration site 
conditions* 

Very Common 

Common

Uncommon 

Injection site reaction (including injection site 
erythema)

Chest pain, 
oedema, 
pyrexia1)

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 

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

Hidradenitis suppurativa

The safety profile for patients with HS treated with adalimumab weekly was consistent with the known 
safety profile 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 

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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. 

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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 160 mg at week 0 and 80 mg at week 2, followed by 
40 mg every week starting at week 4), in patients with hidradenitis suppurativa with a control period duration 
ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3 % of adalimumab-treated patients 
and 0.6 % of control-treated patients.

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 national reporting system listed in Appendix V.

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24

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNF-α) inhibitors. 
ATC code: L04AB04

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

Mechanism of action

Adalimumab binds specifically to TNF and neutralises 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 adalimumab, a rapid decrease in levels of acute phase reactants of inflammation 
(C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL-6) 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 adalimumab administration. Patients treated with adalimumab 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, ulcerative colitis and hidradenitis suppurativa after treatment with adalimumab. In patients 
with Crohn’s disease, a reduction of the number of cells expressing inflammatory markers in the colon 
including a significant reduction of expression of TNFα was seen. Endoscopic studies in intestinal mucosa 
have shown evidence of mucosal healing in adalimumab-treated patients. 

Clinical efficacy and safety 

Rheumatoid arthritis 

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

RA study I evaluated 271 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 
years old, had failed therapy with at least one disease-modifying, anti rheumatic drug and 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 
adalimumab or placebo were given every other week for 24 weeks. 

RA study II evaluated 544 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 
years old and had failed therapy with at least one disease-modifying, anti-rheumatic drugs. Doses of 20 or 
40 mg of adalimumab were given by subcutaneous injection every other week with placebo on alternative 

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25

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 adalimumab every week for 52 
weeks. The third group received 40 mg of adalimumab every other week with placebo injections on alternate 
weeks. Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in 
which 40 mg of adalimumab/MTX 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 adalimumab 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 
adalimumab 40 mg every other week/methotrexate combination therapy, adalimumab 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. Upon completion of the first 104 weeks, 
497 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administered 
every other week up to 10 years.

The primary end point in RA studies I, II and III and the secondary endpoint in RA study IV was 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 adalimumab-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 7.

Table 7: ACR Responses in Placebo-Controlled Trials (Percent of Patients)

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

Placebo/ 
MTXc

n = 60 

Adalimumabb

/MTXc

n = 63 

Placebo 
n = 110 

Adalimumabb

n = 113 
Placebo/ 
MTXc

n = 200 

Adalimumabb

/MTXc

n = 207 
ACR 20

6 months
12 months

13.3 %
NA

65.1 %
NA

19.1 %
NA

46.0 %
NA

29.5 %
24.0 %

63.3 %
58.9 %

ACR 50
6 months
12 months

6.7 %
NA

52.4 %
NA

8.2 %
NA

22.1 %
NA

9.5 %
9.5 %

39.1 %
41.5 %

ACR 70
6 months
12 months

3.3 %
NA

23.8 %
NA

1.8 %
NA

12.4 %
NA

2.5 %
4.5 %

20.8 %
23.2 %

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 adalimumab administered every other week 

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c MTX = methotrexate 
** p < 0.01, adalimumab 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 who were randomised to adalimumab 40 mg every other 
week, 114 patients continued on adalimumab 40 mg every other week for 5 years. Among those, 86 patients 
(75.4 %) had ACR 20 responses; 72 patients (63.2 %) had ACR 50 responses; and 41 patients (36 %) had 
ACR 70 responses. Of 207 patients, 81 patients continued on adalimumab 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 adalimumab 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, adalimumab-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 adalimumab and methotrexate led to faster and significantly greater ACR responses than methotrexate 
monotherapy and adalimumab monotherapy at week 52 and responses were sustained at week 104 (see Table 
8).

Table 8: ACR Responses in RA Study V (percent of patients)

Response
MTX

n = 257
Adalimumab 

n = 274

Adalimumab/
MTX

n = 268
p-valuea p-valueb p-valuec

ACR 20

Week 52 62.6 % 54.4 % 72.8 % 0.013 < 0.001 0.043

Week 104 56.0 % 49.3 % 69.4 % 0.002 < 0.001 0.140

ACR 50

Week 52 45.9 % 41.2 % 61.6 % < 0.001 < 0.001 0.317

Week 104 42.8 % 36.9 % 59.0 % < 0.001 < 0.001 0.162

ACR 70

Week 52 27.2 % 25.9 % 45.5 % < 0.001 < 0.001 0.656

Week 104 28.4 % 28.1 % 46.6 % < 0.001 < 0.001 0.864

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

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

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

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In the open-label extension for RA study V, ACR response rates were maintained when followed for up to 
10 years. Of 542 patients who were randomised to adalimumab 40 mg every other week, 170 patients
continued on adalimumab 40 mg every other week for 10 years. Among those, 154 patients (90.6 %) had
ACR 20 responses; 127 patients (74.7 %) had ACR 50 responses; and 102 patients (60.0 %) had ACR 70 
responses.

At week 52, 42.9 % of patients who received adalimumab/methotrexate combination therapy achieved 
clinical remission (DAS28 (CRP) < 2.6) compared to 20.6 % of patients receiving methotrexate 
monotherapy and 23.4 % of patients receiving adalimumab monotherapy. Adalimumab/methotrexate 
combination therapy was clinically and statistically superior to methotrexate (p < 0.001) and adalimumab 
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). 
Of 342 subjects originally randomised to adalimumab monotherapy or adalimumab/methotrexate 
combination therapy who entered the open-label extension study, 171 subjects completed 10 years of 
adalimumab treatment. Among those, 109 subjects (63.7 %) were reported to be in remission at 10 years.

Radiographic response 

In RA study III, where adalimumab 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. 
Adalimumab/methotrexate patients demonstrated significantly less radiographic progression than patients 
receiving methotrexate alone at 6 and 12 months (see Table 9). 

In the open-label extension of RA Study III, the reduction in rate of progression of structural damage is 
maintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated with 
40 mg adalimumab 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 adalimumab 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 9: Radiographic Mean Changes Over 12 Months in RA Study III

Placebo/MTXa Adalimumab/MTX
40 mg every other 
week

Placebo/MTX-
Adalimumab/MTX 
(95 % Confidence 
Intervalb)

p-value

Total Sharp Score 2.7 0.1 2.6 (1.4, 3.8) < 0.001c

Erosion score 1.6 0.0 1.6 (0.9, 2.2) < 0.001
JSNd score 1.0 0.1 0.9 (0.3, 1.4) 0.002
a methotrexate 
b 95 % confidence intervals for the differences in change scores between methotrexate and adalimumab. 
c Based on rank analysis 
d Joint Space Narrowing 

In RA study V, structural joint damage was assessed radiographically and expressed as change in modified 
Total Sharp Score (see Table 10).

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Table 10: Radiographic Mean Changes at Week 52 in RA Study V 

MTX n=257 
(95 %
confidence 
interval)

Adalimumab 
n = 274 (95 %
confidence 
interval)

Adalimumab/ 
MTX n = 268 
(95 %
confidence 
interval)

p-valuea p-valueb p-valuec

Total Sharp
Score

5.7 (4.2-7.3) 3.0 (1.7-4.3) 1.3 (0.5-2.1) < 0.001 0.0020 < 0.001

Erosion score 3.7 (2.7-4.7) 1.7 (1.0-2.4) 0.8 (0.4-1.2) < 0.001 0.0082 < 0.001

JSN score 2.0 (1.2-2.8) 1.3 (0.5-2.1) 0.5 (0-1.0) < 0.001 0.0037 0.151
a p-value is from the pairwise comparison of methotrexate monotherapy and adalimumab/methotrexate 

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

combination therapy using the Mann-Whitney U test 
c p-value is from the pairwise comparison of adalimumab 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 adalimumab/methotrexate 
combination therapy (63.8 % and 61.2 % respectively) compared to methotrexate monotherapy (37.4 % and 
33.5 % respectively, p < 0.001) and adalimumab monotherapy (50.7 %, p < 0.002 and 44.5 %, p < 0.001 
respectively). 

In the open-label extension of RA study V, the mean change from baseline at Year 10 in the modified Total 
Sharp Score was 10.8, 9.2 and 3.9 in patients originally randomised to methotrexate monotherapy,
adalimumab monotherapy and adalimumab/methotrexate combination therapy, respectively. The
corresponding proportions of patients with no radiographic progression were 31.3 %, 23.7 % and 36.7 %,
respectively.

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 adalimumab 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 adalimumab 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 adalimumab/methotrexate combination therapy versus 
methotrexate monotherapy and adalimumab monotherapy at week 52, which was maintained through 
week 104. Among the 250 subjects who completed the open-label extension study, improvements in physical 
function were maintained through 10 years of treatment.

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Juvenile idiopathic arthritis (JIA)

Polyarticular juvenile idiopathic arthritis (pJIA) 

The safety and efficacy of adalimumab was assessed in two studies (pJIA 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). 

pJIA I 

The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind, 
parallel-group study in 171 children (4-17 years old) with polyarticular JIA. In the open-label 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 adalimumab 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 11.

Table 11: Distribution of patients by age and adalimumab dose received during the OL LI phase

Age Group Number of patients at Baseline 
n (%)

Minimum, median and maximum 
dose

4 to 7 years 31 (18.1) 10, 20 and 25 mg

8 to 12 years 71 (41.5) 20, 25 and 40 mg

13 to 17 years 69 (40.4) 25, 40 and 40 mg

Patients demonstrating a Paediatric ACR 30 response at week 16 were eligible to be randomised into the 
double blind (DB) phase and received either adalimumab 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 Paediatric 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 enrol into the open label extension phase.

Table 12: Ped ACR 30 Responses in the JIA study

Stratum MTX Without MTX
Phase
OL-LI 16 weeks

Ped ACR 30 
response (n/N)

94.1 % (80/85) 74.4 % (64/86)

Efficacy Outcomes
Double Blind 32 weeks Adalimumab / MTX 

(N = 38)
Placebo / MTX 
(N = 37)

Adalimumab
(N = 30)

Placebo
(N = 28)

Disease flares at the 
end of 32 weeksa

(n/N)

36.8 % (14/38) 64.9 % (24/37)b 43.3 % (13/30) 71.4 % (20/28)c

Median time to 
disease flare

> 32 weeks 20 weeks > 32 weeks 14 weeks

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 adalimumab throughout the study. 

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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 adalimumab and MTX compared to adalimumab alone. Taking these results into 
consideration, Cyltezo 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). 

pJIA II 

The safety and efficacy of adalimumab was assessed in an open-label, multicentre study in 32 children 
(2 - < 4 years old or aged 4 and above weighing < 15 kg) with moderately to severely active polyarticular 
JIA. The patients received 24 mg/m² body surface area (BSA) of adalimumab 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 adalimumab throughout this time period. Overall, 20 
subjects were treated for 60 weeks or longer. 

Enthesitis-related arthritis 

The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind study in 46 
paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients were randomised to 
receive either 24 mg/m² body surface area (BSA) of adalimumab up to a maximum of 40 mg, or placebo 
every other week for 12 weeks. The double-blind period is followed by an open-label (OL) period during 
which patients received 24 mg/m² BSA of adalimumab up to a maximum of 40 mg every other week 
subcutaneously for up to an additional 192 weeks. The primary endpoint was the percent change from 
Baseline to week 12 in the number of active joints with arthritis (swelling not due to deformity or joints with 
loss of motion plus pain and/or tenderness), which was achieved with mean percent decrease of -62.6 %
(median percent change -88.9 %) in patients in the adalimumab group compared to -11.6 % (median percent 
change -50.0 %) in patients in the placebo group. Improvement in number of active joints with arthritis was 
maintained during the OL period through week 156 for the 26 of 31 (84%) patients in the adalimumab group 
who remained in the study. Although not statistically significant, the majority of patients demonstrated 
clinical improvement in secondary endpoints such as number of sites of enthesitis, tender joint count (TJC), 
swollen joint count (SJC), Pediatric ACR 50 response, and Pediatric ACR 70 response. 

Axial spondyloarthritis 

Ankylosing spondylitis (AS) 

Adalimumab 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 adalimumab 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. 

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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 adalimumab compared to placebo. 
Significant response was first observed at week 2 and maintained through 24 weeks (Table 13).

Table 13: Efficacy Responses in Placebo-Controlled AS Study – Study I Reduction of Signs and 
Symptoms

Response Placebo
N = 107

Adalimumab
N = 208

ASASa 20
Week 2 16 % 42 %***
Week 12 21 % 58 %***
Week 24 19 % 51 %***

ASAS 50
Week 2 3 % 16 %***
Week 12 10 % 38 %***
Week 24 11 % 35 %***

ASAS 70
Week 2 0 % 7 %**
Week 12 5 % 23 %***
Week 24 8 % 24 %***

BASDAIb 50

Week 2 4 % 20 %***
Week 12 16 % 45 %***
Week 24 15 % 42 %***

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

a Assessments in Ankylosing Spondylitis 
b Bath Ankylosing Spondylitis Disease Activity Index

Adalimumab 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 

The safety and efficacy of adalimumab were assessed in two randomised, double-blind placebo-controlled
studies in patients with non-radiographic axial spondyloarthritis (nr-axSpA). Study nr-axSpA I evaluated
patients with active nr-axSpA. Study nr-axSpA II was a treatment withdrawal study in active nr-axSpA
patients who achieved remission during open-label treatment with adalimumab.

Study nr-axSpA I

In Study nr-axSpA I, adalimumab 40 mg every other week was assessed in 185 patients in a randomised, 12 
week double-blind, placebo-controlled study in patients with active nr-axSpA (mean baseline score of 
disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.4 for patients treated 
with adalimumab 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 %) patients were treated concomitantly with disease modifying anti-rheumatic drugs, and 
146 (79 %) patients with NSAIDs at baseline. The double-blind period was followed by an open-label period 
during which patients receive adalimumab 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 
nr-axSpA in patients treated with adalimumab compared to placebo (Table 14).

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Table 14: Efficacy Response in Placebo-Controlled Study nr-axSpA I

Double-Blind
Response at Week 12

Placebo
N = 94

Adalimumab
N = 91

ASASa 40 15 % 36 %***
ASAS 20 31 % 52 %**
ASAS 5/6 6 % 31 %***
ASAS Partial Remission 5 % 16 %*
BASDAIb 50 15 % 35 %**
ASDASc,d,e -0.3 -1.0***
ASDAS Inactive Disease 4 % 24 %***
hs-CRPd,f,g -0.3 -4.7***
SPARCCh MRI Sacroiliac Jointsd,i -0.6 -3.2**
SPARCC MRI Spined,j -0.2 -1.8**
a Assessments in SpondyloArthritis international Society 
b Bath Ankylosing Spondylitis Disease Activity Index 
c Ankylosing Spondylitis Disease Activity Score
d mean change from baseline
e n = 91 placebo and n = 87 adalimumab
f high sensitivity C-Reactive Protein (mg/L)
g n = 73 placebo and n = 70 adalimumab
h Spondyloarthritis Research Consortium of Canada
i n = 84 placebo and adalimumab
j n = 82 placebo and n = 85 adalimumab
***, **, * Statistically significant at p < 0.001, < 0.01, and < 0.05, respectively, for all comparisons between 

adalimumab and placebo. 

In the open-label extension, improvement in the signs and symptoms was maintained with adalimumab 
therapy through week 156.

Inhibition of inflammation

Significant improvement of signs of inflammation as measured by hs-CRP and MRI of both Sacroiliac Joints 
and the Spine was maintained in adalimumab-treated patients through week 156 and week 104, respectively.

Quality of life and physical function

Health-related quality of life and physical function were assessed using the HAQ-S and the SF-36 
questionnaires. Adalimumab 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. 
Improvement in health-related quality of life and physical function was maintained during the open-label 
extension through week 156.

Study nr-axSpA II

673 patients with active nr-axSpA (mean baseline disease activity [BASDAI] was 7.0) who had an
inadequate response to ≥ 2 NSAIDs, or an intolerance to or a contraindication for NSAIDs enrolled into the 
open-label period of Study nr-axSpA II during which they received adalimumab 40 mg eow for 28 weeks.
These patients also had objective evidence of inflammation in the sacroiliac joints or spine on MRI or
elevated hs-CRP. Patients who achieved sustained remission for at least 12 weeks (N = 305) (ASDAS < 1.3
at weeks 16, 20, 24, and 28) during the open-label period were then randomised to receive either continued 
treatment with adalimumab 40 mg eow (N = 152) or placebo (N = 153) for an additional 40 weeks in a
double-blind, placebo-controlled period (total study duration 68 weeks). Subjects who flared during the
double-blind period were allowed adalimumab 40 mg eow rescue therapy for at least 12 weeks.

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The primary efficacy endpoint was the proportion of patients with no flare by week 68 of the study. Flare
was defined as ASDAS ≥ 2.1 at two consecutive visits four weeks apart. A greater proportion of patients on 
adalimumab had no disease flare during the double-blind period, when compared with those on placebo
(70.4 % vs. 47.1 %, p < 0.001) (Figure 1).

Figure 1: Kaplan-Meier Curves Summarizing Time to Flare in Study nr-axSpA II

Note: P = Placebo (Number at Risk (flared)); A = adalimumab (Number at Risk (flared)).

Among the 68 patients who flared in the group allocated to treatment withdrawal, 65 completed 12 weeks of 
rescue therapy with adalimumab, out of which 37 (56.9 %) had regained remission (ASDAS < 1.3) after
12 weeks of restarting the open-label treatment.

By week 68, patients receiving continuous adalimumab treatment showed statistically significant greater 
improvement of the signs and symptoms of active nr-axSpA as compared to patients allocated to treatment 
withdrawal during the double-blind period of the study (Table 15).

Table 15: Efficacy Response in Placebo-Controlled Period for Study nr-axSpA II

Double-Blind
Response at Week 68

Placebo
N = 153

Adalimumab
N = 152

ASASa,b 20 47.1 % 70.4 %***
ASASa,b 40 45.8 % 65.8 %***
ASASa Partial Remission 26.8 % 42.1%**
ASDASc Inactive Disease 33.3 % 57.2%***
Partial Flared 64.1 % 40.8%***
a Assessment of SpondyloArthritis international Society
b Baseline is defined as open label baseline when patients have active disease.
c Ankylosing Spondylitis Disease Activity Score
d Partial flare is defined as ASDAS ≥ 1.3 but < 2.1 at 2 consecutive visits.
***, ** Statistically significant at p < 0.001 and < 0.01, respectively, for all comparisons between 

adalimumab and placebo.

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Psoriatic arthritis 

Adalimumab, 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 adalimumab was administered every other week. 

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

Table 16: ACR Response in Placebo-Controlled Psoriatic Arthritis Studies (Percent of Patients)

PsA Study I PsA Study II

Response
Placebo
N = 162

Adalimumab
N = 151

Placebo
N = 49

Adalimumab
N = 51

ACR 20
Week 12
Week 24

ACR 50
Week 12
Week 24

ACR 70
Week 12
Week 24

14 %
15 %

4 %
6 %

1 %
1 %

58 %***
57 %***

36 %***
39 %***

20 %***
23 %***

16 %
N/A

2 %
N/A

0 %
N/A

39 %*
N/A

25 %***
N/A

14 %*
N/A

*** p < 0.001 for all comparisons between adalimumab and placebo 
* p < 0.05 for all comparisons between adalimumab 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 adalimumab or 
placebo and at week 48 when all patients were on open-label adalimumab. A modified Total Sharp Score 
(mTSS), which included distal interphalangeal joints (i.e. not identical to the TSS used for rheumatoid 
arthritis), was used. 

Adalimumab 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 adalimumab group (at week 48). 

In subjects treated with adalimumab with no radiographic progression from baseline to week 48 (n = 102), 
84 % continued to show no radiographic progression through 144 weeks of treatment. Adalimumab 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 adalimumab 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. The safety and efficacy of adalimumab 
were also studied in adult patients with moderate to severe chronic plaque psoriasis with concomitant hand 

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and/or foot psoriasis who were candidates for systemic therapy in a randomised double-blind study (Psoriasis 
Study III). 

Psoriasis Study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A, patients 
received placebo or adalimumab 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 adalimumab 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
adalimumab every other week or placebo for an additional 19 weeks. Across all treatment groups, the mean 
baseline PASI score was 18.9 and the baseline Physician’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 adalimumab 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 adalimumab followed 
by 40 mg every other week (starting one week after the initial dose) for 16 weeks. There are no data 
available comparing adalimumab and MTX beyond 16 weeks of therapy. Patients receiving MTX who 
achieved a ≥ PASI 50 response at week 8 and/or 12 did not receive further dose increases. Across all 
treatment groups, the mean baseline PASI score was 19.7 and the baseline PGA score ranged from “mild” 
(< 1 %) to “moderate” (48 %) to “severe” (46 %) to “very severe” (6 %). 

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

In Psoriasis Studies I and II, a primary endpoint was the proportion of patients who achieved a PASI 75 
response from baseline at week 16 (see Tables 17 and 18).

Table 17: Ps Study I (REVEAL) - Efficacy Results at 16 Weeks

Placebo 
N = 398
n (%)

Adalimumab 40 mg eow
N = 814
n (%)

≥PASI 75a 26 (6.5) 578 (70.9)b

PASI 100 3 (0.8) 163 (20.0)b

PGA: Clear/minimal 17 (4.3) 506 (62.2)b
a Percent of patients achieving PASI75 response was calculated as centre-adjusted rate 
b p < 0.001, adalimumab vs. placebo

Table 18: Ps Study II (CHAMPION) - Efficacy Results at 16 Weeks

Placebo
N = 53
n (%)

MTX
N = 110
n (%)

Adalimumab 40 mg eow
N = 108
n (%)

≥PASI 75 10 (18.9) 39 (35.5) 86 (79.6)a, b

PASI 100 1 (1.9) 8 (7.3) 18 (16.7)c, d

PGA: Clear/minimal 6 (11.3) 33 (30.0) 79 (73.1)a, b

a p < 0.001 adalimumab vs. placebo
b p < 0.001 adalimumab vs. methotrexate
c p < 0.01 adalimumab vs. placebo
d p < 0.05 adalimumab vs. methotrexate

In Psoriasis Study I, 28 % of patients who were PASI 75 responders and were re-randomised to placebo at 
week 33 compared to 5 % continuing on adalimumab, 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 

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adequate response after re-randomisation to placebo who then enrolled into the open-label extension trial, 
38 % (25/66) and 55 % (36/66) regained PASI 75 response after 12 and 24 weeks of re-treatment, 
respectively. 

A total of 233 PASI 75 responders at week 16 and week 33 received continuous adalimumab therapy for 52
weeks in Psoriasis Study I, and continued adalimumab 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 %, 26.4 % (92/349) and 37.8 % (132/349) of patients achieved 
PASI 75 response at week 12 and 24, respectively.

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

Psoriasis Study IV compared efficacy and safety of adalimumab versus placebo in 217 adult patients with 
moderate to severe nail psoriasis. Patients received an initial dose of 80 mg adalimumab followed by 40 mg 
every other week (starting one week after the initial dose) or placebo for 26 weeks followed by open-label 
adalimumab treatment for an additional 26 weeks. Nail psoriasis assessments included the Modified Nail 
Psoriasis Severity Index (mNAPSI), the Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) and 
the Nail Psoriasis Severity Index (NAPSI) (see Table 19). Adalimumab demonstrated a treatment benefit in 
nail psoriasis patients with different extents of skin involvement (BSA ≥ 10% (60 % of patients) and 
BSA < 10 % and ≥ 5 % (40 % of patients)).

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Table 19: Ps Study IV Efficacy Results at 16, 26 and 52 Weeks

Endpoint Week 16
Placebo-Controlled

Week 26
Placebo-Controlled

Week 52
Open-label

Placebo
N = 108

Adalimumab
40 mg eow

N = 109

Placebo
N = 108

Adalimumab
40 mg eow

N = 109

Adalimumab
40 mg eow

N = 80
≥ mNAPSI 75 
(%)

2.9 26.0a 3.4 46.6a 65.0

PGA-F 
clear/minimal 
and ≥ 2-grade 
improvement 
(%)

2.9 29.7a 6.9 48.9a 61.3

Percent Change 
in Total
Fingernail 
NAPSI (%)

-7.8 -44.2a -11.5 -56.2a -72.2

a p < 0.001, adalimumab vs. placebo

Adalimumab treated patients showed statistically significant improvements at week 26 compared with
placebo in the DLQI.

Paediatric plaque psoriasis 

The efficacy of adalimumab was assessed in a randomised, double-blind, controlled study of 114 paediatric 
patients from 4 years of age with severe chronic plaque psoriasis (as defined by a PGA ≥ 4 or > 20 % BSA 
involvement or > 10 % BSA involvement with very thick lesions or PASI ≥ 20 or ≥ 10 with clinically 
relevant facial, genital, or hand/ foot involvement) who were inadequately controlled with topical therapy 
and heliotherapy or phototherapy.

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

Table 20: Paediatric Plaque Psoriasis Efficacy Results at 16 Weeks

MTXa

N = 37
Adalimumab 0.8 mg/kg eow

N = 38
PASI 75b 12 (32.4 %) 22 (57.9 %)
PGA: Clear/minimalc 15 (40.5 %) 23 (60.5 %)
a MTX = methotrexate
b p = 0.027, adalimumab 0.8 mg/kg versus MTX
c p = 0.083, adalimumab 0.8 mg/kg versus MTX

Patients who achieved PASI 75 and PGA clear or minimal were withdrawn from treatment for up to 36 
weeks and monitored for loss of disease control (i.e. a worsening of PGA by at least 2 grades). Patients were 
then re-treated with adalimumab 0.8 mg/kg eow for an additional 16 weeks and response rates observed 
during retreatment were similar to the previous double-blind period: PASI 75 response of 78.9 % (15 of 19 
subjects) and PGA clear or minimal of 52.6 % (10 of 19 subjects). 

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

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Hidradenitis suppurativa

The safety and efficacy of adalimumab were assessed in randomised, double-blind, placebo-controlled 
studies and an open-label extension study in adult patients with moderate to severe hidradenitis suppurativa 
(HS) who were intolerant, had a contraindication or an inadequate response to at least a 3-month trial of 
systemic antibiotic therapy. The patients in HS-I and HS-II had Hurley Stage II or III disease with at least 3 
abscesses or inflammatory nodules.

Study HS-I (PIONEER I) evaluated 307 patients with 2 treatment periods. In Period A, patients received 
placebo or adalimumab at an initial dose of 160 mg at week 0, 80 mg at week 2, and 40 mg every week 
starting at week 4 to week 11. Concomitant antibiotic use was not allowed during the study. After 12 weeks 
of therapy, patients who had received adalimumab in Period A were re-randomised in Period B to 1 of 3 
treatment groups (adalimumab 40 mg every week, adalimumab 40 mg every other week, or placebo from 
week 12 to week 35). Patients who had been randomised to placebo in Period A were assigned to receive 
adalimumab 40 mg every week in Period B.

Study HS-II (PIONEER II) evaluated 326 patients with 2 treatment periods. In Period A, patients received 
placebo or adalimumab at an initial dose of 160 mg at week 0 and 80 mg at week 2 and 40 mg every week 
starting at week 4 to week 11. 19.3 % of patients had continued baseline oral antibiotic therapy during the 
study. After 12 weeks of therapy, patients who had received adalimumab in Period A were re-randomised in 
Period B to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg every other week, 
or placebo from week 12 to week 35). Patients who had been randomised to placebo in Period A were 
assigned to receive placebo in Period B.

Patients participating in Studies HS-I and HS-II were eligible to enrol into an open-label extension study in 
which adalimumab 40 mg was administered every week. Mean exposure in all adalimumab population was 
762 days. Throughout all 3 studies patients used topical antiseptic wash daily.

Clinical Response

Reduction of inflammatory lesions and prevention of worsening of abscesses and draining fistulas was 
assessed using Hidradenitis Suppurativa Clinical Response (HiSCR; at least a 50 % reduction in total abscess 
and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count 
relative to Baseline). Reduction in HS-related skin pain was assessed using a Numeric Rating Scale in 
patients who entered the study with an initial baseline score of 3 or greater on a 11 point scale.

At week 12, a significantly higher proportion of patients treated with adalimumab versus placebo achieved 
HiSCR. At week 12, a significantly higher proportion of patients in Study HS-II experienced a clinically 
relevant decrease in HS-related skin pain (see Table 21). Patients treated with adalimumab had significantly 
reduced risk of disease flare during the initial 12 weeks of treatment.

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Table 21: Efficacy Results at 12 Weeks, HS Studies I and II

HS Study I HS Study II
Placebo Adalimumab 40 mg

Weekly
Placebo Adalimumab 40 mg

Weekly
Hidradenitis 
Suppurativa
Clinical Response 
(HiSCR)a

N = 154
40 (26.0 %)

N = 153
64 (41.8 %) *

N = 163
45 (27.6 %)

N = 163
96 (58.9 %) ***

≥ 30 % Reduction 
in Skin Painb

N = 109
27 (24.8 %)

N = 122
34 (27.9 %)

N = 111
23 (20.7 %)

N = 105
48 (45.7 %) ***

* p < 0.05, *** p < 0.001, adalimumab versus placebo
a Among all randomised patients.
b Among patients with baseline HS-related skin pain assessment ≥ 3, based on Numeric Rating Scale 

0 - 10; 0 = no skin pain, 10 = skin pain as bad as you can imagine

Treatment with adalimumab 40 mg every week significantly reduced the risk of worsening of abscesses and 
draining fistulas. Approximately twice the proportion of patients in the placebo group in the first 12 weeks of 
Studies HS-I and HS-II, compared with those in the adalimumab group experienced worsening of abscesses 
(23.0 % vs 11.4 %, respectively) and draining fistulas (30.0 % vs 13.9 %, respectively).

Greater improvements at week 12 from baseline compared to placebo were demonstrated in skin-specific 
health-related quality of life, as measured by the Dermatology Life Quality Index (DLQI; Studies HS-I and 
HS-II), patient global satisfaction with medication treatment as measured by the Treatment Satisfaction 
Questionnaire - medication (TSQM; Studies HS-I and HS-II), and physical health as measured by the 
physical component summary score of the SF-36 (Study HS-I).

In patients with at least a partial response to adalimumab 40 mg weekly at week 12, the HiSCR rate at week
36 was higher in patients who continued weekly adalimumab than in patients in whom dosing frequency was 
reduced to every other week, or in whom treatment was withdrawn (see Table 22).

Table 22: Proportion of Patientsa Achieving HiSCRb at Weeks 24 and 36 After Treatment 
Reassignment from Weekly adalimumab at Week 12

Placebo
(treatment withdrawal)

N = 73

Adalimumab 40 mg
every other week

N = 70

Adalimumab 40 mg
weekly
N = 70

Week 24 24 (32.9 %) 36 (51.4 %) 40 (57.1 %)
Week 36 22 (30.1 %) 28 (40.0 %) 39 (55.7 %)
a Patients with at least a partial response to adalimumab 40 mg weekly after 12 weeks of treatment.
b Patients meeting protocol-specified criteria for loss of response or no improvement were required to 

discontinue from the studies and were counted as nonresponders.

Among patients who were at least partial responders at week 12, and who received continuous weekly 
adalimumab therapy, the HiSCR rate at week 48 was 68.3 % and at week 96 was 65.1 %. Longer term 
treatment with adalimumab 40 mg weekly for 96 weeks identified no new safety findings.

Among patients whose adalimumab treatment was withdrawn at week 12 in Studies HS-I and HS-II, the 
HiSCR rate 12 weeks after re-introduction of adalimumab 40 mg weekly returned to levels similar to that 
observed before withdrawal (56.0 %).

Adolescent hidradenitis suppurativa

There are no clinical trials with adalimumab in adolescent patients with HS. Efficacy of adalimumab for the 
treatment of adolescent patients with HS is predicted based on the demonstrated efficacy and exposure-

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response relationship in adult HS patients and the likelihood that the disease course, pathophysiology, and 
drug effects are substantially similar to that of adults at the same exposure levels. Safety of the recommended 
adalimumab dose in the adolescent HS population is based on cross-indication safety profile of adalimumab 
in both adults and paediatric patients at similar or more frequent doses (see section 5.2).

Crohn’s disease 

The safety and efficacy of adalimumab 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 adalimumab 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
adalimumab 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 23.

Table 23: Induction of Clinical Remission and Response (Percent of Patients)

CD Study I: Infliximab Naive
Patients

CD Study II: Infliximab
Experienced Patients

Placebo
N = 74

Adalimumab
80/40 mg

N = 75

Adalimumab
160/80 mg

N = 76

Placebo
N = 166

Adalimumab
160/80 mg

N = 159

Week 4

Clinical remission 12 % 24 % 36 %* 7 % 21 %*

Clinical response 
(CR-100)

24 % 37 % 49 %** 25 % 38 %**

All p-values are pairwise comparisons of proportions for adalimumab versus placebo 
* p < 0.001 
** p < 0.01 

Similar remission rates were observed for the 160/80 mg and 80/40 mg induction regimens by week 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 24. 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.

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Table 24: Maintenance of Clinical Remission and Response (Percent of Patients)

Placebo 40 mg Adalimumab
every other week

40 mg Adalimumab
every week

Week 26 N = 170 N = 172 N = 157
Clinical remission 17 % 40 %* 47 %*

Clinical response (CR-100) 27 % 52 %* 52 %*

Patients in steroid-free 
remission for ≥ 90 daysa

3 % (2/66) 19 % (11/58)** 15 % (11/74)**

Week 56 N = 170 N = 172 N = 157
Clinical remission 12 % 36 %* 41 %*

Clinical response (CR-100) 17 % 41 %* 48 %*
Patients in steroid-free 
remission for ≥ 90 daysa

5 % (3/66) 29 % (17/58)* 20 % (15/74)**

* p < 0.001 for adalimumab versus placebo pairwise comparisons of proportions 
** p < 0.02 for adalimumab versus placebo pairwise comparisons of proportions 
a Of those receiving corticosteroids at baseline

Among patients who were not in response at week 4, 43 % of adalimumab 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 patients, 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 
adalimumab 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 

Adalimumab was assessed in a multicentre, randomised, 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 randomised 1:1 based on their body weight at the time to either the Low Dose or 
Standard Dose maintenance regimens as shown in Table 25.

Table 25: Maintenance regimen

Patient weight Low dose Standard dose

< 40 kg 10 mg eow 20 mg eow

≥ 40 kg 20 mg eow 40 mg eow

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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 26. Rates of discontinuation of corticosteroids or immunomodulators 
are presented in Table 27.

Table 26: Paediatric CD Study PCDAI Clinical Remission and Response

Standard Dose
40/20 mg eow

N = 93

Low Dose
20/10 mg eow

N = 95

P value*

Week 26
Clinical remission 38.7 % 28.4 % 0.075
Clinical response 59.1 % 48.4 % 0.073

Week 52
Clinical remission 33.3 % 23.2 % 0.100
Clinical response 41.9 % 28.4 % 0.038

* p value for Standard Dose versus Low Dose comparison.

Table 27: Paediatric CD Study Discontinuation of Corticosteroids or Immunomodulators and 
Fistula Remission

Standard Dose
40/20 mg eow

Low Dose
20/10 mg eow

P value1

Discontinued 
corticosteroids

N = 33 N = 38

Week 26 84.8 % 65.8 % 0.066

Week 52 69.7 % 60.5 % 0.420

Discontinuation of 
Immunomodulators2

N = 60 N = 57

Week 52 30.0 % 29.8 % 0.983

Fistula remission3 N = 15 N = 21

Week 26 46.7 % 38.1 % 0.608

Week 52 40.0 % 23.8 % 0.303
1 p value for Standard Dose versus Low Dose comparison. 
2 Immunosuppressant therapy could only be discontinued at or after week 26 at the investigator's 

discretion if the subject met the clinical response criterion 
3 defined as a closure of all fistulas that were draining at Baseline for at least 2 consecutive post-

Baseline visits 

Statistically significant increases (improvement) from Baseline to week 26 and 52 in Body Mass 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). 

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

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Ulcerative colitis 

The safety and efficacy of multiple doses of adalimumab 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 adalimumab at week 0 followed by 80 mg at week 2, or 80 mg adalimumab 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 adalimumab 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. 

Patients induced with 160/80 mg adalimumab 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 adalimumab 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 28.

Table 28: Response, Remission and Mucosal Healing in Study UC-II (Percent of Patients)

Placebo Adalimumab 
40 mg eow

Week 52 N = 246 N = 248

Clinical Response 18 % 30 %*
Clinical Remission 9 % 17 %*

Mucosal Healing 15 % 25 %*
Steroid-free remission for ≥ 90 daysa 6 %

(N = 140)
13 % *

(N = 150)

Week 8 and 52

Sustained Response 12 % 24 %**

Sustained Remission 4 % 8 %*

Sustained Mucosal Healing 11 % 19 %*

Clinical remission is Mayo score ≤ 2 with no subscore > 1; 
Clinical response is decrease from baseline in Mayo score ≥ 3 points and ≥ 30 % plus a decrease in the rectal 
bleeding subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1; 
* p < 0.05 for adalimumab vs. placebo pairwise comparison of proportions 
** p < 0.001 for adalimumab vs. placebo pairwise comparison of proportions 
a Of those receiving corticosteroids at baseline 

Of those patients who had a response at week 8, 47 % were in response, 29 % were in remission, 41 % had 
mucosal healing, and 20 % were in steroid-free remission for ≥ 90 days at week 52. 

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. 

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Patients from studies UC-I and UC-II had the option to roll over into an open-label long-term extension 
study (UC III). Following 3 years of adalimumab therapy, 75 % (301/402) continued to be in clinical 
remission per partial Mayo score.

Hospitalisation rates 

During 52 weeks of studies UC-I and UC-II, lower rates of all-cause hospitalisations and UC-related 
hospitalisations were observed for the adalimumab-treated arm compared to the placebo arm. The number of 
all cause hospitalisations in the adalimumab treatment group was 0.18 per patient year vs. 0.26 per patient 
year in the placebo group and the corresponding figures for UC-related hospitalisations were 0.12 per patient 
year vs. 0.22 per patient year. 

Quality of life 

In study UC-II, treatment with adalimumab resulted in improvements in the Inflammatory Bowel Disease 
Questionnaire (IBDQ) score. 

Uveitis

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

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

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

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

Clinical response

Results from both studies demonstrated statistically significant reduction of the risk of treatment failure in 
patients treated with adalimumab versus patients receiving placebo (see Table 29). Both studies
demonstrated an early and sustained effect of adalimumab on the treatment failure rate versus placebo (see
Figure 2).

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Table 29: Time to Treatment Failure in Studies UV I and UV II

Analysis
Treatment

N Failure
N (%)

Median Time to 
Failure (months)

HRa CI 95 %
for HRa

p valueb

Time to Treatment Failure At or After Week 6 in Study UV I
Primary analysis (ITT)

Placebo 107 84 (78.5) 3.0 -- -- --
Adalimumab 110 60 (54.5) 5.6 0.50 0.36, 0.70 < 0.001

Time to Treatment Failure At or After Week 2 in Study UV II
Primary analysis (ITT)

Placebo 111 61 (55.0) 8.3 -- -- --
Adalimumab 115 45 (39.1) NEc 0.57 0.39, 0.84 0.004

Note: Treatment failure at or after week 6 (Study UV I), or at or after week 2 (Study UV II), was counted as 
event. Drop outs due to reasons other than treatment failure were censored at the time of dropping out.

a HR of adalimumab vs placebo from proportional hazards regression with treatment as factor.
b 2-sided p value from log rank test.
c NE = not estimable. Fewer than half of at-risk subjects had an event.

Figure 2: Kaplan-Meier Curves Summarizing Time to Treatment Failure on or after Week 6
(Study UV I) or Week 2 (Study UV II)

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Note: P# = Placebo (Number of Events/Number at Risk); A# = Adalimumab (Number of Events/Number at Risk).

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

Of the 417 subjects included in the uncontrolled long-term extension of Studies UV I and UV II, 46 subjects 
were regarded ineligible (e.g. developed complications secondary to diabetic retinopathy, due to cataract 
surgery or vitrectomy) and were excluded from the primary analysis of efficacy. Of the 371 remaining 
patients, 276 evaluable patients reached 78 weeks of open-label adalimumab treatment. Based on the 
observed data approach, 222 (80.4 %) were in quiescence (no active inflammatory lesions, AC cell grade  
≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose ≤ 7.5 mg per day, and 184 (66.7 %) were in 
steroid-free quiescence. BCVA was either improved or maintained (< 5 letters deterioration) in 88.4 % of the 
eyes at week 78. Among the patients who discontinued the study prior to week 78, 11 % discontinued due to 
adverse events, and 5 % due to insufficient response to adalimumab treatment.

Quality of Life

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

Paediatric uveitis

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

The primary endpoint was ‘time to treatment failure’. The criteria determining treatment failure were
worsening or sustained non-improvement in ocular inflammation, partial improvement with development of 
sustained ocular co-morbidities or worsening of ocular co-morbidities, non-permitted use of concomitant 
medications, and suspension of treatment for an extended period of time.

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Clinical response

Adalimumab significantly delayed the time to treatment failure, as compared to placebo (See Figure 3,
P < 0.0001 from log rank test).The median time to treatment failure was 24.1 weeks for subjects treated with 
placebo, whereas the median time to treatment failure was not estimable for subjects treated with
adalimumab because less than one-half of these subjects experienced treatment failure. Adalimumab
significantly decreased the risk of treatment failure by 75 % relative to placebo, as shown by the hazard ratio 
(HR = 0.25 [95 % CI: 0.12, 0.49]).

Figure 3: Kaplan-Meier Curves Summarizing Time to Treatment Failure in the Paediatric 
Uveitis Study

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

Immunogenicity 

Anti-adalimumab antibodies may develop during adalimumab treatment. 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. 

Paediatric population 

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

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5.2 Pharmacokinetic properties

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 (Vss) 
ranged from 5 to 6 litres and the mean terminal phase half-life was approximately two weeks. Adalimumab 
concentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31-96 % of those 
in serum. 

Following subcutaneous administration of 40 mg of adalimumab 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) for adalimumab without concomitant methotrexate and 10.9 ± 5.2 μg/mL (47.7 % CV) with 
concomitant methotrexate. 

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

Following the administration of 24 mg/m² (up to a maximum of 40 mg) subcutaneously every other week to 
patients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state (values 
measured at week 24) serum adalimumab concentrations were 8.8 ± 6.6 μg/mL for adalimumab without 
concomitant methotrexate and 11.8 ± 4.3 μg/mL with concomitant methotrexate.

Following subcutaneous administration of 40 mg of adalimumab every other week in adult non-radiographic
axial spondyloarthritis patients, the mean (±SD) trough steady-state concentration at week 68 was 
8.0 ± 4.6 μg/mL.

In adult patients with psoriasis, the mean steady-state trough concentration was 5 μg/mL during adalimumab 
40 mg every other week monotherapy treatment. 

Following the administration of 0.8 mg/kg (up to a maximum of 40 mg) subcutaneously every other week to 
paediatric patients with chronic plaque psoriasis, the mean ± SD steady-state adalimumab trough 
concentration was approximately 7.4 ± 5.8 μg/mL (79 % CV). 

In adult patients with hidradenitis suppurativa, a dose of 160 mg adalimumab on week 0 followed by 80 mg
on week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 µg/mL at week 2 and 
week 4. The mean steady-state trough concentration at week 12 through week 36 were approximately 8 to 
10 µg/mL during adalimumab 40 mg every week treatment.

Adalimumab exposure in adolescent HS patients was predicted using population pharmacokinetic modelling 
and simulation based on cross-indication pharmacokinetics in other paediatric patients (paediatric psoriasis, 
juvenile idiopathic arthritis, paediatric Crohn’s disease, and enthesitis-related arthritis). The recommended 
adolescent HS dosing schedule is 40 mg every other week. Since exposure to adalimumab can be affected by 

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body size, adolescents with higher body weight and inadequate response may benefit from receiving the 
recommended adult dose of 40 mg every week.

In patients with Crohn’s disease, the loading dose of 80 mg adalimumab on week 0 followed by 40 mg
adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 5.5 μg/mL
during the induction period. A loading dose of 160 mg adalimumab on week 0 followed by 80 mg
adalimumab 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 adalimumab every other week. 

In paediatric patients 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, patients 
were randomised 1:1 to either the Standard Dose (40/20 mg eow) or Low Dose (20/10 mg eow) maintenance 
treatment groups based on their body weight. The mean (± SD) serum adalimumab trough concentrations 
achieved at week 4 were 15.7±6.6 μg/mL for patients ≥ 40 kg (160/80 mg) and 10.6 ± 6.1 μg/mL for patients
< 40 kg (80/40 mg). 

For patients who stayed on their randomised therapy, the mean (± SD) adalimumab trough concentrations at 
week 52 were 9.5 ± 5.6 μg/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 patients who continued to receive adalimumab treatment 
eow for 52 weeks. For patients who dose escalated from eow to weekly regimen, the mean (± SD) serum 
concentrations of adalimumab at week 52 were 15.3 ± 11.4 μg/mL (40/20 mg, weekly) and 6.7 ± 3.5 μg/mL
(20/10 mg, weekly). 

In patients with ulcerative colitis, a loading dose of 160 mg adalimumab on week 0 followed by 80 mg
adalimumab 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 adalimumab every other week. 

In adult patients with uveitis, a loading dose of 80 mg adalimumab on week 0 followed by 40 mg
adalimumab every other week starting at week 1, resulted in mean steady-state concentrations of
approximately 8 to 10 μg/mL.

Adalimumab exposure in paediatric uveitis patients was predicted using population pharmacokinetic
modelling and simulation based on cross-indication pharmacokinetics in other paediatric patients (paediatric 
psoriasis, juvenile idiopathic arthritis, paediatric Crohn’s disease, and enthesitis-related arthritis). No clinical 
exposure data are available on the use of a loading dose in children < 6 years. The predicted exposures 
indicate that in the absence of methotrexate, a loading dose may lead to an initial increase in systemic 
exposure.

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

Exposure-response relationship in paediatric population

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

Exposure-response relationships between adalimumab concentration and efficacy in paediatric patients with 
severe chronic plaque psoriasis were established for PASI 75 and PGA clear or minimal, respectively. 
PASI 75 and PGA clear or minimal increased with increasing adalimumab concentrations, both with a 
similar apparent EC50 of approximately 4.5 µg/mL (95 % CI 0.4-47.6 and 1.9-10.5, respectively).

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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. 

Hepatic or renal impairment

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

5.3 Preclinical safety data

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 cynomolgus 
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 neutralising antibodies in rodents.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium acetate trihydrate
Acetic acid, glacial
Trehalose dihydrate
Polysorbate 80
Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

2 years

6.4 Special precautions for storage

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

A single Cyltezo pre-filled syringe/pre-filled pen may be stored at temperatures up to a maximum of 25°C 
for a period of up to 14 days. The pre-filled syringe/pre-filled pen must be protected from light, and 
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6.5 Nature and contents of container

Cyltezo 40 mg solution for injection in pre-filled syringe
Cyltezo 40 mg solution for injection in single-use pre-filled syringe (type I glass) with a plunger stopper 
(butyl rubber) and a needle with a cap (outer part made of plastic material and inner part made of elastomer
containing latex). 

Packs of: 
• 1 pre-filled syringe (0.8 mL sterile solution) in a blister, with 2 alcohol pads. 
• 2 pre-filled syringes (0.8 mL sterile solution), each in a blister, with 2 alcohol pads. 
• 4 pre-filled syringes (0.8 mL sterile solution), each in a blister, with 4 alcohol pads. 
• 6 pre-filled syringes (0.8 mL sterile solution), each in a blister, with 6 alcohol pads. 

Not all pack sizes may be marketed.

Cyltezo 40 mg solution for injection in pre-filled pen
Cyltezo 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 I glass with a plunger stopper (butyl rubber) and a 
needle with a cap (outer part made of plastic material and inner part made of elastomer containing latex).

Packs of: 
• 1 pre-filled pen (0.8 mL sterile solution) in a blister, with 2 alcohol pads. 
• 2 pre-filled pens (0.8 mL sterile solution), each in a blister, with 2 alcohol pads. 
• 4 pre-filled pens (0.8 mL sterile solution), each in a blister, with 4 alcohol pads. 
• 6 pre-filled pens (0.8 mL sterile solution), each in a blister, with 6 alcohol pads. 

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S) 

Cyltezo 40 mg solution for injection in pre-filled syringe
EU/1/17/1240/001
EU/1/17/1240/002
EU/1/17/1240/003
EU/1/17/1240/004

Cyltezo 40 mg solution for injection in pre-filled pen
EU/1/17/1240/005
EU/1/17/1240/006
EU/1/17/1240/007
EU/1/17/1240/008

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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 10 November 2017

10. DATE OF REVISION OF THE TEXT

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

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http://www.ema.europa.eu


53

ANNEX II

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 
USE OF THE MEDICINAL PRODUCT

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A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) of the biological active substance(s) 

Boehringer Ingelheim Fremont, Inc.
6701 Kaiser Drive
Fremont, CA 94555
United States

Name and address of the manufacturer(s) responsible for batch release

Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
88397 Biberach an der Riss
GERMANY

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 

 Periodic safety update reports 

The requirements for submission of periodic safety update reports for this medicinal product are set out in 
the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 
OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed 
RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the 
RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information being 

received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached. 

 Additional risk minimisation measures

Prior to launch of Cyltezo in each Member State the Marketing Authorisation Holder (MAH) must agree 
about the content and format of the educational programme, including communication media, distribution 
modalities, and any other aspects of the programme, with the National Competent Authority. 

The MAH shall ensure that in each Member State where Cyltezo is marketed, all healthcare professionals 
who are expected to prescribe Cyltezo have are provided with the following educational package:

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 Physician educational material
 Patient information 

The physician educational material should contain:

 The Summary of Product Characteristics
 Guide for healthcare professionals
 Patient alert card

The Guide for healthcare professionals shall contain the following key elements:

 Relevant information on the safety concerns of serious infections, sepsis, tuberculosis and 
opportunistic infections; congestive heart failure; demyelinating disorders; malignancies to be 
addressed by the additional risk minimisation measures (e.g. seriousness, severity, frequency, time to 
onset, reversibility of the AE as applicable).

The patient alert card shall contain the following key messages: 

 A warning message for HCPs treating the patient at any time, including in conditions of emergency, 
that the patient is using Cyltezo.

 That Cyltezo treatment may increase the potential risks of serious infections, sepsis, tuberculosis and 
opportunistic infections; congestive heart failure; demyelinating disorders; malignancies.

 Signs or symptoms of the safety concern and when to seek attention from a HCP
 Contact details of the prescriber 

The patient information pack should contain:

Patient information leaflet

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ANNEX III

LABELLING AND PACKAGE LEAFLET

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A. LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Cyltezo 40 mg solution for injection in pre-filled syringe
adalimumab

2. STATEMENT OF ACTIVE SUBSTANCE(S)

One 0.8 mL pre-filled syringe contains 40 mg adalimumab.

3. LIST OF EXCIPIENTS

Excipients: sodium acetate trihydrate, glacial acetic acid, trehalose dihydrate, polysorbate 80 and water for 
injections. The needle cover of the syringe contains natural rubber (latex). See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection
1 pre-filled syringe 
2 alcohol pads
2 pre-filled syringes
2 alcohol pads
4 pre-filled syringes
4 alcohol pads
6 pre-filled syringes
6 alcohol pads

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Subcutaneous use
For single use only

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 
THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY
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8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2ºC - 8ºC). Do not freeze.
Keep the syringe in the outer carton in order to protect from light.
Keep the syringes in the outer carton in order to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/17/1240/001 1 pre-filled syringe
EU/1/17/1240/002 2 pre-filled syringes
EU/1/17/1240/003 4 pre-filled syringes
EU/1/17/1240/004 6 pre-filled syringes

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Cyltezo

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

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18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER 

1. NAME OF THE MEDICINAL PRODUCT

Cyltezo 40 mg solution for injection in pre-filled syringe
adalimumab

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

For storage information, see package leaflet.
For single use only

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

SYRINGE LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Cyltezo 40 mg injection
adalimumab
Subcutaneous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Cyltezo 40 mg solution for injection in pre-filled pen
adalimumab

2. STATEMENT OF ACTIVE SUBSTANCE(S)

One 0.8 mL pre-filled pen contains 40 mg adalimumab.

3. LIST OF EXCIPIENTS

Excipients: sodium acetate trihydrate, glacial acetic acid, trehalose dihydrate, polysorbate 80 and water for 
injections. The needle cover of the syringe contains natural rubber (latex). See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection
1 pre-filled pen
2 alcohol pads
2 pre-filled pens
2 alcohol pads
4 pre-filled pens
4 alcohol pads
6 pre-filled pens
6 alcohol pads

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Subcutaneous use
For single use only

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 
THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY
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8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/17/1240/005 1 pre-filled pen
EU/1/17/1240/006 2 pre-filled pens
EU/1/17/1240/007 4 pre-filled pens
EU/1/17/1240/008 6 pre-filled pens

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Cyltezo

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

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18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER 

1. NAME OF THE MEDICINAL PRODUCT

Cyltezo 40 mg solution for injection in pre-filled pen
adalimumab

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

For storage information, see package leaflet.
For single use only

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PEN LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Cyltezo 40 mg injection
adalimumab
Subcutaneous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

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B. PACKAGE LEAFLET

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Package leaflet: Information for the patient

Cyltezo 40 mg solution for injection in pre-filled syringe
Adalimumab

This medicine is subject to additional monitoring. This will allow quick identification of new safety 
information. You can help by reporting any side effects you may get. See the end of section 4 for how to 
report side effects.

Read all of this leaflet carefully before you start using this medicine because it contains important 
information for you.
- Keep this leaflet. You may need to read it again.
- Your doctor will also give you a Patient Alert Card, which contains important safety information that 

you need to be aware of before you are given Cyltezo and during treatment with Cyltezo. Keep this 
Patient Alert Card with you.

- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. See section 4.

What is in this leaflet

1. What Cyltezo is and what it is used for
2. What you need to know before you use Cyltezo
3. How to use Cyltezo
4. Possible side effects
5. How to store Cyltezo
6. Contents of the pack and other information
7. Instructions for use

1. What Cyltezo is and what it is used for

Cyltezo contains the active substance adalimumab, a medicine that acts on your body’s immune (defence) 
system. 

Cyltezo is intended for the treatment of the inflammatory diseases described below:
 Rheumatoid arthritis, 
 Polyarticular juvenile idiopathic arthritis, 
 Enthesitis-related arthritis, 
 Ankylosing spondylitis, 
 Axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, 
 Psoriatic arthritis, 
 Psoriasis, 
 Hidradenitis suppurativa, 
 Crohn’s disease,
 Ulcerative colitis and 
 Non-infectious uveitis

The active ingredient in Cyltezo, adalimumab, is a monoclonal antibody. Monoclonal antibodies are proteins 
that attach to a specific target.

The target of adalimumab is a protein called tumour necrosis factor (TNFα), which is present at increased 
levels in the inflammatory diseases listed above. By attaching to TNFα, Cyltezo decreases the process of 
inflammation in these diseases.

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Rheumatoid arthritis

Rheumatoid arthritis is an inflammatory disease of the joints.

Cyltezo is used to treat rheumatoid arthritis in adults. If you have moderate to severe active rheumatoid 
arthritis, you may first be given other disease-modifying medicines, such as methotrexate. If these medicines
do not work well enough, you will be given Cyltezo to treat your rheumatoid arthritis.

Cyltezo can also be used to treat severe, active and progressive rheumatoid arthritis without previous
methotrexate treatment. 

Cyltezo can slow down the damage to the cartilage and bone of the joints caused by the disease and improve 
physical function.

Usually, Cyltezo is used with methotrexate. If your doctor considers that methotrexate is inappropriate, 
Cyltezo can be given alone.

Polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis

Polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis are inflammatory diseases of the 
joints that usually first appear in childhood.

Cyltezo is used to treat polyarticular juvenile idiopathic arthritis in children and adolescents aged 2 to 17 
years and enthesitis-related arthritis in children and adolescents aged 6 to 17 years. Patients may first be 
given other disease-modifying medicines, such as methotrexate. If these medicines do not work well enough, 
patients will be given Cyltezo to treat their polyarticular juvenile idiopathic arthritis or enthesitis-related
arthritis.

Ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis

Ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, 
are inflammatory diseases of the spine.

Cyltezo is used to treat ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of 
ankylosing spondylitis in adults. If you have ankylosing spondylitis or axial spondyloarthritis without 
radiographic evidence of ankylosing spondylitis, you will first be given other medicines. If these medicines
do not work well enough, you will be given Cyltezo to reduce the signs and symptoms of your disease.

Psoriatic arthritis

Psoriatic arthritis is an inflammatory disease of the joints associated with psoriasis.

Cyltezo is used to treat psoriatic arthritis in adults. Cyltezo can slow down the damage to the cartilage and 
bone of the joints caused by the disease and improve physical function.

Plaque psoriasis in adults and children

Plaque psoriasis is an inflammatory skin condition that causes red, flaky, crusty patches of skin covered with 
silvery scales. Plaque psoriasis can also affect the nails, causing them to crumble, become thickened and lift
away from the nail bed which can be painful. Psoriasis is believed to be caused by a problem with the body’s 
immune system that leads to an increased production of skin cells.

Cyltezo is used to treat moderate to severe plaque psoriasis in adults. Cyltezo is also used to treat severe 
plaque psoriasis in children and adolescents aged 4 to 17 years for whom topical therapy and phototherapies 
have either not worked very well or are not suitable. 

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Hidradenitis suppurativa in adults and adolescents

Hidradenitis suppurativa (sometimes called acne inversa) is a chronic and often painful inflammatory skin 
disease. Symptoms may include tender nodules (lumps) and abscesses (boils) that may leak pus. It most 
commonly affects specific areas of the skin, such as under the breasts, the armpits, inner thighs, groin and 
buttocks. Scarring may also occur in affected areas.

Cyltezo is used to treat hidradenitis suppurativa in adults and adolescents from 12 years of age. 
Cyltezo can reduce the number of nodules and abscesses you have and the pain that is often associated with 
the disease. You may first be given other medicines. If these medicines do not work well enough, you will be 
given Cyltezo.

Crohn’s disease in adults and children

Crohn’s disease is an inflammatory disease of the digestive tract.

Adalimumab is used to treat Crohn’s disease in adults and children aged 6 to 17 years. If you have Crohn’s 
disease you will first be given other medicines. If these medicines do not work well enough, you will be 
given Cyltezo to reduce the signs and symptoms of your Crohn’s disease.

Ulcerative colitis

Ulcerative colitis is an inflammatory disease of the bowel.

Cyltezo is used to treat ulcerative colitis in adults. If you have ulcerative colitis you will first be given other 
medicines. If these medicines do not work well enough, you will be given Cyltezo to reduce the signs and 
symptoms of your disease.

Non-infectious uveitis in adults and children

Non-infectious uveitis is an inflammatory disease affecting certain parts of the eye. Cyltezo works by 
reducing this inflammation.

Cyltezo is used to treat
 Adults with non-infectious uveitis with inflammation affecting the back of the eye
 Children from 2 years of age with chronic non-infectious uveitis with inflammation affecting the

front of the eye

This inflammation may lead to a decrease of vision and/or the presence of floaters in the eye (black dots or 
wispy lines that move across the field of vision). 

2. What you need to know before you use Cyltezo

Do not use Cyltezo

 If you are allergic to adalimumab or any of the other ingredients of this medicine (listed in section 6).

 If you have a severe infection, including tuberculosis (see “Warnings and precautions”). It is important 
that you tell your doctor if you have symptoms of infections, e.g. fever, wounds, feeling tired, dental 
problems. 

 If you have moderate or severe heart failure. It is important to tell your doctor if you have had or have a 
serious heart condition (see “Warnings and precautions”).

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Warnings and precautions

Talk to your doctor or pharmacist before using Cyltezo

Allergic reaction

 If you have allergic reactions with symptoms such as chest tightness, wheezing, dizziness, swelling or 
rash do not inject more Cyltezo and contact your doctor immediately since, in rare cases, these reactions 
can be life threatening.

Infection

 If you have an infection, including long-term or localised infection (for example, leg ulcer) consult your 
doctor before starting Cyltezo. If you are unsure, contact your doctor.

 You might get infections more easily while you are receiving Cyltezo treatment. This risk may increase 
if your lung function is impaired. These infections may be serious and include tuberculosis, infections 
caused by viruses, fungi, parasites or bacteria, other opportunistic infections (unusual infections 
associated with a weakened immune system) and sepsis (blood poisoning). In rare cases, these 
infections may be life-threatening. It is important to tell your doctor if you get symptoms such as fever, 
wounds, feeling tired or dental problems. Your doctor may recommend temporary discontinuation of 
Cyltezo.

Tuberculosis

 As cases of tuberculosis have been reported in patients treated with adalimumab, your doctor will check 
you for signs and symptoms of tuberculosis before starting Cyltezo. This will include a thorough 
medical evaluation including your medical history and screening tests (for example chest X-ray and a 
tuberculin test). The conduct and results of these tests should be recorded on your patient alert card. It is 
very important that you tell your doctor if you have ever had tuberculosis, or if you have been in close 
contact with someone who has had tuberculosis. Tuberculosis can develop during therapy even if you 
have received preventative treatment for tuberculosis. If symptoms of tuberculosis (persistent cough, 
weight loss, listlessness, mild fever), or any other infection appear during or after therapy tell your 
doctor immediately.

Travel/recurrent infection

 Tell your doctor if you reside or travel in regions where fungal infections such as histoplasmosis,
coccidioidomycosis or blastomycosis are endemic.

 Tell your doctor if you have a history of recurrent infections or other conditions that increase the risk of 
infections.

Hepatitis B virus

 Tell your doctor if you are a carrier of the hepatitis B virus (HBV), if you have an active HBV infection 
or if you think you might be at risk of contracting HBV. Your doctor should test you for HBV. Cyltezo
can reactivate HBV infection in people who carry this virus. In some rare cases, especially if you are 
taking other medicines that suppress the immune system, reactivation of HBV infection can be life-
threatening. 

Age over 65 years

 If you are over 65 years you may be more susceptible to infections while taking Cyltezo. You and your 
doctor should pay special attention to signs of infection while you are being treated with Cyltezo. It is 

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important to tell your doctor if you get symptoms of infections, such as fever, wounds, feeling tired or 
dental problems.

Surgery or dental procedure

 If you are about to have a surgery or dental procedures, tell your doctor that you are taking Cyltezo. 
Your doctor may recommend temporary discontinuation of Cyltezo.

Demyelinating disease

 If you have or develop a demyelinating disease (a disease that affects the insulating layer around the 
nerves, such as multiple sclerosis), your doctor will decide if you should receive or continue to receive
Cyltezo. Tell your doctor immediately if you get symptoms like changes in your vision, weakness in 
your arms or legs or numbness or tingling in any part of your body.

Vaccine

 Certain vaccines contain weakened but live forms of bacteria or viruses that cause diseases, and should 
not be given while receiving Cyltezo because they may cause infections. Check with your doctor before 
you receive any vaccines. It is recommended that children, if possible, be given all the scheduled 
vaccinations for their age before they start treatment with Cyltezo. If you received Cyltezo while you 
are pregnant, your baby may be at higher risk for getting an infection for up to about five months after 
the last dose you received during pregnancy. It is important that you tell your baby's doctors and other 
health care professionals about your Cyltezo use during your pregnancy so they can decide when your 
baby should receive any vaccine.

Heart Failure

 If you have mild heart failure and you are being treated with Cyltezo, your heart failure status must be 
closely monitored by your doctor. It is important to tell your doctor if you have had or have a serious 
heart condition. If you develop new or worsening symptoms of heart failure (e.g. shortness of breath, or 
swelling of your feet), you must contact your doctor immediately. Your doctor will decide if you should 
receive Cyltezo.

Fever, bruising, bleeding or looking pale

 In some patients the body may fail to produce enough of the blood cells to fight off infections or help 
you to stop bleeding. If you develop a fever that does not go away, or you bruise or bleed very easily or 
look very pale, call your doctor right away. Your doctor may decide to stop treatment.

Cancer

 There have been very rare cases of certain kinds of cancer in children and adults taking adalimumab or 
other TNFα blockers. People with more serious rheumatoid arthritis who have had the disease for a long 
time may have a higher than average risk of getting lymphoma (a cancer that affects the lymph system), 
and leukaemia (a cancer that affects the blood and bone marrow). If you take Cyltezo the risk of getting 
lymphoma, leukaemia, or other cancers may increase. On rare occasions, a specific and severe type of 
lymphoma has been observed in patients taking adalimumab. Some of those patients were also treated 
with the medicines azathioprine or mercaptopurine. Tell your doctor if you are taking azathioprine or 
mercaptopurine with Cyltezo. 

 In addition cases of non-melanoma skin cancer have been observed in patients taking adalimumab. If 
new areas of damaged skin appear during or after therapy or if existing marks or areas of damage
change appearance, tell your doctor.

 There have been cases of cancers other than lymphoma in patients with a specific type of lung disease 
called chronic obstructive pulmonary disease (COPD) treated with another TNFα blocker. If you have 

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COPD, or you are a heavy smoker, you should discuss with your doctor whether treatment with a TNFα
blocker is appropriate for you.

Lupus-like syndrome

 On rare occasions, treatment with Cyltezo could result in lupus-like syndrome. Contact your doctor if 
symptoms such as persistent unexplained rash, fever, joint pain or tiredness occur.

Children and adolescents

 Vaccinations: if possible children should be up to date with all vaccinations before using Cyltezo.
 Do not give Cyltezo to children with polyarticular juvenile idiopathic arthritis below the age of 2 years.
 Do not use the 40 mg pre-filled syringe, if doses other than 40 mg are recommended.

Other medicines and Cyltezo

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Cyltezo can be taken together with methotrexate or certain disease-modifying anti-rheumatic agents 
(sulfasalazine, hydroxychloroquine, leflunomide and injectable gold preparations), corticosteroids or pain 
medications including non-steroidal anti-inflammatory drugs (NSAIDs).

You should not take Cyltezo with medicines containing the active substances anakinra or abatacept due to
increased risk of serious infection. If you have questions, please ask your doctor.

Pregnancy and breast-feeding

 You should consider the use of adequate contraception to prevent pregnancy and continue its use for 
at least 5 months after the last Cyltezo treatment.

 If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for
advice about taking this medicine.

 Cyltezo should only be used during a pregnancy if needed.
 According to a pregnancy study, there was no higher risk of birth defects when the mother had

received adalimumab during pregnancy compared with mothers with the same disease who did not
receive adalimumab.

 Cyltezo can be used during breast-feeding.
 If you receive Cyltezo during your pregnancy, your baby may have a higher risk for getting an

infection.
 It is important that you tell your baby’s doctors and other health care professionals about your

Cyltezo use during your pregnancy before the baby receives any vaccine. For more information on 
vaccines see the “Warnings and precautions” section).

Driving and using machines

Cyltezo may have a minor influence on your ability to drive, cycle or use machines. Room spinning 
sensation (vertigo) and vision disturbances may occur after taking Cyltezo.

The needle cover of the syringe contains latex

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

Cyltezo contains sodium

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8 mL dose, i.e. essentially 
‘sodium-free’.

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3. How to use Cyltezo

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or 
pharmacist if you are not sure.

Adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis
without radiographic evidence of ankylosing spondylitis

The usual dose for adults with rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without 
radiographic evidence of ankylosing spondylitis and for patients with psoriatic arthritis is 40 mg adalimumab 
given every other week as a single dose.

In rheumatoid arthritis, methotrexate is continued while using Cyltezo. If your doctor determines that 
methotrexate is inappropriate, Cyltezo can be given alone.

If you have rheumatoid arthritis and you do not receive methotrexate with your Cyltezo therapy, your doctor 
may decide to give 40 mg adalimumab every week or 80 mg every other week.

Children, adolescents and adults with polyarticular juvenile idiopathic arthritis

Children and adolescents from 2 years of age weighing 10 kg to less than 30 kg

Cyltezo is only available as 40 mg pre-filled syringe and pre-filled pen. Thus, it is not possible to use Cyltezo 
for children who require less than a full 40 mg dose. If an alternate dose is required, other adalimumab 
products offering such an option should be used.

Children, adolescents and adults from 2 years of age weighing 30 kg or more

The recommended dose of Cyltezo is 40 mg every other week.

Children, adolescents and adults with enthesitis-related arthritis

Children and adolescents from 6 years of age weighing 15 kg to less than 30 kg

Cyltezo is only available as 40 mg pre-filled syringe and pre-filled pen. Thus, it is not possible to use Cyltezo 
for children who require less than a full 40 mg dose. If an alternate dose is required, other adalimumab 
products offering such an option should be used.

Children, adolescents and adults from 6 years of age weighing 30 kg or more

The recommended dose of Cyltezo is 40 mg every other week.

Adults with psoriasis

The usual dose for adults with psoriasis is an initial dose of 80 mg (as two 40 mg injections in one day), 
followed by 40 mg given every other week starting one week after the initial dose. You should continue to 
inject Cyltezo for as long as your doctor has told you. Depending on your response, your doctor may 
increase the dosage to 40 mg every week or 80 mg every other week.

Children and adolescents with plaque psoriasis

Children and adolescents from 4 to 17 years of age weighing 15 kg to less than 30 kg

Cyltezo is only available as 40 mg pre-filled syringe and pre-filled pen. Thus, it is not possible to use Cyltezo 
for children who require less than a full 40 mg dose. If an alternate dose is required, other adalimumab 
products offering such an option should be used.

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Children and adolescents from 4 to 17 years of age weighing 30 kg or more

The recommended dose of Cyltezo is an initial dose of 40 mg, followed by 40 mg one week later. Thereafter, 
the usual dose is 40 mg every other week.

Adults with hidradenitis suppurativa

The usual dose regimen for hidradenitis suppurativa is an initial dose of 160 mg (as four 40 mg injections in 
one day or two 40 mg injections per day for two consecutive days), followed by an 80 mg dose (as two
40 mg injections in one day) two weeks later. After two further weeks, continue with a dosage of 40 mg
every week or 80 mg every other week, as prescribed by your doctor. It is recommended that you use an 
antiseptic wash daily on the affected areas.

Adolescents with hidradenitis suppurativa from 12 to 17 years of age weighing 30 kg or more

The recommended dose of Cyltezo is an initial dose of 80 mg (as two 40 mg injections in one day), followed 
by 40 mg every other week starting one week later. If this dose does not work well enough, your doctor may 
increase the dosage to 40 mg every week or 80 mg every other week.

It is recommended that you use an antiseptic wash daily on the affected areas.

Adults with Crohn’s disease

The usual dose regimen for Crohn’s disease is 80 mg (as two 40 mg injections in one day) initially followed 
by 40 mg every other week starting two weeks later. If a faster effect is required your doctor may prescribe 
an initial dose of 160 mg (as four 40 mg injections in one day or two 40 mg injections per day for two 
consecutive days), followed by 80 mg (as two 40 mg injections in one day) two weeks later, and thereafter as 
40 mg every other week. If this dose does not work well enough, your doctor may increase the dosage to 
40 mg every week or 80 mg every other week.

Children and adolescents with Crohn's disease

Children and adolescents from 6 to 17 years of age weighing less than 40 kg

Cyltezo is only available as 40 mg pre-filled syringe and pre-filled pen. Thus, it is not possible to use Cyltezo 
for children who require less than a full 40 mg dose. If an alternate dose is required, other adalimumab 
products offering such an option should be used.

Children and adolescents from 6 to 17 years of age weighing 40 kg or more

The usual dose regimen is 80 mg (as two 40 mg injections in one day) initially followed by 40 mg two weeks 
later. If a faster response is required, your doctor may prescribe an initial dose of 160 mg (as four 40 mg 
injections in one day or as two 40 mg injections per day for two consecutive days) followed by 80 mg (as 
two 40 mg injections in one day) two weeks later.

Thereafter, the usual dose is 40 mg every other week. If this dose does not work well enough, your doctor 
may increase the dosage to 40 mg every week or 80 mg every other week.

Adults with ulcerative colitis

The usual Cyltezo dose for adults with ulcerative colitis is 160 mg (as four 40 mg injections in one day or as 
two 40 mg injections per day for two consecutive days) at week 0 and 80 mg (as two 40 mg injections in one 
day) at week 2 and thereafter 40 mg every other week. If this dose does not work well enough, your doctor 
may increase the dosage to 40 mg every week or 80 mg every other week.

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Adults with non-infectious uveitis

The usual dose for adults with non-infectious uveitis is an initial dose of 80 mg (as two injections in one
day), followed by 40 mg given every other week starting one week after the initial dose. You should 
continue to inject Cyltezo for as long as your doctor has told you.

In non-infectious uveitis, corticosteroids or other medicines that influence the immune system may be
continued while using Cyltezo. Cyltezo can also be given alone.

Children and adolescents with chronic non-infectious uveitis from 2 years of age

Children and adolescents from 2 years of age weighing less than 30 kg

Cyltezo is only available as 40 mg pre-filled syringe and pre-filled pen. Thus, it is not possible to use Cyltezo 
for children who require less than a full 40 mg dose. If an alternate dose is required, other adalimumab 
products offering such an option should be used.

Children and adolescents from 2 years of age weighing 30 kg or more

The usual dose of Cyltezo is 40 mg every other week with methotrexate.

Your doctor may also prescribe an initial dose of 80 mg which may be administered one week prior to the
start of the usual dose.

Method and route of administration

Cyltezo is administered by injection under the skin (by subcutaneous injection).

Detailed instructions on how to inject Cyltezo are provided in section 7 ‘Instructions for use’.

If you use more Cyltezo than you should

If you accidentally inject Cyltezo more frequently than you should, call your doctor or pharmacist and 
explain that you have taken more. Always take the outer carton of the medicine with you, even if it is empty.

If you forget to use Cyltezo

If you forget to give yourself an injection, you should inject the next dose of Cyltezo as soon as you 
remember. Then take your next dose as you would have on your originally scheduled day, had you not 
forgotten a dose.

If you stop using Cyltezo

The decision to stop using Cyltezo should be discussed with your doctor. Your symptoms may return upon 
stopping treatment.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Most side effects 
are mild to moderate. However, some may be serious and require treatment. Side effects may occur up to 4 
months or more after the last Cyltezo injection.

Seek medical attention urgently, if you notice any of the following:
 severe rash, hives or other signs of allergic reaction;

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 swollen face, hands, feet;
 trouble breathing, swallowing;
 shortness of breath with exertion or upon lying down or swelling of the feet.

Tell your doctor as soon as possible, if you notice any of the following:
 signs of infection such as fever, feeling sick, wounds, dental problems, burning on urination;
 feeling weak or tired;
 coughing;
 tingling;
 numbness;
 double vision;
 arm or leg weakness;
 a bump or open sore that doesn't heal;
 signs and symptoms suggestive of blood disorders such as persistent fever, bruising, bleeding, paleness.

The symptoms described above can be signs of the below listed side effects, which have been observed with 
adalimumab.

Very common (may affect more than 1 in 10 people):
 injection site reactions (including pain, swelling, redness or itching);
 respiratory tract infections (including cold, runny nose, sinus infection, pneumonia);
 headache;
 abdominal (belly) pain;
 nausea and vomiting;
 rash;
 pain in the muscles.

Common (may affect up to 1 in 10 people):
 serious infections (including blood poisoning and influenza);
 intestinal infections (including gastroenteritis);
 skin infections (including cellulitis and shingles);
 ear infections;
 mouth infections (including tooth infections and cold sores);
 reproductive tract infections;
 urinary tract infection;
 fungal infections;
 joint infections;
 benign tumours;
 skin cancer;
 allergic reactions (including seasonal allergy);
 dehydration;
 mood swings (including depression);
 anxiety;
 difficulty sleeping;
 sensation disorders such as tingling, prickling or numbness;
 migraine;
 symptoms of nerve root compression (including low back pain and leg pain);
 vision disturbances;
 eye inflammation;
 inflammation of the eyelid and eye swelling;
 vertigo (sensation of the room spinning);
 sensation of heart beating rapidly;
 high blood pressure;
 flushing;

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 haematoma (a solid sweling with clotted blood);
 cough;
 asthma;
 shortness of breath;
 gastrointestinal bleeding;
 dyspepsia (indigestion, bloating, heart burn);
 acid reflux disease;
 sicca syndrome (including dry eyes and dry mouth);
 itching;
 itchy rash;
 bruising;
 inflammation of the skin (such as eczema);
 breaking of finger nails and toe nails;
 increased sweating;
 hair loss;
 new onset or worsening of psoriasis;
 muscle spasms;
 blood in urine;
 kidney problems;
 chest pain;
 oedema (a build up of fluid in the body which causes the affected tissue to swell);
 fever;
 reduction in blood platelets which increases risk of bleeding or bruising;
 impaired healing.

Uncommon (may affect up to 1 in 100 people):
 opportunistic infections (which include tuberculosis and other infections that occur when resistance to 

disease is lowered);
 neurological infections (including viral meningitis);
 eye infections;
 bacterial infections;
 diverticulitis (inflammation and infection of the large intestine);
 cancer;
 including cancer of the lymph system (lymphoma) and
 melanoma (a type of skin cancer);
 immune disorders that could affect the lungs, skin and lymph nodes (most commonly as a condition 

called sarcoidosis);
 vasculitis (inflammation of blood vessels);
 tremor;
 neuropathy (nerve damage);
 stroke;
 hearing loss, buzzing;
 sensation of heart beating irregularly such as skipped beats;
 heart problems that can cause shortness of breath or ankle swelling;
 heart attack;
 a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel;
 lung diseases causing shortness of breath (including inflammation);
 pulmonary embolism (blockage in an artery of the lung);
 pleural effusion (abnormal collection of fluid in the pleural space);
 inflammation of the pancreas which causes severe pain in the abdomen and back;
 difficulty in swallowing;
 facial oedema;
 gallbladder inflammation, gallbladder stones;
 fatty liver (build up of fat in liver cells);

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80

 night sweats;
 scar;
 abnormal muscle breakdown;
 systemic lupus erythematosus (including inflammation of skin, heart, lung, joints and other organ 

systems);
 sleep interruptions;
 impotence;
 inflammations.

Rare (may affect up to 1 in 1,000 people):
 leukaemia (cancer affecting the blood and bone marrow);
 severe allergic reaction with shock;
 multiple sclerosis;
 nerve disorders (such as inflammation of the optic nerve to the eye and Guillain-Barré syndrome, a 

condition that may cause muscle weakness, abnormal sensations, tingling in the arms and upper body);
 heart stops pumping;
 pulmonary fibrosis (scarring of the lung);
 intestinal perforation;
 hepatitis;
 reactivation of hepatitis B;
 autoimmune hepatitis (inflammation of the liver caused by the body's own immune system);
 cutaneous vasculitis (inflammation of blood vessels in the skin);
 Stevens-Johnson syndrome (early symptoms include malaise, fever, headache and rash);
 facial oedema associated with allergic reactions;
 erythema multiforme (inflammatory skin rash);
 lupus-like syndrome;
 angioedema (localised swelling of the skin)
 lichenoid skin reaction (itchy reddish-purple skin rash).

Not known (frequency cannot be estimated from available data):
 hepatosplenic T-cell lymphoma (a rare blood cancer that is often fatal);
 Merkel cell carcinoma (a type of skin cancer);
 liver failure;
 worsening of a condition called dermatomyositis (seen as a skin rash accompanying muscle weakness).

Some side effects observed with adalimumab may not have symptoms and may only be discovered through 
blood tests. These include:

Very common (may affect more than 1 in 10 people):
 low blood measurements for white blood cells;
 low blood measurements for red blood cells;
 increased lipids in the blood;
 raised liver enzymes.

Common (may affect up to 1 in 10 people):
 high blood measurements for white blood cells;
 low blood measurements for platelets;
 increased uric acid in the blood;
 abnormal blood measurements for sodium;
 low blood measurements for calcium;
 low blood measurements for phosphate;
 high blood sugar;
 high blood measurements for lactate dehydrogenase;
 autoantibodies present in the blood;

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 low blood potassium.

Uncommon (may affect up to 1 in 100 people):
 elevated bilirubin measurement (liver blood test).

Rare (may affect up to 1 in 1,000 people):
 low blood measurements for white blood cells, red blood cells and platelet count.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed 
in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix 
V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Cyltezo

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label/blister/carton after EXP. The 
expiry date refers to the last day of that month.

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

Alternative Storage:

When needed (for example when you are travelling), a single Cyltezo pre-filled syringe may be stored at 
room temperature (up to 25°C) for a maximum period of 14 days – be sure to protect it from light. Once 
removed from the refrigerator for room temperature storage, the syringe must be used within 14 days or 
discarded, even if it is returned to the refrigerator.

You should record the date when the syringe is first removed from refrigerator and the date after which it 
should be discarded.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Cyltezo contains 

The active substance is adalimumab.
The other ingredients are sodium acetate trihydrate, glacial acetic acid, trehalose dihydrate, polysorbate 80 
and water for injections.

What Cyltezo looks like and contents of the pack

Cyltezo 40 mg solution for injection (injection) in pre-filled syringe is supplied as a sterile 0.8 mL clear to 
slightly opalescent solution of 40 mg adalimumab.

The Cyltezo pre-filled syringe is made of glass. Each pack contains 1, 2, 4 or 6 pre-filled syringes for patient 
use with 2, 2, 4 or 6 alcohol pads, respectively. Not all pack sizes may be marketed.

Cyltezo may be available as a pre-filled syringe and/or a pre-filled pen.

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


82

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
D-88397 Biberach an der Riss
Germany

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For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp.zo.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucureşti
Tel: +40 21 302 28 00

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211

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84

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG 
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last revised in MM/YYYY.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

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http://www.ema.europa.eu


85

7. Instructions for use

 The following instructions explain how to give yourself a subcutaneous injection of CYLTEZO using 
the pre-filled syringe. First read all the instructions carefully and then follow them step by step.

 You will be instructed by your doctor, nurse or pharmacist on the technique of self-injection.

 DO NOT attempt to self-inject until you are sure that you understand how to prepare and give the 
injection.

 After proper training, the injection can be given by yourself or given by another person, for example, a 
family member or friend.

 Only use each pre-filled syringe for one injection.

 Keep out of reach of children.

Cyltezo Pre-filled Syringe.

The Cyltezo pre-filled syringe is a single-use syringe that delivers a pre-set dose of medication.

 DO NOT remove cap until right before injection (step 6).

1) Gather supplies

Gather supplies onto clean, flat surface:
a. One Cyltezo pre-filled syringe, removed from refrigerator. Wait 30 minutes for medication to 

warm. Injecting medication that is cold can cause discomfort.
b. “Sharps” container (not included)
c. Cotton ball or gauze (not included)
d. Alcohol wipe

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86

If you do not have all the supplies listed above, contact your pharmacist before proceeding.

2) Inspect pre-filled syringe

 Inspect Cyltezo pre-filled syringe, medication, and expiration date.
 It is normal to see an air bubble. The air bubble does not need to be removed prior to injection.
 DO NOT use pre-filled syringe if:

o Expiration date on pre-filled syringe or carton has passed
o Medication is cloudy, discolored, frozen, or contains flakes or particles
o Pre-filled syringe appears cracked, damaged, or leaking
o Pre-filled syringe has already been used
o Pre-filled syringe has been left in direct light

3) Wash hands

 Wash your hands with soap and water, then dry them completely.

4) Select injection site

 Select an area on the upper thighs or abdomen/belly (at least 5 centimetres away from navel).
 Select a different site each time you inject at least 2.5 centimetres away from a previous site.
 Do not select tender, bruised, or scarred areas.

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87

 Do not inject through clothes.

5) Clean injection site

 Use alcohol wipe to clean selected injection site.
 Do not touch this area again before injecting.

6) Remove cap

 Gently remove cap by pulling it straight off. Do not touch needle or let needle touch anything.
 Discard cap into “sharps” container.
 Do not attempt to recap needle.

7) Squeeze skin

 Gently squeeze skin around cleaned injection site and hold firmly. You will inject into this raised area of 
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8) Insert needle

 Hold syringe at about a 45 degree angle to injection site, then insert needle into skin with a quick, 
smooth motion.

9) Inject medication

 Using your thumb, slowly push plunger down until all medication in syringe has been delivered. 
Plunger should reach bottom of syringe.

10) Remove needle from skin

 Remove needle from skin at the same angle you inserted it (45 degree angle).
 Do not touch the needle.
 If needed, press cotton ball or gauze over injection site to stop any bleeding.
 Do not rub the injection site.

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11) Discard pre-filled syringe

 Discard Cyltezo pre-filled syringe into “sharps” container. 
 Do not reuse a used pre-filled syringe.
 Always keep “sharps” container out of sight and reach of children.
 DO NOT throw away (dispose of) pre-filled syringes in your household trash.

If something goes wrong with the injection, do not use another Cyltezo pre-filled syringe. Call your 
healthcare professional.

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90

Package leaflet: Information for the patient

Cyltezo 40 mg solution for injection in pre-filled pen
Adalimumab

This medicine is subject to additional monitoring. This will allow quick identification of new safety 
information. You can help by reporting any side effects you may get. See the end of section 4 for how to 
report side effects.

Read all of this leaflet carefully before you start using this medicine because it contains important 
information for you.
- Keep this leaflet. You may need to read it again.
- Your doctor will also give you a Patient Alert Card, which contains important safety information that 

you need to be aware of before you are given Cyltezo and during treatment with Cyltezo. Keep this 
Patient Alert Card with you.

- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. See section 4.

What is in this leaflet

1. What Cyltezo is and what it is used for
2. What you need to know before you use Cyltezo
3. How to use Cyltezo
4. Possible side effects
5. How to store Cyltezo
6. Contents of the pack and other information
7. Instructions for use

1. What Cyltezo is and what it is used for

Cyltezo contains the active substance adalimumab, a medicine that acts on your body’s immune (defence) 
system. 

Cyltezo is intended for the treatment of the inflammatory diseases described below:
 Rheumatoid arthritis, 
 Polyarticular juvenile idiopathic arthritis, 
 Enthesitis-related arthritis, 
 Ankylosing spondylitis, 
 Axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, 
 Psoriatic arthritis, 
 Psoriasis, 
 Hidradenitis suppurativa, 
 Crohn’s disease,
 Ulcerative colitis and 
 Non-infectious uveitis

The active ingredient in Cyltezo, adalimumab, is a monoclonal antibody. Monoclonal antibodies are proteins 
that attach to a specific target. 

The target of adalimumab is a protein called tumour necrosis factor (TNFα), which is present at increased 
levels in the inflammatory diseases listed above. By attaching to TNFα, Cyltezo decreases the process of 
inflammation in these diseases.

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Rheumatoid arthritis

Rheumatoid arthritis is an inflammatory disease of the joints.

Cyltezo is used to treat rheumatoid arthritis in adults. If you have moderate to severe active rheumatoid 
arthritis, you may first be given other disease-modifying medicines, such as methotrexate. If these medicines
do not work well enough, you will be given Cyltezo to treat your rheumatoid arthritis.

Cyltezo can also be used to treat severe, active and progressive rheumatoid arthritis without previous 
methotrexate treatment. 

Cyltezo can slow down the damage to the cartilage and bone of the joints caused by the disease and improve 
physical function.

Usually, Cyltezo is used with methotrexate. If your doctor considers that methotrexate is inappropriate, 
Cyltezo can be given alone.

Polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis

Polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis are inflammatory diseases of the 
joints that usually first appear in childhood.

Cyltezo is used to treat polyarticular juvenile idiopathic arthritis in children and adolescents aged 2 to 17 
years and enthesitis-related arthritis in children and adolescents aged 6 to 17 years. Patients may first be 
given other disease-modifying medicines, such as methotrexate. If these medicines do not work well enough, 
patients will be given Cyltezo to treat their polyarticular juvenile idiopathic arthritis or enthesitis-related 
arthritis.

Ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis

Ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, 
are inflammatory diseases of the spine.

Cyltezo is used to treat ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of 
ankylosing spondylitis in adults. If you have ankylosing spondylitis or axial spondyloarthritis without 
radiographic evidence of ankylosing spondylitis, you will first be given other medicines. If these medicines
do not work well enough, you will be given Cyltezo to reduce the signs and symptoms of your disease.

Psoriatic arthritis

Psoriatic arthritis is an inflammatory disease of the joints associated with psoriasis.

Cyltezo is used to treat psoriatic arthritis in adults. Cyltezo can slow down the damage to the cartilage and 
bone of the joints caused by the disease and improve physical function.

Plaque psoriasis in adults and children

Plaque psoriasis is an inflammatory skin condition that causes red, flaky, crusty patches of skin covered with 
silvery scales. Plaque psoriasis can also affect the nails, causing them to crumble, become thickened and lift
away from the nail bed which can be painful. Psoriasis is believed to be caused by a problem with the body’s 
immune system that leads to an increased production of skin cells.

Cyltezo is used to treat moderate to severe plaque psoriasis in adults. Cyltezo is also used to treat severe 
plaque psoriasis in children and adolescents aged 4 to 17 years for whom topical therapy and phototherapies 
have either not worked very well or are not suitable. 

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Hidradenitis suppurativa in adults and adolescents

Hidradenitis suppurativa (sometimes called acne inversa) is a chronic and often painful inflammatory skin 
disease. Symptoms may include tender nodules (lumps) and abscesses (boils) that may leak pus. It most 
commonly affects specific areas of the skin, such as under the breasts, the armpits, inner thighs, groin and 
buttocks. Scarring may also occur in affected areas.

Cyltezo is used to treat hidradenitis suppurativa in adults and adolescents from 12 years of age. 
Cyltezo can reduce the number of nodules and abscesses you have and the pain that is often associated with 
the disease. You may first be given other medicines. If these medicines do not work well enough, you will be 
given Cyltezo.

Crohn’s disease in adults and children

Crohn’s disease is an inflammatory disease of the digestive tract.

Adalimumab is used to treat Crohn’s disease in adults and children aged 6 to 17 years. If you have Crohn’s 
disease you will first be given other medicines. If these medicines do not work well enough, you will be 
given Cyltezo to reduce the signs and symptoms of your Crohn’s disease.

Ulcerative colitis

Ulcerative colitis is an inflammatory disease of the bowel.

Cyltezo is used to treat ulcerative colitis in adults. If you have ulcerative colitis you will first be given other 
medicines. If these medicines do not work well enough, you will be given Cyltezo to reduce the signs and 
symptoms of your disease.

Non-infectious uveitis in adults and children

Non-infectious uveitis is an inflammatory disease affecting certain parts of the eye. Cyltezo works by 
reducing this inflammation.

Cyltezo is used to treat
 Adults with non-infectious uveitis with inflammation affecting the back of the eye
 Children from 2 years of age with chronic non-infectious uveitis with inflammation affecting the

front of the eye

This inflammation may lead to a decrease of vision and/or the presence of floaters in the eye (black dots or 
wispy lines that move across the field of vision). 

2. What you need to know before you use Cyltezo

Do not use Cyltezo

 If you are allergic to adalimumab or any of the other ingredients of this medicine (listed in section 6).

 If you have a severe infection, including tuberculosis (see “Warnings and precautions”). It is important 
that you tell your doctor if you have symptoms of infections, e.g. fever, wounds, feeling tired, dental 
problems. 

 If you have moderate or severe heart failure. It is important to tell your doctor if you have had or have a 
serious heart condition (see “Warnings and precautions”).

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Warnings and precautions

Talk to your doctor or pharmacist before using Cyltezo

Allergic reaction

 If you have allergic reactions with symptoms such as chest tightness, wheezing, dizziness, swelling or 
rash do not inject more Cyltezo and contact your doctor immediately since, in rare cases, these reactions 
can be life threatening.

Infection

 If you have an infection, including long-term or localised infection (for example, leg ulcer) consult your 
doctor before starting Cyltezo. If you are unsure, contact your doctor.

 You might get infections more easily while you are receiving Cyltezo treatment. This risk may increase 
if your lung function is impaired. These infections may be serious and include tuberculosis, infections 
caused by viruses, fungi, parasites or bacteria, other opportunistic infections (unusual infections 
associated with a weakened immune system) and sepsis (blood poisoning). In rare cases, these 
infections may be life-threatening. It is important to tell your doctor if you get symptoms such as fever, 
wounds, feeling tired or dental problems. Your doctor may recommend temporary discontinuation of 
Cyltezo.

Tuberculosis

 As cases of tuberculosis have been reported in patients treated with adalimumab, your doctor will check 
you for signs and symptoms of tuberculosis before starting Cyltezo. This will include a thorough 
medical evaluation including your medical history and screening tests (for example chest X-ray and a 
tuberculin test). The conduct and results of these tests should be recorded on your patient alert card. It is 
very important that you tell your doctor if you have ever had tuberculosis, or if you have been in close 
contact with someone who has had tuberculosis. Tuberculosis can develop during therapy even if you 
have received preventative treatment for tuberculosis. If symptoms of tuberculosis (persistent cough, 
weight loss, listlessness, mild fever), or any other infection appear during or after therapy tell your 
doctor immediately.

Travel/recurrent infection

 Tell your doctor if you reside or travel in regions where fungal infections such as histoplasmosis,
coccidioidomycosis or blastomycosis are endemic.

 Tell your doctor if you have a history of recurrent infections or other conditions that increase the risk of 
infections.

Hepatitis B virus

 Tell your doctor if you are a carrier of the hepatitis B virus (HBV), if you have an active HBV infection 
or if you think you might be at risk of contracting HBV. Your doctor should test you for HBV. Cyltezo
can reactivate HBV infection in people who carry this virus. In some rare cases, especially if you are 
taking other medicines that suppress the immune system, reactivation of HBV infection can be life-
threatening. 

Age over 65 years

 If you are over 65 years you may be more susceptible to infections while taking Cyltezo. You and your 
doctor should pay special attention to signs of infection while you are being treated with Cyltezo. It is 

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important to tell your doctor if you get symptoms of infections, such as fever, wounds, feeling tired or 
dental problems.

Surgery or dental procedure

 If you are about to have a surgery or dental procedures, tell your doctor that you are taking Cyltezo. 
Your doctor may recommend temporary discontinuation of Cyltezo.

Demyelinating disease

 If you have or develop a demyelinating disease (a disease that affects the insulating layer around the 
nerves, such as multiple sclerosis), your doctor will decide if you should receive or continue to receive 
Cyltezo. Tell your doctor immediately if you get symptoms like changes in your vision, weakness in 
your arms or legs or numbness or tingling in any part of your body.

Vaccine

 Certain vaccines contain weakened but live forms of bacteria or viruses that cause diseases, and should 
not be given while receiving Cyltezo because they may cause infections. Check with your doctor before 
you receive any vaccines. It is recommended that children, if possible, be given all the scheduled 
vaccinations for their age before they start treatment with Cyltezo. If you received Cyltezo while you 
are pregnant, your baby may be at higher risk for getting an infection for up to about five months after 
the last dose you received during pregnancy. It is important that you tell your baby's doctors and other 
health care professionals about your Cyltezo use during your pregnancy so they can decide when your 
baby should receive any vaccine.

Heart Failure

 If you have mild heart failure and you are being treated with Cyltezo, your heart failure status must be 
closely monitored by your doctor. It is important to tell your doctor if you have had or have a serious 
heart condition. If you develop new or worsening symptoms of heart failure (e.g. shortness of breath, or 
swelling of your feet), you must contact your doctor immediately. Your doctor will decide if you should 
receive Cyltezo.

Fever, bruising, bleeding or looking pale

 In some patients the body may fail to produce enough of the blood cells to fight off infections or help 
you to stop bleeding. If you develop a fever that does not go away, or you bruise or bleed very easily or 
look very pale, call your doctor right away. Your doctor may decide to stop treatment.

Cancer

 There have been very rare cases of certain kinds of cancer in children and adults taking adalimumab or 
other TNFα blockers. People with more serious rheumatoid arthritis who have had the disease for a long 
time may have a higher than average risk of getting lymphoma (a cancer that affects the lymph system), 
and leukaemia (a cancer that affects the blood and bone marrow). If you take Cyltezo the risk of getting 
lymphoma, leukaemia, or other cancers may increase. On rare occasions, a specific and severe type of 
lymphoma has been observed in patients taking adalimumab. Some of those patients were also treated 
with the medicines azathioprine or mercaptopurine. Tell your doctor if you are taking azathioprine or 
mercaptopurine with Cyltezo. 

 In addition cases of non-melanoma skin cancer have been observed in patients taking adalimumab. If 
new areas of damaged skin appear during or after therapy or if existing marks or areas of damage
change appearance, tell your doctor.

 There have been cases of cancers other than lymphoma in patients with a specific type of lung disease 
called chronic obstructive pulmonary disease (COPD) treated with another TNFα blocker. If you have 

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COPD, or you are a heavy smoker, you should discuss with your doctor whether treatment with a TNFα
blocker is appropriate for you.

Lupus-like syndrome

 On rare occasions, treatment with Cyltezo could result in lupus-like syndrome. Contact your doctor if 
symptoms such as persistent unexplained rash, fever, joint pain or tiredness occur.

Children and adolescents

 Vaccinations: if possible children should be up to date with all vaccinations before using Cyltezo.
 Do not give Cyltezo to children with polyarticular juvenile idiopathic arthritis below the age of 2 years.
 Do not use the 40 mg pre-filled pen, if doses other than 40 mg are recommended.

Other medicines and Cyltezo

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Cyltezo can be taken together with methotrexate or certain disease-modifying anti-rheumatic agents 
(sulfasalazine, hydroxychloroquine, leflunomide and injectable gold preparations), corticosteroids or pain 
medications including non-steroidal anti-inflammatory drugs (NSAIDs).

You should not take Cyltezo with medicines containing the active substances anakinra or abatacept due to
increased risk of serious infection. If you have questions, please ask your doctor.

Pregnancy and breast-feeding

 You should consider the use of adequate contraception to prevent pregnancy and continue its use for 
at least 5 months after the last Cyltezo treatment.

 If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for
advice about taking this medicine.

 Cyltezo should only be used during a pregnancy if needed.
 According to a pregnancy study, there was no higher risk of birth defects when the mother had

received adalimumab during pregnancy compared with mothers with the same disease who did not
receive adalimumab.

 Cyltezo can be used during breast-feeding.
 If you receive Cyltezo during your pregnancy, your baby may have a higher risk for getting an

infection.
 It is important that you tell your baby’s doctors and other health care professionals about your

Cyltezo use during your pregnancy before the baby receives any vaccine. For more information on 
vaccines see the “Warnings and precautions” section).

Driving and using machines

Cyltezo may have a minor influence on your ability to drive, cycle or use machines. Room spinning 
sensation (vertigo) and vision disturbances may occur after taking Cyltezo.

The needle cover of the syringe contains latex

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

Cyltezo contains sodium

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8 mL dose, i.e. essentially 
‘sodium-free’.

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3. How to use Cyltezo

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or 
pharmacist if you are not sure.

Adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis
without radiographic evidence of ankylosing spondylitis

The usual dose for adults with rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without 
radiographic evidence of ankylosing spondylitis and for patients with psoriatic arthritis is 40 mg adalimumab 
given every other week as a single dose.

In rheumatoid arthritis, methotrexate is continued while using Cyltezo. If your doctor determines that 
methotrexate is inappropriate, Cyltezo can be given alone.

If you have rheumatoid arthritis and you do not receive methotrexate with your Cyltezo therapy, your doctor 
may decide to give 40 mg adalimumab every week or 80 mg every other week.

Children, adolescents and adults with polyarticular juvenile idiopathic arthritis

Children and adolescents from 2 years of age weighing 10 kg to less than 30 kg

Cyltezo is only available as 40 mg pre-filled syringe and pre-filled pen. Thus, it is not possible to use Cyltezo 
for children who require less than a full 40 mg dose. If an alternate dose is required, other adalimumab 
products offering such an option should be used.

Children, adolescents and adults from 2 years of age weighing 30 kg or more

The recommended dose of Cyltezo is 40 mg every other week.

Children, adolescents and adults with enthesitis-related arthritis

Children and adolescents from 6 years of age weighing 15 kg to less than 30 kg

Cyltezo is only available as 40 mg pre-filled syringe and pre-filled pen. Thus, it is not possible to use Cyltezo 
for children who require less than a full 40 mg dose. If an alternate dose is required, other adalimumab 
products offering such an option should be used.

Children, adolescents and adults from 6 years of age weighing 30 kg or more

The recommended dose of Cyltezo is 40 mg every other week.

Adults with psoriasis

The usual dose for adults with psoriasis is an initial dose of 80 mg (as two 40 mg injections in one day), 
followed by 40 mg given every other week starting one week after the initial dose. You should continue to 
inject Cyltezo for as long as your doctor has told you. Depending on your response, your doctor may 
increase the dosage to 40 mg every week or 80 mg every other week.

Children and adolescents with plaque psoriasis

Children and adolescents from 4 to 17 years of age weighing 15 kg to less than 30 kg

Cyltezo is only available as 40 mg pre-filled syringe and pre-filled pen. Thus, it is not possible to use Cyltezo 
for children who require less than a full 40 mg dose. If an alternate dose is required, other adalimumab 
products offering such an option should be used.

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Children and adolescents from 4 to 17 years of age weighing 30 kg or more

The recommended dose of Cyltezo is an initial dose of 40 mg, followed by 40 mg one week later. Thereafter, 
the usual dose is 40 mg every other week.

Adults with hidradenitis suppurativa

The usual dose regimen for hidradenitis suppurativa is an initial dose of 160 mg (as four 40 mg injections in 
one day or two 40 mg injections per day for two consecutive days), followed by an 80 mg dose (as two
40 mg injections in one day) two weeks later. After two further weeks, continue with a dosage of 40 mg
every week or 80 mg every other week, as prescribed by your doctor. It is recommended that you use an 
antiseptic wash daily on the affected areas.

Adolescents with hidradenitis suppurativa from 12 to 17 years of age weighing 30 kg or more

The recommended dose of Cyltezo is an initial dose of 80 mg (as two 40 mg injections in one day), followed 
by 40 mg every other week starting one week later. If this dose does not work well enough, your doctor may 
increase the dosage to 40 mg every week or 80 mg every other week. 

It is recommended that you use an antiseptic wash daily on the affected areas.

Adults with Crohn’s disease

The usual dose regimen for Crohn’s disease is 80 mg (as two 40 mg injections in one day) initially followed 
by 40 mg every other week starting two weeks later. If a faster effect is required your doctor may prescribe 
an initial dose of 160 mg (as four 40 mg injections in one day or two 40 mg injections per day for two 
consecutive days), followed by 80 mg (as two 40 mg injections in one day) two weeks later, and thereafter as 
40 mg every other week. If this dose does not work well enough, your doctor may increase the dosage to 
40 mg every week or 80 mg every other week.

Children and adolescents with Crohn's disease

Children and adolescents from 6 to 17 years of age weighing less than 40 kg

Cyltezo is only available as 40 mg pre-filled syringe and pre-filled pen. Thus, it is not possible to use Cyltezo 
for children who require less than a full 40 mg dose. If an alternate dose is required, other adalimumab 
products offering such an option should be used.

Children and adolescents from 6 to 17 years of age weighing 40 kg or more

The usual dose regimen is 80 mg (as two 40 mg injections in one day) initially followed by 40 mg two weeks 
later. If a faster response is required, your doctor may prescribe an initial dose of 160 mg (as four 40 mg
injections in one day or as two 40 mg injections per day for two consecutive days) followed by 80 mg (as 
two 40 mg injections in one day) two weeks later.

Thereafter, the usual dose is 40 mg every other week. If this dose does not work well enough, your doctor 
may increase the dosage to 40 mg every week or 80 mg every other week.

Adults with ulcerative colitis

The usual Cyltezo dose for adults with ulcerative colitis is 160 mg (as four 40 mg injections in one day or as 
two 40 mg injections per day for two consecutive days) at week 0 and 80 mg (as two 40 mg injections in one 
day) at week 2 and thereafter 40 mg every other week. If this dose does not work well enough, your doctor 
may increase the dosage to 40 mg every week or 80 mg every other week.

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Adults with non-infectious uveitis

The usual dose for adults with non-infectious uveitis is an initial dose of 80 mg (as two injections in one
day), followed by 40 mg given every other week starting one week after the initial dose. You should 
continue to inject Cyltezo for as long as your doctor has told you.

In non-infectious uveitis, corticosteroids or other medicines that influence the immune system may be
continued while using Cyltezo. Cyltezo can also be given alone.

Children and adolescents with chronic non-infectious uveitis from 2 years of age

Children and adolescents from 2 years of age weighing less than 30 kg

Cyltezo is only available as 40 mg pre-filled syringe and pre-filled pen. Thus, it is not possible to use Cyltezo 
for children who require less than a full 40 mg dose. If an alternate dose is required, other adalimumab 
products offering such an option should be used.

Children and adolescents from 2 years of age weighing 30 kg or more

The usual dose of Cyltezo is 40 mg every other week with methotrexate.

Your doctor may also prescribe an initial dose of 80 mg which may be administered one week prior to the
start of the usual dose.

Method and route of administration

Cyltezo is administered by injection under the skin (by subcutaneous injection).

Detailed instructions on how to inject Cyltezo are provided in section 7 ‘Instructions for use’.

If you use more Cyltezo than you should

If you accidentally inject Cyltezo more frequently than you should, call your doctor or pharmacist and 
explain that you have taken more. Always take the outer carton of the medicine with you, even if it is empty.

If you forget to use Cyltezo

If you forget to give yourself an injection, you should inject the next dose of Cyltezo as soon as you 
remember. Then take your next dose as you would have on your originally scheduled day, had you not 
forgotten a dose.

If you stop using Cyltezo

The decision to stop using Cyltezo should be discussed with your doctor. Your symptoms may return upon 
stopping treatment.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Most side effects 
are mild to moderate. However, some may be serious and require treatment. Side effects may occur up to 4 
months or more after the last Cyltezo injection.

Seek medical attention urgently, if you notice any of the following:
 severe rash, hives or other signs of allergic reaction;

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 swollen face, hands, feet;
 trouble breathing, swallowing;
 shortness of breath with exertion or upon lying down or swelling of the feet.

Tell your doctor as soon as possible, if you notice any of the following:
 signs of infection such as fever, feeling sick, wounds, dental problems, burning on urination;
 feeling weak or tired;
 coughing;
 tingling;
 numbness;
 double vision;
 arm or leg weakness;
 a bump or open sore that doesn't heal;
 signs and symptoms suggestive of blood disorders such as persistent fever, bruising, bleeding, paleness.

The symptoms described above can be signs of the below listed side effects, which have been observed with 
adalimumab.

Very common (may affect more than 1 in 10 people):
 injection site reactions (including pain, swelling, redness or itching);
 respiratory tract infections (including cold, runny nose, sinus infection, pneumonia);
 headache;
 abdominal (belly) pain;
 nausea and vomiting;
 rash;
 pain in the muscles.

Common (may affect up to 1 in 10 people):
 serious infections (including blood poisoning and influenza);
 intestinal infections (including gastroenteritis);
 skin infections (including cellulitis and shingles);
 ear infections;
 mouth infections (including tooth infections and cold sores);
 reproductive tract infections;
 urinary tract infection;
 fungal infections;
 joint infections;
 benign tumours;
 skin cancer;
 allergic reactions (including seasonal allergy);
 dehydration;
 mood swings (including depression);
 anxiety;
 difficulty sleeping;
 sensation disorders such as tingling, prickling or numbness;
 migraine;
 symptoms of nerve root compression (including low back pain and leg pain);
 vision disturbances;
 eye inflammation;
 inflammation of the eyelid and eye swelling;
 vertigo (sensation of the room spinning);
 sensation of heart beating rapidly;
 high blood pressure;
 flushing;

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 haematoma (a solid sweling with clotted blood);
 cough;
 asthma;
 shortness of breath;
 gastrointestinal bleeding;
 dyspepsia (indigestion, bloating, heart burn);
 acid reflux disease;
 sicca syndrome (including dry eyes and dry mouth);
 itching;
 itchy rash;
 bruising;
 inflammation of the skin (such as eczema);
 breaking of finger nails and toe nails;
 increased sweating;
 hair loss;
 new onset or worsening of psoriasis;
 muscle spasms;
 blood in urine;
 kidney problems;
 chest pain;
 oedema (a build up of fluid in the body which causes the affected tissue to swell);
 fever;
 reduction in blood platelets which increases risk of bleeding or bruising;
 impaired healing.

Uncommon (may affect up to 1 in 100 people):
 opportunistic infections (which include tuberculosis and other infections that occur when resistance to 

disease is lowered);
 neurological infections (including viral meningitis);
 eye infections;
 bacterial infections;
 diverticulitis (inflammation and infection of the large intestine);
 cancer;
 including cancer of the lymph system (lymphoma) and
 melanoma (a type of skin cancer);
 immune disorders that could affect the lungs, skin and lymph nodes (most commonly as a condition 

called sarcoidosis);
 vasculitis (inflammation of blood vessels);
 tremor;
 neuropathy (nerve damage);
 stroke;
 hearing loss, buzzing;
 sensation of heart beating irregularly such as skipped beats;
 heart problems that can cause shortness of breath or ankle swelling;
 heart attack;
 a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel;
 lung diseases causing shortness of breath (including inflammation);
 pulmonary embolism (blockage in an artery of the lung);
 pleural effusion (abnormal collection of fluid in the pleural space);
 inflammation of the pancreas which causes severe pain in the abdomen and back;
 difficulty in swallowing;
 facial oedema;
 gallbladder inflammation, gallbladder stones;
 fatty liver (build up of fat in liver cells);

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 night sweats;
 scar;
 abnormal muscle breakdown;
 systemic lupus erythematosus (including inflammation of skin, heart, lung, joints and other organ 

systems);
 sleep interruptions;
 impotence;
 inflammations.

Rare (may affect up to 1 in 1,000 people):
 leukaemia (cancer affecting the blood and bone marrow);
 severe allergic reaction with shock;
 multiple sclerosis;
 nerve disorders (such as inflammation of the optic nerve to the eye and Guillain-Barré syndrome, a 

condition that may cause muscle weakness, abnormal sensations, tingling in the arms and upper body);
 heart stops pumping;
 pulmonary fibrosis (scarring of the lung);
 intestinal perforation;
 hepatitis;
 reactivation of hepatitis B;
 autoimmune hepatitis (inflammation of the liver caused by the body's own immune system);
 cutaneous vasculitis (inflammation of blood vessels in the skin);
 Stevens-Johnson syndrome (early symptoms include malaise, fever, headache and rash);
 facial oedema associated with allergic reactions;
 erythema multiforme (inflammatory skin rash);
 lupus-like syndrome;
 angioedema (localised swelling of the skin);
 lichenoid skin reaction (itchy reddish-purple skin rash).

Not known (frequency cannot be estimated from available data):
 hepatosplenic T-cell lymphoma (a rare blood cancer that is often fatal);
 Merkel cell carcinoma (a type of skin cancer);
 liver failure;
 worsening of a condition called dermatomyositis (seen as a skin rash accompanying muscle weakness).

Some side effects observed with adalimumab may not have symptoms and may only be discovered through 
blood tests. These include:

Very common (may affect more than 1 in 10 people):
 low blood measurements for white blood cells;
 low blood measurements for red blood cells;
 increased lipids in the blood;
 raised liver enzymes.

Common (may affect up to 1 in 10 people):
 high blood measurements for white blood cells;
 low blood measurements for platelets;
 increased uric acid in the blood;
 abnormal blood measurements for sodium;
 low blood measurements for calcium;
 low blood measurements for phosphate;
 high blood sugar;
 high blood measurements for lactate dehydrogenase;
 autoantibodies present in the blood;

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 low blood potassium.

Uncommon (may affect up to 1 in 100 people):
 elevated bilirubin measurement (liver blood test).

Rare (may affect up to 1 in 1,000 people):
 low blood measurements for white blood cells, red blood cells and platelet count.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed 
in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix 
V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Cyltezo

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label/blister/carton after EXP. The 
expiry date refers to the last day of that month.

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.

Alternative Storage:

When needed (for example when you are travelling), a single Cyltezo pre-filled pen may be stored at room 
temperature (up to 25°C) for a maximum period of 14 days – be sure to protect it from light. Once removed 
from the refrigerator for room temperature storage, the pen must be used within 14 days or discarded, even 
if it is returned to the refrigerator.

You should record the date when the pen is first removed from refrigerator and the date after which it should 
be discarded.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Cyltezo contains 

The active substance is adalimumab.
The other ingredients are sodium acetate trihydrate, glacial acetic acid, trehalose dihydrate, polysorbate 80 
and water for injections.

What Cyltezo looks like and contents of the pack

Cyltezo 40 mg solution for injection (injection) in pre-filled pen is supplied as a sterile 0.8 mL clear to 
slightly opalescent solution of 40 mg adalimumab.

The Cyltezo pre-filled pen is a single-use white- and green-coloured pen with a grey-coloured cap which 
contains a glass syringe with Cyltezo. There is a window on each side of the pen through which you can see 
the Cyltezo solution inside the syringe.

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


103

The Cyltezo pre-filled pen is available in packs containing 1, 2, 4 and 6 pre-filled pens. The 1 pre-filled pen 
pack comes with 2 alcohol pads (1 spare). For the 2, 4 and 6 pre-filled pen packs, each pre-filled pen comes 
with 1 alcohol pad. Not all pack sizes may be marketed.

Cyltezo may be available as a pre-filled syringe and/or a pre-filled pen.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
D-88397 Biberach an der Riss
Germany

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104

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp.zo.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucureşti
Tel: +40 21 302 28 00

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211

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105

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG 
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last revised in MM/YYYY.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

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http://www.ema.europa.eu


106

7. Instructions for use

 The following instructions explain how to give yourself a subcutaneous injection of CYLTEZO using 
the pre-filled pen. First read all the instructions carefully and then follow them step by step.

 You will be instructed by your doctor, nurse or pharmacist on the technique of self-injection.

 DO NOT attempt to self-inject until you are sure that you understand how to prepare and give the 
injection.

 After proper training, the injection can be given by yourself or given by another person, for example, a 
family member or friend.

 Only use each pre-filled pen for one injection.

 Keep out of reach of children.

Cyltezo Pre-filled Pen. 

The Cyltezo pen is a single-use pre-filled pen that delivers a pre-set dose of medication.

 DO NOT remove cap until right before injection (step 6).

1) Gather supplies

Gather supplies onto clean, flat surface:
a. One Cyltezo pre-filled pen, removed from refrigerator. Wait 30 minutes for medication to warm. 

Injecting medication that is cold can cause discomfort.
b. “Sharps” container (not included)
c. Cotton ball or gauze (not included)
d. Alcohol wipe

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107

If you do not have all the supplies listed above, contact your pharmacist before proceeding.

2) Inspect pen

 Inspect Cyltezo pen, medication and expiration date.
 It is normal to see one or more bubbles in the medication.
 DO NOT use Cyltezo pen if:

o Expiration date on pen or carton has passed
o Medication is cloudy, discoloured, frozen, or contains flakes or particles
o Pen appears cracked, damaged, or leaking
o Pen has already been used
o Pen was dropped
o Pen has been left in direct light

3) Wash hands

 Wash your hands with soap and water, then dry them completely.

4) Select injection site

 Select an area on the upper thighs or abdomen/belly (at least 5 centimetres away from navel).
 Select a different site each time you inject at least 2.5 centimetres away from a previous site.
 Do not select tender, bruised, or scarred areas.
 Do not inject through clothes.

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108

5) Clean injection site

 Use alcohol wipe to clean selected injection site.
 Do not touch this area again before injecting.

6) Remove cap

 Remove cap by pulling it straight off pen. Do not twist cap. Twisting cap could damage needle.
 Discard cap into “sharps” container.

7) Squeeze skin

 Gently squeeze skin around cleaned injection site and hold firmly. You will inject into this raised area of 
skin.

 Before injecting, read steps 8 A-C to learn correct way to administer dose.Me
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109

8) Before injecting, read steps A-C to learn correct way to administer dose.
A. Prepare to administer dose

 Hold pen straight up from injection site (at a 90 degree angle). Try not to cover the window with your 
hand.

 Press tip firmly against squeezed injection site. The injection button will unlock and be ready for use.

B. Administer dose

 Administer the entire dose:
o Press injection button once (you should hear a ‘click’ that indicates the start of injection) and keep 

pen pressed firmly against skin while you slowly count to 10.
o Do not move pen during injection.

 Before removing pen from skin, confirm entire dose was delivered by making sure plunger (seen in 
window) reached bottom of pen.

C. Remove pen

 Lift pen straight up from skin. The tip’s needle guard will automatically move down to cover the needle.
 If needed, press cotton ball or gauze over injection site to stop any bleeding.

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110

 Do not rub the injection site.

9) Discard pen

 Do not attempt to reuse a used Cyltezo pen.
 Discard entire Cyltezo pen into “sharps” container.
 Always keep “sharps” container out of sight and reach of children.

If something goes wrong with the injection, do not use another Cyltezo pen. Call your healthcare 
professional.

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A.	MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B.	CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.	OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D.	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET