Imraldi

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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 
 
Imraldi 40 mg solution for injection in pre-filled syringe 
Imraldi 40 mg solution for injection in pre-filled pen 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Imraldi 40 mg solution for injection in pre-filled syringe 
Each 0.8 ml single dose pre-filled syringe contains 40 mg of adalimumab. 
 
Imraldi 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. 
 
Excipient(s) with known effect 
 
This medicinal product contains 20.0 mg sorbitol. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection. 
Clear, colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rheumatoid arthritis 
 
Imraldi 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. 
 
Imraldi can be given as monotherapy in case of intolerance to methotrexate or when continued treatment 
with methotrexate is inappropriate. 
 
Adalimumab has been shown to reduce the rate of progression of joint damage as measured by X-ray and 
to improve physical function, when given in combination with methotrexate. 
 
Juvenile idiopathic arthritis 
 
Polyarticular juvenile idiopathic arthritis 
 



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Imraldi 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). Imraldi can be given as monotherapy in case of 
intolerance to methotrexate or when continued treatment with methotrexate is inappropriate (for the 
efficacy in monotherapy see section 5.1). Adalimumab has not been studied in patients aged less than 
2 years. 
 
Enthesitis-related arthritis 
 
Imraldi 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) 
 
Imraldi 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 
 
Imraldi 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 
 
Imraldi 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 
 
Imraldi is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who 
are candidates for systemic therapy. 
 
Paediatric plaque psoriasis 
 
Imraldi 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) 
 
Imraldi 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 
 
Imraldi 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. 



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Paediatric Crohn's disease 
 
Imraldi is indicated for the treatment of moderately to severely active Crohn's disease in paediatric 
patients (from 6 years of age) who have had an inadequate response to conventional therapy including 
primary nutrition therapy and a corticosteroid and/or an immunomodulator, or who are intolerant to or 
have contraindications for such therapies. 
 
Ulcerative colitis  
 
Imraldi 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 
 
Imraldi 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 
 
Imraldi 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 
 
Imraldi treatment should be initiated and supervised by specialist physicians experienced in the diagnosis 
and treatment of conditions for which Imraldi is indicated. Ophthalmologists are advised to consult with 
an appropriate specialist before initiation of treatment with Imraldi (see section 4.4). Patients treated with 
Imraldi should be given the Patient Reminder Card. 
 
After proper training in injection technique, patients may self-inject with Imraldi if their physician 
determines that it is appropriate and with medical follow-up as necessary. 
 
During treatment with Imraldi, other concomitant therapies (e.g., corticosteroids and/or 
immunomodulatory agents) should be optimised. 
 
Posology 
 
Rheumatoid arthritis 
 
The recommended dose of Imraldi 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 Imraldi. 
 
Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics can be continued during 
treatment with Imraldi. 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 Imraldi 40 mg every other 
week dosing may benefit from an increase in dosage to 40 mg adalimumab every week or 80 mg every 
other week. 
 



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



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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 Imraldi and signs and symptoms of disease recur, Imraldi may be 
re-administered. There is little experience from re-administration after more than 8 weeks since the 
previous dose. 
 
During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice 
guidelines. 
 
Some patients who experience decrease in their response to Imraldi 40 mg every other week may benefit 
from an increase in dosage to 40 mg Imraldi 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 Imraldi 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 Imraldi 40 mg every other week may benefit 
from an increase in dosage to 40 mg Imraldi every week or 80 mg every other week. 
 
Available data suggest that the clinical response is usually achieved within 2-8 weeks of treatment. 
Imraldi therapy should not be continued in patients failing to respond within this time period. 
 
Uveitis 
 
The recommended dose of Imraldi 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 Imraldi alone. Treatment with Imraldi 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 
Imraldi. 
 
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. 
 



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

Table 1. Imraldi Dose for Patients with Polyarticular Juvenile Idiopathic Arthritis  
Patient Weight Dosing Regimen 
10 kg to < 30 kg 20 mg every other week 

≥ 30 kg 40 mg every other week 
 
Available data suggest that clinical response is usually achieved within 12 weeks of treatment. Continued 
therapy should be carefully reconsidered in a patient not responding within this time period. 
 
There is no relevant use of adalimumab in patients aged less than 2 years for this indication. 
 
Enthesitis-related arthritis 
 
The recommended dose of Imraldi for patients with enthesitis-related arthritis from 6 years of age is based 
on body weight (Table 2). Imraldi is administered every other week via subcutaneous injection.  
 

Table 2. Imraldi Dose for Patients with Enthesitis-Related Arthritis 
 

Patient Weight Dosing Regimen 
15 kg to < 30 kg 20 mg every other week 

≥ 30 kg 40 mg every other week 
 
Adalimumab has not been studied in patients with enthesitis-related arthritis aged less than 6 years. 
 
Paediatric plaque psoriasis 
 
The recommended Imraldi dose for patients with plaque psoriasis from 4 to 17 years of age is based on 
body weight (Table 3). Imraldi is administered via subcutaneous injection.  
 

Table 3. Imraldi Dose for Paediatric Patients with Plaque Psoriasis 
 

Patient Weight Dosing Regimen 

15 kg to < 30 kg 

Initial dose of 20 mg, followed by 
20 mg given every other week 

starting one week after the initial 
dose 

≥ 30 kg 

Initial dose of 40 mg, followed by 
40 mg given every other week 

starting one week after the initial 
dose 

 
Continued therapy beyond 16 weeks should be carefully considered in a patient not responding within this 
time period. 
 
If retreatment with Imraldi is indicated, the above guidance on dose and treatment duration should be 
followed. 



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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 Imraldi 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 Imraldi 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 Imraldi 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 
Imraldi. 
 
Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no improvement 
within this time period. 
 
Should treatment be interrupted, Imraldi 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 Imraldi for patients with Crohn’s disease from 6 to 17 years of age is based on 
body weight (Table 4). Imraldi is administered via subcutaneous injection. 
 

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

Patient 
Weight 

Induction Dose Maintenance 
Dose 

Starting at 
Week 4 

< 40 kg 

• 40 mg at week 0 and 20 mg at week 2 
 
In case there is a need for a more rapid response to therapy with the 
awareness that the risk for adverse events may be higher with use of the 
higher induction dose, the following dose may be used: 
• 80 mg at week 0 and 40 mg at week 2 

20 mg every 
other week 

≥ 40 kg 

• 80 mg at week 0 and 40 mg at week 2 
 
In case there is a need for a more rapid response to therapy with the 
awareness that the risk for adverse events may be higher with use of the 
higher induction dose, the following dose may be used: 
• 160 mg at week 0 and 80 mg at week 2 

40 mg every 
other week 

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



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 < 40 kg: 20 mg every week 
 ≥ 40 kg: 40 mg every week or 80 mg every other week 
 
Continued therapy should be carefully considered in a subject not responding by week 12. 
 
There is no relevant use of adalimumab in children aged below 6 years for this indication. 
 
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 Imraldi 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 psoriatric arthritis. 
 
Paediatric uveitis 
 
The recommended dose of Imraldi for paediatric patients with uveitis from 2 years of age is based on 
body weight (Table 5). Imraldi is administered via subcutaneous injection. 
 
In paediatric uveitis, there is no experience in the treatment with adalimumab without concomitant 
treatment with methotrexate. 
 

Table 5 Imraldi Dose for Paediatric Patients with Uveitis 
 

Patient Weight Dosing Regimen 

< 30 kg 20 mg every other week in combination with methotrexate 

≥ 30 kg 40 mg every other week in combination with methotrexate 
 
When Imraldi 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). 
 
Method of administration  
 
Imraldi is administered by subcutaneous injection. Full instructions for use are provided in the package 
leaflet. 
 
A 40 mg pre-filled syringe and pre-filled pen are 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. 
 
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). 



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4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the 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 Imraldi. Because the elimination of 
adalimumab may take up to four months, monitoring should be continued throughout this period. 
 
Treatment with Imraldi 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 Imraldi 
should be considered prior to initiating therapy (see Other opportunistic infections). 
 
Patients who develop a new infection while undergoing treatment with Imraldi, should be monitored 
closely and undergo a complete diagnostic evaluation. Administration of Imraldi 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 Imraldi 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 Imraldi, all patients must be evaluated for both active or inactive 
(“latent”) tuberculosis infection. This evaluation should include a detailed medical assessment of patient 
history of tuberculosis or possible previous exposure to people with active tuberculosis and previous 
and/or current immunosuppressive therapy. Appropriate screening tests (i.e. tuberculin skin test and chest 
X-ray) should be performed in all patients (local recommendations may apply). It is recommended that the 
conduct and results of these tests are recorded in the Patient Reminder Card. Prescribers are reminded of 
the risk of false negative tuberculin skin test results, especially in patients who are severely ill or 
immunocompromised. 
 
If active tuberculosis is diagnosed, Imraldi therapy must not be initiated (see section 4.3). 
 
In all situations described below, the benefit/risk balance of therapy should be very carefully considered. 
 
If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be 
consulted. 



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If latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosis 
prophylaxis treatment before the initiation of Imraldi, and in accordance with local recommendations. 
 
Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of Imraldi 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 Imraldi. 
 
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 Imraldi 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 Imraldi. 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 Imraldi 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, Imraldi 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 Imraldi in patients 
with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders; 
discontinuation of Imraldi should be considered if any of these disorders develop. There is a known 
association between intermediate uveitis and central demyelinating disorders. Neurologic evaluation 
should be performed in patients with non-infectious intermediate uveitis prior to the initiation of Imraldi 
therapy and regularly during treatment to assess for pre-existing or developing central demyelinating 
disorders. 



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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 Imraldi should be 
discontinued immediately and appropriate therapy initiated. 
 
Immunosuppression 
 
In a study of 64 patients with rheumatoid arthritis that were treated with adalimumab, there was no 
evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change 
in enumeration of effector T-, B-, NK-cells, monocyte/macrophages, and neutrophils. 
 
Malignancies and lymphoproliferative disorders 
 
In the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies including 
lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. 
However, the occurrence was rare. In the post marketing setting, cases of leukaemia have been reported in 
patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and 
leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which 
complicates the risk estimation. With the current knowledge, a possible risk for the development of 
lymphomas, leukaemia, and other malignancies in patients treated with a TNF-antagonist cannot be 
excluded. 
 
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 
22 years of age) treated with TNF-antagonists (initiation of therapy ≤18 years of age), including 
adalimumab in the post marketing setting. Approximately half the cases were lymphomas. The other cases 
represented a variety of different malignancies and included rare malignancies usually associated with 
immunosuppression. A risk for the development of malignancies in children and adolescents treated with 
TNF-antagonists cannot be excluded. 
 
Rare postmarketing cases of hepatosplenic T-cell lymphoma have been identified in patients treated with 
adalimumab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. 
Some of these hepatosplenic T-cell lymphomas with adalimumab have occurred in young adult patients on 
concomitant treatment with azathioprine or 6-mercaptopurine used for inflammatory bowel disease. The 
potential risk with the combination of azathioprine or 6-mercaptopurine and adalimumab should be 
carefully considered. A risk for the development of hepatosplenic T-cell lymphoma in patients treated 
with Imraldi 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 adalimumab 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 Imraldi. Melanoma and Merkel cell carcinoma 
have also been reported in patients treated with TNF-antagonists including adalimumab (see section 4.8). 
 
In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patients with 
moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung 
or head and neck, were reported in infliximab-treated patients compared with control patients. All patients 
had a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist 
in COPD patients, as well as in patients with increased risk for malignancy due to heavy smoking. 
 



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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 Imraldi. Discontinuation of Imraldi 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 adalimumab 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. Imraldi should be used with caution in patients with mild 
heart failure (NYHA class I/II). Imraldi is contraindicated in moderate to severe heart failure (see section 
4.3). Treatment with Imraldi must be discontinued in patients who develop new or worsening symptoms 
of congestive heart failure. 
 
Autoimmune processes  
 
Treatment with Imraldi may result in the formation of autoimmune antibodies. The impact of long-term 
treatment with adalimumab on the development of autoimmune diseases is unknown. If a patient develops 
symptoms suggestive of a lupus-like syndrome following treatment with Imraldi and is positive for 
antibodies against double-stranded DNA, further treatment with Imraldi should not be given (see 
section 4.8). 
 
Concurrent administration of biologic DMARDS or TNF-antagonists  
 
Serious infections were seen in clinical studies with concurrent use of anakinra and another TNF-
antagonist, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature 
of the adverse events seen with the combination of etanercept and anakinra therapy, similar toxicities may 
also result from the combination of anakinra and other TNF-antagonists. Therefore, the combination of 
adalimumab and anakinra is not recommended. (See section 4.5). 
 
Concomitant administration of adalimumab with other biologic DMARDS (e.g, anakinra and abatacept) or 



14 
 

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 Imraldi 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 20 mg sorbitol in each pre-filled syringe/pre-filled pen. Patients with rare 
hereditary problems of fructose intolerance should not take this medicinal product. 
 
Also, 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 Imraldi and anakinra is not recommended (see section 4.4 “Concurrent administration 
of biologic DMARDS or TNF-antagonists”). 
 
The combination of Imraldi 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 Imraldi treatment. 
 
Pregnancy  



15 
 

 
A large number (approximately 2,100) of prospectively collected pregnancies exposed to adalimumab 
resulting in live birth with known outcomes, including more than 1,500 exposed during the first trimester, 
does not indicate an increase in the rate of malformation in the newborn. 
 
In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn’s disease (CD) 
treated with adalimumab at least during the first trimester and 120 women with RA or CD not treated with 
adalimumab were enrolled. The primary endpoint was the birth prevalence of major birth defects. The rate 
of pregnancies ending with at least one live born infant with a major birth defect was 6/69 (8.7 %) in the 
adalimumab-treated women with RA and 5/74 (6.8 %) in the untreated women with RA (unadjusted OR 
1.31, 95 % CI 0.38-4.52) and 16/152 (10.5 %) in the adalimumab-treated women with CD and 3/32 
(9.4 %) in the untreated women with CD (unadjusted OR 1.14, 95 % CI 0.31-4.16). The adjusted OR 
(accounting for baseline differences) was 1.10 (95 % CI 0.45-2.73) with RA and CD combined. There 
were no distinct differences between adalimumab-treated and untreated women for the secondary 
endpoints spontaneous abortions, minor birth defects, preterm delivery, birth size and serious or 
opportunistic infections and no stillbirths or malignancies were reported. The interpretation of data may be 
impacted due to methodological limitations of the study, including small sample size and non-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 adalimumab in utero is not recommended for 5 
months following the mother’s last adalimumab injection during pregnancy. 
 
Breast-feeding 
 
Limited information from the published literature indicates that adalimumab is excreted in breast milk at 
very low concentrations with the presence of adalimumab in human milk at concentrations of 0.1 % to 
1 % of the maternal serum level. Given orally, immunoglobulin G proteins undergo intestinal proteolysis 
and have poor bioavailability. No effects on the breastfed newborns/infants are anticipated. Consequently, 
adalimumab 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 
 
Imraldi may have a minor influence on the ability to drive and use machines. Vertigo and visual 
impairment may occur following administration of Imraldi (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Adalimumab was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months 
or more. These trials included rheumatoid arthritis patients with short term and long standing disease, 
juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as 
well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic 
evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa, 



16 
 

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 defense against infection and cancer. 
 
Fatal and life-threatening infections (including sepsis, opportunistic infections and TB), HBV reactivation 
and various malignancies (including leukaemia, lymphoma and HSTCL) have also been reported with use 
of adalimumab. 
 
Serious haematological, neurological and autoimmune reactions have also been reported. These include 
rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports of 
lupus, lupus-related conditions and Stevens-Johnson syndrome. 
 
Paediatric population  
 
In general, the adverse events in paediatric patients were similar in frequency and type to those seen in 
adult patients. 
 
Tabulated list of adverse reactions 
 
The following list of adverse reactions is based on experience from clinical trials and on postmarketing 
experience and are displayed by system organ class and frequency in Table 6 below: 
very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥ 1/10,000 to 
<1/1,000); and not known (cannot be estimated from the available data). Within each frequency grouping, 
undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among 
the various indications has been included. An asterisk (*) appears in the System Organ Class (SOC) 
column if further information is found elsewhere in sections 4.3, 4.4 and 4.8. 
 

Table 6 
Undesirable Effects 

 
System Organ Class Frequency Adverse Reaction 
Infections and 
infestations* 

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

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



17 
 

System Organ Class Frequency Adverse Reaction 
joint infections 

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

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

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

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

Rare Leukaemia1) 
Not known Hepatosplenic T-cell lymphoma1) 

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

Blood and the 
lymphatic system 
disorders* 

Very common Leukopenia (including neutropenia and agranulocytosis), 
anaemia 

Common Leukocytosis, 
thrombocytopenia 

Uncommon Idiopathic thrombocytopenic purpura 
Rare Pancytopenia 

Immune system 
disorders* 

Common Hypersensitivity, 
allergies (including seasonal allergy) 

Uncommon Sarcoidosis1), 
vasculitis 

Rare Anaphylaxis1) 
Metabolism and 
nutrition disorders 

Very common Lipids increased 
Common Hypokalaemia, 

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

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

Nervous system 
disorders* 

Very common Headache 
Common Paraesthesias (including hypoesthesia), 

migraine, 
nerve root compression 

Uncommon Cerebrovascular accident1), 
tremor, 
neuropathy 

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



18 
 

System Organ Class Frequency Adverse Reaction 
syndrome)1) 

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

Uncommon Diplopia 
Ear and labyrinth 
disorders 

Common Vertigo 
Uncommon Deafness, 

tinnitus 
Cardiac disorders* Common Tachycardia 

Uncommon Myocardial infarction1), 
arrhythmia, 
congestive heart failure 

Rare Cardiac arrest 
Vascular disorders Common Hypertension, 

flushing, 
haematoma 

Uncommon Aortic aneurysm, 
vascular arterial occlusion, 
thrombophlebitis 

Respiratory, thoracic 
and mediastinal 
disorders* 

Common Asthma, 
dyspnoea, 
cough 

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

Rare Pulmonary fibrosis1) 
Gastrointestinal 
disorders 

Very common Abdominal pain, 
nausea and vomiting 

Common GI haemorrhage, 
dyspepsia, 
gastroesophageal reflux disease, 
sicca syndrome 

Uncommon Pancreatitis, 
dysphagia, 
face oedema 

Rare Intestinal perforation1) 
Hepatobiliary 
disorders* 

Very common Elevated liver enzymes 
Uncommon Cholecystitis and cholelithiasis, 

hepatic steatosis, 
bilirubin increased 

Rare Hepatitis 
reactivation of hepatitis B1) 
autoimmune hepatitis1) 

Not Known Liver failure1) 
Skin and subcutaneous 
tissue disorders 

Very common Rash (including exfoliative rash) 
Common Worsening or new onset of psoriasis (including palmoplantar 

pustular psoriasis)1), 
urticaria, 
bruising (including purpura), 
dermatitis (including eczema), 
onychoclasis, 
hyperhidrosis, 



19 
 

System Organ Class Frequency Adverse Reaction 
alopecia1), 
pruritus 

Uncommon Night sweats, 
scar 

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

Not known Worsening of symptoms of dermatomyositis1) 
Musculoskeletal and 
connective tissue 
disorders 

Very common Musculoskeletal pain 
Common Muscle spasms (including blood creatine phosphokinase 

increased) 
Uncommon Rhabdomyolysis, 

systemic lupus erythematosus 
Rare Lupus-like syndrome1) 

Renal and urinary 
disorders 

Common Renal impairment, 
haematuria 

Uncommon Nocturia 
Reproductive system 
and breast disorders 

Uncommon Erectile dysfunction 

General disorders and 
administration site 
conditions* 

Very common Injection site reaction (including injection site erythema) 
Common Chest pain, 

oedema, 
pyrexia1) 

Uncommon Inflammation 
Investigations* Common Coagulation and bleeding disorders (including activated 

partial thromboplastin time prolonged), 
autoantibody test positive (including double stranded DNA 
antibody), 
blood lactate dehydrogenase increased 

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 



20 
 

7.2 % of patients receiving placebo or active control. Injection site reactions generally did not necessitate 
discontinuation of the medicinal product. 
 
Infections 
 
In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the 
adalimumab treated patients and 1.46 per patient year in the placebo and active control-treated patients. 
The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most 
patients continued on adalimumab after the infection resolved. 
 
The incidence of serious infections was 0.04 per patient year in adalimumab treated patients and 0.03 per 
patient year in placebo and active control-treated patients. 
 
In controlled and open label adult and paediatric studies with adalimumab, serious infections (including 
fatal infections, which occurred rarely) have been reported, which include reports of tuberculosis 
(including miliary and extra-pulmonary locations) and invasive opportunistic infections (e.g. disseminated 
or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, pneumocystis, candidiasis, 
aspergillosis and listeriosis). Most of the cases of tuberculosis occurred within the first eight months after 
initiation of therapy and may reflect recrudescence of latent disease. 
 
Malignancies and lymphoproliferative disorders  
 
No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years during 
adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis 
and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric patients with 
an exposure of 498.1 patient years during adalimumab trials in paediatric patients with Crohn’s disease. 
No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during an 
adalimumab trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 
60 paediatric patients with an exposure of 58.4 patient years during an adalimumab trial in paediatric 
patients with uveitis. 
 
During the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in duration in 
patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial 
spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis 
suppurativa, Crohn’s disease, ulcerative colitis, and uveitis, malignancies, other than lymphoma and non-
melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 
1,000 patient-years among 5,291 adalimumab treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 
patient-years among 3,444 control patients (median duration of treatment was 4.0 months for adalimumab 
and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin 
cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among adalimumab-treated patients and 3.2 (1.3, 7.6) 
per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred 
at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among adalimumab-treated 
patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95 % confidence 
interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among adalimumab-treated patients and 
0.6 (0.1, 4.5) per 1,000 patient-years among control patients. 
 
When combining controlled portions of these trials and ongoing and completed open label extension 
studies with a median duration of approximately 3.3 years including 6,427 patients and over 
26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-
melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma 
skin cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is 
approximately 1.3 per 1,000 patient-years. 
 
In post-marketing experience from January 2003 to December 2010, predominantly in patients with 
rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient treatment 
years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 0.3 
per 1,000 patient treatment years, respectively (see section 4.4). 



21 
 

 
Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with 
adalimumab (see section 4.4). 
 
Autoantibodies 
 
Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis studies 
I − V. In these trials, 11.9 % of patients treated with adalimumab and 8.1% of placebo and active control − 
treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at week 24. 
Two patients out of 3,441 treated with adalimumab in all rheumatoid arthritis and psoriatic arthritis studies 
developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following 
discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. 
 
Hepato-biliary events 
 
In controlled Phase 3 trials of adalimumab in patients with rheumatoid arthritis and psoriatic arthritis with 
a control period duration ranging from 4 to 104 weeks, ALT elevations ≥3 ×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 × 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 × 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 × 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 × 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 × ULN occurred in 1.8% of adalimumab-treated patients 
and 1.8 % of control-treated patients.  
 
No ALT elevations ≥3 × 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 × 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 × 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. 
 



22 
 

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. 
 
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 
 
Imraldi 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 

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


23 
 

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 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. 
 



24 
 

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 13.3% 65.1% 19.1% 46.0% 29.5% 63.3% 
12 months - - - - 24.0% 58.9% 
ACR 50 
6 months 6.7% 52.4% 8.2% 22.1% 9.5% 39.1% 
12 months - - - - 9.5% 41.5% 
ACR 70 
6 months 3.3% 23.8% 1.8% 12.4% 2.5% 20.8% 
12 months - - - - 4.5% 23.2% 
a  RA study I at 24 weeks, RA study II at 26 weeks, and RA study III at 24 and 52 weeks 
b  40 mg adalimumab administered every other week 
c  MTX = methotrexate 
**p <0.01, adalimumab versus placebo 
- Not applicable 
 
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). 
 



25 
 

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 
52 Week 62.6% 54.4% 72.8% 0.013 <0.001 0.043 
104 Week 56.0% 49.3% 69.4% 0.002 <0.001 0.140 

ACR 50 
52 Week 45.9% 41.2% 61.6% <0.001 <0.001 0.317 
104 Week 42.8% 36.9% 59.0% <0.001 <0.001 0.162 

ACR 70 
52 Week 27.2% 25.9% 45.5% <0.001 <0.001 0.656 
104 Week 28.4% 28.1% 46.6% <0.001 <0.001 0.864 

a p-value is from the pairwise comparison of methotrexate monotherapy and 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 
 
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 <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 randomized 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. 
 



26 
 

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). 
 

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 randomized 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 



27 
 

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. 
 
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 

 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. 
 



28 
 

Table 12 
Paed 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 Paediatric 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. 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, adalimumab 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, PaedACR30 response was 93.5% and 90.0%, respectively, using the observed 
data approach. The proportions of subjects with PaedACR50/70/90 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 (Paediatric 
ACR 30) at week 24 (n=27 out of 30 patients), the Paediatric 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 



29 
 

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), Paediatric ACR 50 
response, and Paediatric 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. 
 
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). 



30 
 

 
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 randomized, 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). 
 

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. 
 



31 
 

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 openlabel 
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 randomized 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. 
 
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 

   
   

   
   

   
   

 P
R

O
B

A
B

IL
IT

Y
 O

F 
N

O
 F

L
A

R
E

 

 
 TIME (WEEKS) 
                                  Treatment        Placebo      Adalimumab     ∆ Censored 
 
Note: P = Placebo (Number at Risk (flared)); A = Adalimumab (Number at Risk (flared)). 
 



32 
 

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. 
 
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 14% 58%*** 16% 39%* 
Week 24 15% 57%*** - - 

ACR 50 
Week 12 4% 36%*** 2% 25%*** 
Week 24 6% 39%*** - - 

ACR 70 
Week 12 1% 20%*** 0% 14%* 
Week 24 1% 23%*** - - 

*** p < 0.001 for all comparisons between adalimumab and placebo 
*     p < 0.05 for all comparisons between adalimumab and placebo 



33 
 

- 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 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 and18). 
 



34 
 

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 PASI 75 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 
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.  



35 
 

 
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)). 
 

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 26.0

a 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. 
 



36 
 

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. 
 
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. 
 



37 
 

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. 
 

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 



38 
 

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-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 1,500 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. 



39 
 

 
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. 
 

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. 
 



40 
 

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 

 
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 value
1 

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 



41 
 

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. 
 
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 



42 
 

** 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. 
 
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). 
 
Patients who completed Studies UV I and UV II were eligible to enroll in an uncontrolled long-term 
extension study with an originally planned duration of 78 weeks. Patients were allowed to continue on 
study medication beyond Week 78 until they had access to adalimumab. 
Clinical Response 
 



43 
 

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). 
 

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

 
Analysis 

Treatment N 
Failure N 

(%) 
Median Time to 
Failure (months) HR

a CI 95% for HR 
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 

 



44 
 

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

 

 
 

 
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 424 subjects included in the uncontrolled long-term extension of studies UV I and UV II, 
60 subjects were regarded ineligible (e.g. due to deviations or due to complications secondary to diabetic 
retinopathy, due to cataract surgery or vitrectomy) and were excluded from the primary analysis of 
efficacy. Of the 364 remaining patients, 269 evaluable patients (74%) reached 78 weeks of open-label 
adalimumab treatment. Based on the observed data approach, 216 (80.3%) 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 178 (66.2%) were in steroid-free quiescence. BCVA was either improved or maintained (< 5 
letters deterioration) in 88.6 % of the eyes at week 78. Data beyond Week 78 were generally consistent 
with these results but the number of enrolled subjects declined after this time. Overall,among the patients 
who discontinued the study, 18% discontinued due to adverse events, and 8 % due to insufficient response 
to adalimumab treatment. 
 
Quality of Life 
 



45 
 

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 randomized, 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. 
 
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]). 



46 
 

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

 

PR
O

B
A

B
IL

IT
Y

 O
F 

FA
IL

IN
G

 T
R

E
A

T
M

E
N

T
 

 
 TIME (WEEKS) 
 Treatment  Placebo  Adalimumab 
 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 the 
reference medicinal product containing adalimumab in one or more subsets of the paediatric population in 
ulcerative colitis, see section 4.2 for information on paediatric use. 
 
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 



47 
 

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 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. 



48 
 

 
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). 
 
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 



49 
 

 
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 citrate 
Citric acid monohydrate 
Histidine  
Histidine hydrochloride monohydrate 
Sorbitol 
Polysorbate 20  
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 
 
3 years 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the pre-filled syringe or pre-filled pen in  outer 
carton in order to protect from light.  
 
A single Imraldi pre-filled syringe or pre-filled pen may be stored at temperatures up to a maximum of 
25°C for a period of up to 28 days. The syringe or pen must be protected from light, and discarded if not 
used within the 28-day period. 
 
6.5 Nature and contents of container 
 
Imraldi 40 mg solution for injection in pre-filled syringe 
 
0.8 ml solution for injection in single-use pre-filled syringe (type I glass) with a stainless steel needle, a 
rigid needle shield, a rubber plunger (bromobutyl), a plunger rod, a safe-shield body and a finger flange 
for patient use. 
 
Packs of: 
 1 pre-filled syringe, with 2 alcohol pads 
 2 pre-filled syringes, each with 1 alcohol pad 



50 
 

 4 pre-filled syringes, each with 1 alcohol pad 
 6 pre-filled syringes, each with 1 alcohol pad 
 
Imraldi 40 mg solution for injection in pre-filled pen 
 
0.8 ml 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 stainless steel needle, a rigid needle shield, a 
rubber plunger (bromobutyl). 
 
Packs of: 
 1 pre-filled pen, with 2 alcohol pads 
 2 pre-filled pens, each with 1 alcohol pad 
 4 pre-filled pens, each with 1 alcohol pad 
 6 pre-filled pens, each with 1 alcohol pad 
 
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 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616 LR Delft 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
Imraldi 40 mg solution for injection in pre-filled syringe 
EU/1/17/1216/001 
EU/1/17/1216/002 
EU/1/17/1216/003 
EU/1/17/1216/004 
 
Imraldi 40 mg solution for injection in pre-filled pen 
EU/1/17/1216/005 
EU/1/17/1216/006 
EU/1/17/1216/007 
EU/1/17/1216/008 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 24 August 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. 

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


51 
 

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 
 
Imraldi 40 mg/0.8 ml solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each 0.8 ml single dose vial contains 40 mg of adalimumab. 
 
Adalimumab is a recombinant human monoclonal antibody produced in Chinese Hamster Ovary cells. 
 
Excipient(s) with known effect 
 
This medicinal product contains 20.0 mg sorbitol. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection). 
Clear, colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Juvenile idiopathic arthritis 
 
Polyarticular juvenile idiopathic arthritis 
 
Imraldi 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). Imraldi can be given as monotherapy in case of 
intolerance to methotrexate or when continued treatment with methotrexate is inappropriate (for the 
efficacy in monotherapy see section 5.1). Adalimumab has not been studied in patients aged less than 
2 years. 
 
Enthesitis-related arthritis 
 
Imraldi is indicated for the treatment of active enthesitis-related arthritis in patients, 6 years of age and 
older, who have had an inadequate response to, or who are intolerant of, conventional therapy (see section 
5.1). 
 
Paediatric plaque psoriasis 
 
Imraldi is indicated for the treatment of severe chronic plaque psoriasis in children and adolescents from 
4 years of age who have had an inadequate response to or are inappropriate candidates for topical therapy 
and phototherapies. 
 
Paediatric Crohn's disease 
 



52 
 

Imraldi is indicated for the treatment of moderately to severely active Crohn's disease in paediatric 
patients (from 6 years of age) who have had an inadequate response to conventional therapy including 
primary nutrition therapy and a corticosteroid and/or an immunomodulator, or who are intolerant to or 
have contraindications for such therapies. 
 
Adolescent hidradenitis suppurativa 
 
Imraldi is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) 
in adolescents from 12 years of age with an inadequate response to conventional systemic HS therapy 
(see sections 5.1 and 5.2). 
 
Paediatric Uveitis 
 
Imraldi 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 
 
Imraldi treatment should be initiated and supervised by specialist physicians experienced in the diagnosis 
and treatment of conditions for which Imraldi is indicated. Ophthalmologists are advised to consult with 
an appropriate specialist before initiation of treatment with Imraldi (see section 4.4). Patients treated with 
Imraldi should be given the Patient Reminder cCard. 
 
After proper training in injection technique, patients may self-inject with Imraldi if their physician 
determines that it is appropriate and with medical follow-up as necessary. 
 
During treatment with Imraldi, other concomitant therapies (e.g., corticosteroids and/or 
immunomodulatory agents) should be optimised. 
 
Posology 
 
Paediatric population 
 
Juvenile idiopathic arthritis 
 
Polyarticular juvenile idiopathic arthritis from 2 years of age 
 
The recommended dose of Imraldi for patients with polyarticular juvenile idiopathic arthritis from 2 years 
of age is based on body weight (Table 1). Imraldi is administered every other week via subcutaneous 
injection. 
 

Table 1 Imraldi Dose for Patients with Polyarticular Juvenile Idiopathic Arthritis  
 

Patient Weight Dosing Regimen 
10 kg to < 30 kg 20 mg every other week 

≥ 30 kg 40 mg every other week 
 
Available data suggest that clinical response is usually achieved within 12 weeks of treatment. Continued 
therapy should be carefully reconsidered in a patient not responding within this time period. 
 
There is no relevant use of adalimumab in patients aged less than 2 years for this indication. 
 
Enthesitis-related arthritis 
 



53 
 

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

Table 2 Imraldi Dose for Patients with Enthesitis-Related Arthritis 
 

Patient Weight Dosing Regimen 
15 kg to < 30 kg 20 mg every other week 

≥ 30 kg 40 mg every other week 
 
Adalimumab has not been studied in patients with enthesitis-related arthritis aged less than 6 years. 
 
Paediatric plaque psoriasis 
 
The recommended Imraldi dose for patients with plaque psoriasis from 4 to 17 years of age is based on 
body weight (Table 3). Imraldi is administered via subcutaneous injection. 
 

Table 3 Imraldi Dose for Paediatric Patients with Plaque Psoriasis 
 

Patient Weight Dosing Regimen 

15 kg to < 30 kg 

Initial dose of 20 mg, followed by 
20 mg given every other week 

starting one week after the initial 
dose 

≥ 30 kg 

Initial dose of 40 mg, followed by 
40 mg given every other week 

starting one week after the initial 
dose 

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



54 
 

 
Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no improvement 
within this time period. 
 
Should treatment be interrupted, Imraldi 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 Imraldi for patients with Crohn’s disease from 6 to 17 years of age is based on 
body weight (Table 4). Imraldi is administered via subcutaneous injection. 
 

Table 4 Imraldi Dose for Paediatric Patients with Crohn’s disease 
 

Patient 
Weight 

Induction Dose Maintenance 
Dose 

Starting at 
Week 4 

< 40 kg 

• 40 mg at week 0 and 20 mg at week 2 
 
In case there is a need for a more rapid response to therapy with the 
awareness that the risk for adverse events may be higher with use of the 
higher induction dose, the following dose may be used: 
• 80 mg at week 0 and 40 mg at week 2 

20 mg every 
other week 

≥ 40 kg 

• 80 mg at week 0 and 40 mg at week 2 
 
In case there is a need for a more rapid response to therapy with the 
awareness that the risk for adverse events may be higher with use of the 
higher induction dose, the following dose may be used: 
• 160 mg at week 0 and 80 mg at week 2 

40 mg every 
other week 

 
Patients who experience insufficient response may benefit from an increase in dosage: 
 < 40 kg: 20 mg every week 
 ≥ 40 kg: 40 mg every week or 80 mg every other week 
 
Continued therapy should be carefully considered in a subject not responding by week 12. 
 
There is no relevant use of adalimumab in children aged below 6 years for this indication. 
 
Paediatric uveitis 
  
The recommended dose of Imraldi for paediatric patients with uveitis from 2 years of age is based on 
body weight (Table 5). Imraldi is administered via subcutaneous injection. 
 
In paediatric uveitis, there is no experience in the treatment with adalimumab without concomitant 
treatment with methotrexate. 
 

Table 5 Imraldi Dose for Paediatric Patients with Uveitis 
 

Patient Weight Dosing Regimen 

< 30 kg 20 mg every other week in combination with methotrexate 



55 
 

≥ 30 kg 40 mg every other week in combination with methotrexate 
 
When Imraldi 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). 
 
Renal and/or hepatic impairment 
 
Imraldi has not been studied in these patient populations. No dose recommendations can be made. 
 
Method of administration  
 
Imraldi is administered by subcutaneous injection. Full instructions for use are provided in the package 
leaflet. 
 
A 40 mg pre-filled pen and a 40 mg pre-filled syringe are also 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. 
 
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 the 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 Imraldi. Because the elimination of 
adalimumab may take up to four months, monitoring should be continued throughout this period. 
 
Treatment with Imraldi 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 Imraldi 
should be considered prior to initiating therapy (see Other opportunistic infections). 
 
Patients who develop a new infection while undergoing treatment with Imraldi, should be monitored 
closely and undergo a complete diagnostic evaluation. Administration of Imraldi 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 



56 
 

the use of Imraldi 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 Imraldi, all patients must be evaluated for both active or inactive 
(“latent”) tuberculosis infection. This evaluation should include a detailed medical assessment of patient 
history of tuberculosis or possible previous exposure to people with active tuberculosis and previous 
and/or current immunosuppressive therapy. Appropriate screening tests (i.e. tuberculin skin test and chest 
X-ray) should be performed in all patients (local recommendations may apply). It is recommended that the 
conduct and results of these tests are recorded in the Patient Reminder Card. Prescribers are reminded of 
the risk of false negative tuberculin skin test results, especially in patients who are severely ill or 
immunocompromised. 
 
If active tuberculosis is diagnosed, Imraldi therapy must not be initiated (see section 4.3). 
 
In all situations described below, the benefit/risk balance of therapy should be very carefully considered. 
 
If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be 
consulted. 
 
If latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosis 
prophylaxis treatment before the initiation of Imraldi, and in accordance with local recommendations. 
 
Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of Imraldi 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 Imraldi. 
 
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. 
 



57 
 

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 Imraldi 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 Imraldi. 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 Imraldi 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, Imraldi 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 Imraldi in patients 
with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders; 
discontinuation of Imraldi should be considered if any of these disorders develop. There is a known 
association between intermediate uveitis and central demyelinating disorders. Neurologic evaluation 
should be performed in patients with non-infectious intermediate uveitis prior to the initiation of Imraldi 
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 Imraldi should be 
discontinued immediately and appropriate therapy initiated. 
 
Immunosuppression 
 
In a study of 64 patients with rheumatoid arthritis that were treated with adalimumab, there was no 
evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change 
in enumeration of effector T-, B-, NK-cells, monocyte/macrophages, and neutrophils. 
 
Malignancies and lymphoproliferative disorders 
 
In the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies including 
lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. 
However, the occurrence was rare. In the post marketing setting, cases of leukaemia have been reported in 
patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and 
leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which 
complicates the risk estimation. With 



58 
 

 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 adalimumab should be 
carefully considered. A risk for the development of hepatosplenic T-cell lymphoma in patients treated 
with Imraldi 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 adalimumab 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 Imraldi. Melanoma and Merkel cell carcinoma 
have also been reported in patients treated with TNF-antagonists including adalimumab (see section 4.8). 
 
In an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patients with 
moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung 
or head and neck, were reported in infliximab-treated patients compared with control patients. All patients 
had a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist 
in COPD patients, as well as in patients with increased risk for malignancy due to heavy smoking. 
 
With current data it is not known if adalimumab treatment influences the risk for developing dysplasia or 
colon cancer. All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma 
(for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had 
a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before 
therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per 
local recommendations. 
 
Haematologic reactions 
 
Rare reports of pancytopenia including aplastic anaemia have been reported with TNF-antagonists. 
Adverse events of the haematologic system, including medically significant cytopenia (e.g. 
thrombocytopenia, leukopenia) have been reported with adalimumab. All patients should be advised to 
seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. 
persistent fever, bruising, bleeding, pallor) while on Imraldi. Discontinuation of Imraldi 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. 
 



59 
 

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 adalimumab 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. Imraldi should be used with caution in patients with mild 
heart failure (NYHA class I/II). Imraldi is contraindicated in moderate to severe heart failure (see section 
4.3). Treatment with Imraldi must be discontinued in patients who develop new or worsening symptoms 
of congestive heart failure. 
 
Autoimmune processes  
 
Treatment with Imraldi may result in the formation of autoimmune antibodies. The impact of long-term 
treatment with adalimumab on the development of autoimmune diseases is unknown. If a patient develops 
symptoms suggestive of a lupus-like syndrome following treatment with Imraldi and is positive for 
antibodies against double-stranded DNA, further treatment with Imraldi should not be given (see 
section 4.8). 
 
Concurrent administration of biologic DMARDS or TNF-antagonists  
 
Serious infections were seen in clinical studies with concurrent use of anakinra and another TNF-
antagonist, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature 
of the adverse events seen with the combination of etanercept and anakinra therapy, similar toxicities may 
also result from the combination of anakinra and other TNF-antagonists. Therefore, the combination of 
adalimumab and anakinra is not recommended. (See section 4.5). 
 
Concomitant administration of adalimumab with other biologic DMARDS (e.g, anakinra and abatacept) or 
other TNF-antagonists is not recommended based upon the possible increased risk for infections, 
including serious infections and other potential pharmacological interactions. (See section 4.5). 
 
Surgery 
 
There is limited safety experience of surgical procedures in patients treated with adalimumab. The long 
half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A patient 
who requires surgery while on Imraldi 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 



60 
 

 
See Vaccinations above. 
 
Excipients with known effects 
 
This medicinal product contains 20 mg sorbitol in each vial. Patients with rare hereditary problems of 
fructose intolerance should not take this medicinal product. 
 
Also, 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 Imraldi and anakinra is not recommended (see section 4.4 “Concurrent administration 
of biologic DMARDS or TNF-antagonists”). 
 
The combination of Imraldi 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 Imraldi treatment. 
 
Pregnancy  
 
A large number (approximately 2,100) of prospectively collected pregnancies exposed to adalimumab 
resulting in live birth with known outcomes, including more than 1,500 exposed during the first trimester, 
does not indicate an increase in the rate of malformation in the newborn. 
 
In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn’s disease (CD) 
treated with adalimumab at least during the first trimester and 120 women with RA or CD not treated with 
adalimumab were enrolled. The primary endpoint was the birth prevalence of major birth defects. The rate 
of pregnancies ending with at least one live born infant with a major birth defect was 6/69 (8.7 %) in the 
adalimumab-treated women with RA and 5/74 (6.8 %) in the untreated women with RA (unadjusted OR 
1.31, 95 % CI 0.38-4.52) and 16/152 (10.5 %) in the adalimumab-treated women with CD and 3/32 
(9.4 %) in the untreated women with CD (unadjusted OR 1.14, 95 % CI 0.31-4.16). The adjusted OR 
(accounting for baseline differences) was 1.10 (95 % CI 0.45-2.73) with RA and CD combined. There 
were no distinct differences between adalimumab-treated and untreated women for the secondary 
endpoints spontaneous abortions, minor birth defects, preterm delivery, birth size and serious or 
opportunistic infections and no stillbirths or malignancies were reported. The interpretation of data may be 
impacted due to methodological limitations of the study, including small sample size and non-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 



61 
 

responses in the newborn. Adalimumab should only be used during pregnancy if clearly needed. 
 
Adalimumab may cross the placenta into the serum of infants born to women treated with adalimumab 
during pregnancy. Consequently, these infants may be at increased risk for infection. Administration of 
live vaccines (e.g., BCG vaccine) to infants exposed to adalimumab in utero is not recommended for 5 
months following the mother’s last adalimumab injection during pregnancy. 
 
Breast-feeding 
 
Limited information from the published literature indicates that adalimumab is excreted in breast milk at 
very low concentrations with the presence of adalimumab in human milk at concentrations of 0.1 % to 
1 % of the maternal serum level. Given orally, immunoglobulin G proteins undergo intestinal proteolysis 
and have poor bioavailability. No effects on the breastfed newborns/infants are anticipated. Consequently, 
adalimumab 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 
 
Imraldi may have a minor influence on the ability to drive and use machines. Vertigo and visual 
impairment may occur following administration of Imraldi (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Adalimumab was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months 
or more. These trials included rheumatoid arthritis patients with short term and long standing disease, 
juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as 
well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic 
evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa, 
and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving adalimumab and 
3,801 patients receiving placebo or active comparator during the controlled period. 
 
The proportion of patients who discontinued treatment due to adverse events during the double-blind, 
controlled portion of pivotal studies was 5.9 % for patients taking adalimumab and 5.4 % for control 
treated patients. 
 
The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory 
tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), 
headache and musculoskeletal pain. 
 
Serious adverse reactions have been reported for adalimumab. TNF-antagonists, such as adalimumab 
affect the immune system and their use may affect the body’s defense 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  
 



62 
 

In general, the adverse events in paediatric patients were similar in frequency and type to those seen in 
adult patients. 
 
Tabulated list of adverse reactions 
 
The following list of adverse reactions is based on experience from clinical trials and on postmarketing 
experience and are displayed by system organ class and frequency in Table 6 below: 
very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥ 1/10,000 to 
<1/1,000); and not known (cannot be estimated from the available data). Within each frequency grouping, 
undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among 
the various indications has been included. An asterisk (*) appears in the System Organ Class (SOC) 
column if further information is found elsewhere in sections 4.3, 4.4 and 4.8. 
 



63 
 

Table 6 
Undesirable Effects 

 
System Organ Class Frequency Adverse Reaction 
Infections and 
infestations* 

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

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

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

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

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

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

Rare Leukaemia1) 
Not known Hepatosplenic T-cell lymphoma1), 

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

Blood and the 
lymphatic system 
disorders* 

Very common Leukopenia (including neutropenia and agranulocytosis), 
anaemia 

Common Leukocytosis, 
thrombocytopenia 

Uncommon Idiopathic thrombocytopenic purpura 
Rare Pancytopenia 

Immune system 
disorders* 

Common Hypersensitivity, 
allergies (including seasonal allergy) 

Uncommon Sarcoidosis1), 
vasculitis 

Rare Anaphylaxis1) 
Metabolism and 
nutrition disorders 

Very common Lipids increased 
Common Hypokalaemia, 

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



64 
 

System Organ Class Frequency Adverse Reaction 
dehydration 

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

Nervous system 
disorders* 

Very common Headache 
Common Paraesthesias (including hypoesthesia), 

migraine, 
nerve root compression 

Uncommon Cerebrovascular accident1), 
tremor, 
neuropathy 

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

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

Uncommon Diplopia 
Ear and labyrinth 
disorders 

Common Vertigo 
Uncommon Deafness, 

tinnitus 
Cardiac disorders* Common Tachycardia 

Uncommon Myocardial infarction1), 
arrhythmia, 
congestive heart failure 

Rare Cardiac arrest 
Vascular disorders Common Hypertension, 

flushing, 
haematoma 

Uncommon Aortic aneurysm, 
vascular arterial occlusion, 
thrombophlebitis 

Respiratory, thoracic 
and mediastinal 
disorders* 

Common Asthma, 
dyspnoea, 
cough 

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

Rare Pulmonary fibrosis1) 
Gastrointestinal 
disorders 

Very common Abdominal pain, 
nausea and vomiting 

Common GI haemorrhage, 
dyspepsia, 
gastroesophageal reflux disease, 
sicca syndrome 

Uncommon Pancreatitis, 
dysphagia, 
face oedema 

Rare Intestinal perforation1) 
Hepatobiliary 
disorders* 

Very common Elevated liver enzymes 
Uncommon Cholecystitis and cholelithiasis, 

hepatic steatosis, 



65 
 

System Organ Class Frequency Adverse Reaction 
bilirubin increased 

Rare Hepatitis 
reactivation of hepatitis B1) 
autoimmune hepatitis1) 

Not known Liver failure1) 
Skin and subcutaneous 
tissue disorders 

Very common Rash (including exfoliative rash) 
Common Worsening or new onset of psoriasis (including palmoplantar 

pustular psoriasis)1), 
urticaria, 
bruising (including purpura), 
dermatitis (including eczema), 
onychoclasis, 
hyperhidrosis, 
alopecia1), 
pruritus 

Uncommon Night sweats, 
scar 

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

Not Known Worsening of symptoms of dermatomyositis1) 
Musculoskeletal and 
connective tissue 
disorders 

Very common Musculoskeletal pain 
Common Muscle spasms (including blood creatine phosphokinase 

increased) 
Uncommon Rhabdomyolysis, 

systemic lupus erythematosus 
Rare Lupus-like syndrome1) 

Renal and urinary 
disorders 

Common Renal impairment, 
haematuria 

Uncommon Nocturia 
Reproductive system 
and breast disorders 

Uncommon Erectile dysfunction 

General disorders and 
administration site 
conditions* 

Very Common Injection site reaction (including injection site erythema) 
Common Chest pain, 

oedema, 
pyrexia1) 

Uncommon Inflammation 
Investigations* Common Coagulation and bleeding disorders (including activated 

partial thromboplastin time prolonged), 
autoantibody test positive (including double stranded DNA 
antibody), 
blood lactate dehydrogenase increased 

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. 



66 
 

 
Uveitis 
 
The safety profile for patients with uveitis treated with adalimumab every other week was consistent with 
the known safety profile of adalimumab. 
 
Description of selected adverse reactions 
 
Injection site reactions 
 
In the pivotal controlled trials in adults and children, 12.9 % of patients treated with adalimumab 
developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 
7.2 % of patients receiving placebo or active control. Injection site reactions generally did not necessitate 
discontinuation of the medicinal product. 
 
Infections 
 
In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the 
adalimumab treated patients and 1.46 per patient year in the placebo and active control-treated patients. 
The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most 
patients continued on adalimumab after the infection resolved. 
 
The incidence of serious infections was 0.04 per patient year in adalimumab treated patients and 0.03 per 
patient year in placebo and active control-treated patients. 
 
In controlled and open label adult and paediatric studies with adalimumab, serious infections (including 
fatal infections, which occurred rarely) have been reported, which include reports of tuberculosis 
(including miliary and extra-pulmonary locations) and invasive opportunistic infections (e.g. disseminated 
or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, pneumocystis, candidiasis, 
aspergillosis and listeriosis). Most of the cases of tuberculosis occurred within the first eight months after 
initiation of therapy and may reflect recrudescence of latent disease. 
 
Malignancies and lymphoproliferative disorders  
 
No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years during 
adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis 
and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric patients with 
an exposure of 498.1 patient years during adalimumab trials in paediatric patients with Crohn’s disease. 
No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during an 
adalimumab trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 
60 paediatric patients with an exposure of 58.4 patient years during an adalimumab trial in paediatric 
patients with uveitis. 
 
During the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in duration in 
patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial 
spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis 
suppurativa, Crohn’s disease, ulcerative colitis, and uveitis, malignancies, other than lymphoma and non-
melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 
1,000 patient-years among 5,291 adalimumab treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 
patient-years among 3,444 control patients (median duration of treatment was 4.0 months for adalimumab 
and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin 
cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among adalimumab-treated patients and 3.2 (1.3, 7.6) 
per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred 
at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among adalimumab-treated 
patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95 % confidence 
interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among adalimumab-treated patients and 
0.6 (0.1, 4.5) per 1,000 patient-years among control patients. 



67 
 

 
When combining controlled portions of these trials and ongoing and completed open label extension 
studies with a median duration of approximately 3.3 years including 6,427 patients and over 
26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-
melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma 
skin cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is 
approximately 1.3 per 1,000 patient-years. 
 
In post-marketing experience from January 2003 to December 2010, predominantly in patients with 
rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient treatment 
years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 0.3 
per 1,000 patient treatment years, respectively (see section 4.4). 
 
Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with 
adalimumab (see section 4.4). 
 
Autoantibodies 
 
Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis studies 
I − V. In these trials, 11.9 % of patients treated with adalimumab and 8.1% of placebo and active control − 
treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at week 24. 
Two patients out of 3,441 treated with adalimumab in all rheumatoid arthritis and psoriatic arthritis studies 
developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following 
discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. 
 
Hepato-biliary events 
 
In controlled Phase 3 trials of adalimumab in patients with rheumatoid arthritis and psoriatic arthritis with 
a control period duration ranging from 4 to 104 weeks, ALT elevations ≥3 ×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 × 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 × 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 × 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 × 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 × ULN occurred in 1.8% of adalimumab-treated patients 
and 1.8 % of control-treated patients.  
 
No ALT elevations ≥3 × 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 × ULN occurred in 0.3 % of adalimumab-



68 
 

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 × 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. 
 
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 
 
Imraldi 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. 

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


69 
 

 
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 
 
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 7. 
 

Table 7 
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 

 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. 
 



70 
 

Table 8 
Paed 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 Paediatric 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. 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, adalimumab 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, PaedACR30 response was 93.5% and 90.0%, respectively, using the observed 
data approach. The proportions of subjects with PaedACR50/70/90 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 (Paediatric 
ACR 30) at week 24 (n=27 out of 30 patients), the Paediatric 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 



71 
 

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), Paediatric ACR 50 
response, and Paediatric ACR 70 response. 
 
Adults with 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 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 
 



72 
 

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 9. 
 

Table 9 
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 13.3% 65.1% 19.1% 46.0% 29.5% 63.3% 
12 months - - - - 24.0% 58.9% 
ACR 50 
6 months 6.7% 52.4% 8.2% 22.1% 9.5% 39.1% 
12 months - - - - 9.5% 41.5% 
ACR 70 
6 months 3.3% 23.8% 1.8% 12.4% 2.5% 20.8% 
12 months - - - - 4.5% 23.2% 
a  RA study I at 24 weeks, RA study II at 26 weeks, and RA study III at 24 and 52 weeks 
b  40 mg adalimumab administered every other week 
c  MTX = methotrexate 
**p <0.01, adalimumab versus placebo 
- Not applicable 
 
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 10). 
 



73 
 

Table 10 
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 
52 Week 62.6% 54.4% 72.8% 0.013 <0.001 0.043 
104 Week 56.0% 49.3% 69.4% 0.002 <0.001 0.140 

ACR 50 
52 Week 45.9% 41.2% 61.6% <0.001 <0.001 0.317 
104 Week 42.8% 36.9% 59.0% <0.001 <0.001 0.162 

ACR 70 
52 Week 27.2% 25.9% 45.5% <0.001 <0.001 0.656 
104 Week 28.4% 28.1% 46.6% <0.001 <0.001 0.864 

a p-value is from the pairwise comparison of methotrexate monotherapy and 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 
 
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 <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 randomized 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 11). 
 
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. 
 



74 
 

Table 11 
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 12). 
 

Table 12 
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 randomized 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 



75 
 

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. 
 
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 
Physician’s Global Assessment (PGA) ≥4 or >20% BSA involvement or >10 % BSA involvement with 
very thick lesions or Psoriasis Area and Severity Index (PASI) ≥20 or ≥10 with clinically relevant facial, 
genital, or hand/ 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 13 
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. 
 
Adult plaque psoriasis 
 
The safety and efficacy of adalimumab were studied in adult patients with chronic plaque psoriasis (≥10% 
BSA involvement and PASI ≥12 or ≥10) who were candidates for systemic therapy or phototherapy in 
randomised, double-blind studies. 73% of patients enrolled in Psoriasis studies I and II had received prior 



76 
 

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 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 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 14 and 15). 
 

Table 14 
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 PASI 75 response was calculated as centre-adjusted rate 
b p<0.001, adalimumab vs. placebo 
 

Table 15 
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 
 



77 
 

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 
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 16). 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)). 
 



78 
 

Table 16 
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. 
 
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-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). 
 
Adult 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. 
 



79 
 

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 17). Patients treated with adalimumab had 
significantly reduced risk of disease flare during the initial 12 weeks of treatment. 
 

Table 17 
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 18). 
 

Table 18 
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 



80 
 

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 %). 
 
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 19. 
 

Table 19 
Maintenance regimen 

 
Patient Weight Low dose Standard dose 

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

 
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 20. Rates of discontinuation of corticosteroids or 
immunomodulators are presented in Table 21. 
 



81 
 

Table 20 
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 21 
Paediatric CD Study 

Discontinuation of Corticosteroids or Immunomodulators and Fistula Remission 
 

 Standard Dose 40/20 mg eow 
Low Dose 

20/10 mg eow P value
1 

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. 
 
Adult Crohn’s disease 
 
The safety and efficacy of adalimumab were assessed in over 1,500 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 



82 
 

(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 22. 

 
Table 22 

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 23. 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. 
 



83 
 

Table 23 
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 Uveitis 
 
The safety and efficacy of adalimumab was assessed in a randomized, 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. 
 
Clinical Response 
 
Adalimumab significantly delayed the time to treatment failure, as compared to placebo (See Figure 1, 
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 



84 
 

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

Study 
 

PR
O

B
A

B
IL

IT
Y

 O
F 

FA
IL

IN
G

 T
R

E
A

T
M

E
N

T
 

 
 TIME (WEEKS) 
 Treatment  Placebo  Adalimumab 
 Note: P = Placebo (Number at Risk); H = Adalimumab (Number at Risk). 
 
Adult 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. 
 



85 
 

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). 
 
Patients who completed Studies UV I and UV II were eligible to enroll in an uncontrolled long-term 
extension study with an originally planned duration of 78 weeks. Patients were allowed to continue on 
study medication beyond Week 78 until they had access to adalimumab. 
 
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 24). Both studies 
demonstrated an early and sustained effect of adalimumab on the treatment failure rate versus placebo 
(see Figure 2). 
 

Table 24 
Time to Treatment Failure in Studies UV I and UV II 

 
Analysis 

Treatment N 
Failure N 

(%) 
Median Time to Failure 

(months) HR
a CI 95% for HR 

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 



86 
 
 
 

 
Figure 2: Kaplan-Meier Curves Summarizing Time to Treatment Failure on or after 

Week 6 (Study UV I) or Week 2 (Study UV II) 
 
 

 
 

 
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 424 subjects included in the uncontrolled long-term extension of studies UV I and UV II, 
60 subjects were regarded ineligible (e.g. due to deviations or due to complications secondary to 
diabetic retinopathy, due to cataract surgery or vitrectomy) and were excluded from the primary 
analysis of efficacy. Of the 364 remaining patients, 269 evaluable patients (74%) reached 78 weeks of 
open-label adalimumab treatment. Based on the observed data approach, 216 (80.3%) 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 178 (66.2%) were in steroid-free quiescence. BCVA 
was either improved or maintained (< 5 letters deterioration) in 88.6% of the eyes at week 78. Data 



87 

beyond Week 78 were generally consistent with these results but the number of enrolled subjects 
declined after this time. Overall, among the patients who discontinued the study, 18% discontinued 
due to adverse events, and 8% 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. 
 
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 
the reference medicinal product containing adalimumab in one or more subsets of the paediatric 
population in ulcerative colitis, see section 4.2 for information on paediatric use. 
 
5.2 Pharmacokinetic properties 
 
Absorption and distribution 
 
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 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). 
 
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 body size, adolescents with higher body weight and 
inadequate response may benefit from receiving the recommended adult dose of 40 mg every week. 
 



88 

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). 
 
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. 
 
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). 
 
Adults 
 
After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab 
was slow, with peak serum concentrations being reached about 5 days after administration. The 
average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg 
subcutaneous dose was 64 %. After single intravenous doses ranging from 0.25 to 10 mg/kg, 
concentrations were dose proportional. After doses of 0.5 mg/kg (~40 mg), clearances ranged from 11 
to 15 ml/hour, the distribution volume (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. 
 
In adult patients with psoriasis, the mean steady-state trough concentration was 5 μg/ml during 
adalimumab 40 mg every other week monotherapy treatment. 
 
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 



89 

approximately 8 to 10 μg/ml during adalimumab 40 mg every week treatment. 
 
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 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. 
 
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). 
 
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 citrate 
Citric acid monohydrate 
Histidine  
Histidine hydrochloride monohydrate 
Sorbitol 
Polysorbate 20  
Water for injections 
 
6.2 Incompatibilities 
 



90 

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial in the outer carton in order to protect 
from light. 
 
6.5 Nature and contents of container 
 
Imraldi 40 mg solution for injection in single-use vial (type I glass), fitted with rubber stoppers, 
aluminium crimps and flip-off seals. 
 
1 Pack of 2 boxes each containing: 
1 vial (0.8 ml sterile solution), 1 empty sterile injection syringe, 1 needle, 1 vial adapter and 2 alcohol 
pads. 
 
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 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616LR Delft 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1216/009 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 24 August 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. 

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


91 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 



92 

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)  
 
Biogen Inc. 
5000 Davis Drive 
Research Triangle Park 
North Carolina 
27709 
United States 
 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
3400 Hillerød 
Denmark 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
3400 Hillerød 
Denmark 
 
 
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 (PSURs) 
 
The requirements for submission of PSURs 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 marketing authorisation holder (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. 



93 

 

• Additional risk minimisation measures 
 

Prior to launch of Imraldi in each Member State the Marketing Authorisation Holder (MAH) must 
agree about the content and format of the educational programme, including distribution modalities, 
and any other aspects of the programme, with the National Competent Authority. The educational 
program consists of a Patient Reminder Card.  

 
The Patient Reminder Cards should contain the following key elements:  

• serious infections 
• tuberculosis 
• cancer 
• nervous system problems 
• vaccinations 



94 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



95 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



96 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (PRE-FILLED SYRINGE PACK) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imraldi 40 mg solution for injection in pre-filled syringe 
adalimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.8 ml pre-filled syringe contains 40 mg adalimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Sodium citrate, citric acid monohydrate, histidine, histidine hydrochloride monohydrate, 
sorbitol, polysorbate 20, and water for injections. 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 
 
Subcutaneous use. 
Read the package leaflet before use. 
 
Do not remove the needle cap before you are ready to inject. 
Open. 
 
For single use. 
 
 
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. 
 



97 

 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
Keep the syringe 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 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616 LR Delft 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1216/001 1 pre-filled syringe 
EU/1/17/1216/002 2 pre-filled syringes 
EU/1/17/1216/003 4 pre-filled syringes 
EU/1/17/1216/004 6 pre-filled syringes 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Imraldi 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 



98 

2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



99 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PRE-FILLED SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Imraldi 40 mg injection 
adalimumab 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
40 mg/0.8 ml 
 
 
6. OTHER 
 
 



100 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (PRE-FILLED PEN PACK) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imraldi 40 mg solution for injection in pre-filled pen 
adalimumab  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.8 ml pre-filled pen contains 40 mg adalimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Sodium citrate, citric acid monohydrate, histidine, histidine hydrochloride monohydrate, 
sorbitol, polysorbate 20, and water for injections. 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 
 
Subcutaneous use. 
Read the package leaflet before use. 
 
Do not remove the needle cap before you are ready to inject. 
There is no button on your pre-filled pen. 
 
Open. 
 
For single use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 



101 

Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
Keep the pen 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 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616 LR Delft 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1216/005 1 pre-filled pen 
EU/1/17/1216/006 2 pre-filled pens 
EU/1/17/1216/007 4 pre-filled pens 
EU/1/17/1216/008 6 pre-filled pens 
 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Imraldi 40 mg 
 



102 

 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



103 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PRE-FILLED PEN LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Imraldi 40 mg injection 
adalimumab 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
40 mg/0.8 ml 
 
 
6. OTHER 
 
 



104 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (VIAL PACK) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imraldi 40 mg/0.8 ml solution for injection 
adalimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.8 ml vial contains 40 mg adalimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Sodium citrate, citric acid monohydrate, histidine, histidine hydrochloride monohydrate, 
sorbitol, polysorbate 20, and water for injections. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
solution for injection 
Contains 2 cartons each for a single injection only 
Contains 2 cartons and 
each carton contains: 
1 vial 
1 sterile injection syringe 
1 sterile needle 
1 sterile vial adapter 
2 alcohol pads 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
 
Read the package leaflet before use. 
 
Open. 
 
For single use only. 
 
For paediatric use. 
 
 
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. 
 
 



105 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
Keep the vial 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 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616LR Delft 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1216/009 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Imraldi 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 



106 

 
PC 
SN 
NN 
 
 



107 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INNER CARTON (VIAL PACK) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imraldi 40 mg/0.8 ml solution for injection 
adalimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each 0.8 ml vial contains 40 mg adalimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Sodium citrate, citric acid monohydrate, histidine, histidine hydrochloride monohydrate, 
sorbitol, polysorbate 20, and water for injections. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
solution for injection 
1 vial 
1 sterile injection syringe 
1 sterile needle 
1 sterile vial adapter 
2 alcohol pads 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Subcutaneous use. 
 
Read the package leaflet before use. 
 
Open. 
 
For single use only. 
 
For paediatric use. 
 
 
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 
 
 



108 

8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
Keep the vial 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 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616LR Delft 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1216/009 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Imraldi 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 



109 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Imraldi 40 mg/0.8 ml injection 
adalimumab 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
40 mg/0.8 ml 
 
 
6. OTHER 
 
For single use only 
 
 



110 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



111 

Package leaflet: Information for the patient 
 

Imraldi 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 Reminder Card, which contains important safety 

information that you need to be aware of before you are given Imraldi and during treatment with 
Imraldi. Keep this Patient Reminder Card with you during your treatment and for 4 months after 
your (or your child’s) last injection of Imraldi. 

- If you have any further questions, please 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 Imraldi is and what it is used for  
2. What you need to know before you use Imraldi 
3. How to use Imraldi  
4. Possible side effects  
5. How to store Imraldi  
6. Contents of the pack and other information 
7. Instructions for use 
 
 
1. What Imraldi is and what it is used for 
 
Imraldi contains the active substance adalimumab, a medicine that acts on your body’s immune 
(defence) system. 
 
Imraldi is intended for treatment of: 
 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 Imraldi, 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, Imraldi decreases 
the process of inflammation in these diseases. 



112 

 
Rheumatoid arthritis 
 
Rheumatoid arthritis is an inflammatory disease of the joints. 
 
Imraldi 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 Imraldi to treat your rheumatoid arthritis. 
 
Imraldi can also be used to treat severe, active and progressive rheumatoid arthritis without previous 
methotrexate treatment. 
 
Imraldi can slow down the damage to the cartilage and bone of the joints caused by the disease and 
improve physical function. 
 
Usually, Imraldi is used with methotrexate. If your doctor considers that methotrexate is inappropriate, 
Imraldi 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. 
 
Imraldi 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 Imraldi 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. 
 
Imraldi 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 Imraldi to reduce the signs 
and symptoms of your disease. 
 
Psoriatic arthritis 
 
Psoriatic arthritis is an inflammatory disease of the joints associated with psoriasis. 
 
Imraldi is used to treat psoriatic arthritis in adults. Imraldi can slow down the damage to the cartilage 
and bone of the joints caused by the disease and to 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. 
 



113 

Imraldi is used to treat moderate to severe plaque psoriasis in adults. Imraldi is also used to treat 
severe plaque psoriasis in children and adolescents weighing 30 kg or greater for whom topical 
therapy and phototherapies have either not worked very well or are not suitable. 
 
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. 
 
Imraldi is used to treat hidradenitis suppurativa in adults and adolescents from 12 years of age. Imraldi 
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 Imraldi. 
 
Crohn’s disease in adults and children 
 
Crohn’s disease is an inflammatory disease of the digestive tract. 
 
Imraldi 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 Imraldi to reduce the signs and symptoms of your Crohn’s disease. 
 
Ulcerative colitis 
 
Ulcerative colitis is an inflammatory disease of the bowel. 
 
Imraldi 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 Imraldi 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.  
 
Imraldi 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). Imraldi works by reducing this inflammation. 
 
 
2. What you need to know before you use Imraldi 
 
Do not use Imraldi 
- 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”). 

 
Warnings and precautions 



114 

 
Talk to your doctor or pharmacist before using Imraldi. 
 
Allergic reaction 
 
• If you have allergic reactions with symptoms such as chest tightness, wheezing, dizziness, 

swelling or rash do not inject more Imraldi 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 Imraldi. If you are unsure, contact your doctor.  
• You might get infections more easily while you are receiving Imraldi 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 Imraldi. 

 
Tuberculosis 
 
• As cases of tuberculosis have been reported in patients treated with Imraldi, your doctor will 

check you for signs and symptoms of tuberculosis before starting Imraldi. 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 Reminder 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 active HBV 

infection or if you think you might be at risk of contracting HBV. Your doctor should test you 
for HBV. Imraldi 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 Imraldi. You 

and your doctor should pay special attention to signs of infection while you are being treated 
with Imraldi. It is important to tell your doctor if you get symptoms of infections, such as fever, 
wounds, feeling tired or dental problems. 

 
Surgery or dental procedure 
 



115 

• If you are about to have surgery or dental procedures tell your doctor that you are taking 
Imraldi. Your doctor may recommend temporary discontinuation of Imraldi. 

 
Demyelinating disease 
 
• If you have or develop 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 Imraldi. 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 disease-causing bacteria or viruses, and 

these vaccines should not be given while receiving Imraldi. 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 Imraldi. If you receive Imraldi 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 Imraldi 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 Imraldi, 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 Imraldi. 

 
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 Imraldi 

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 Imraldi 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 
Imraldi. Some of those patients were also treated with the medicines azathioprine or 
mercaptopurine. Tell your doctor if you are taking azathioprine or mercaptopurine with Imraldi. 

• In addition, cases of non-melanoma skin cancer have been observed in patients taking Imraldi. 
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 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 
 



116 

• On rare occasions, treatment with Imraldi 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 
 
• Do not give Imraldi 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 Imraldi 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Imraldi 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 Imraldi 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 Imraldi injection. 
• 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. 
• Imraldi 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. 

• Imraldi can be used during breast-feeding. 
• If you received Imraldi 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 

Imraldi 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 
 
Imraldi 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 Imraldi. 
 
Imraldi contains sodium and sorbitol 
 
This medicinal product contains 20 mg sorbitol in each pre-filled syringe. If you have been told by 
your doctor that you have an intolerance to some sugars, contact your doctor before taking this 
medicinal product. 
 
Also this medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8 ml dose, i.e. 
essentially ‘sodium-free’. 
 
 
3. How to use Imraldi 
 



117 

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 
 
Imraldi is injected under the skin (subcutaneous use). 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 two weeks as a 
single dose. 
 
In rheumatoid arthritis, methotrexate is continued while using Imraldi. If your doctor determines that 
methotrexate is inappropriate, Imraldi can be given alone. 
 
If you have rheumatoid arthritis and you do not receive methotrexate with your Imraldi 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 
 
The recommended dose of Imraldi is 20 mg every other week. 
 
Children, adolescents and adults from 2 years of age weighing 30 kg or more 
 
The recommended dose of Imraldi 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 
 
The recommended dose of Imraldi is 20 mg every other week. 
 
Children, adolescents and adults from 6 years of age weighing 30 kg or more 
 
The recommended dose of Imraldi 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 Imraldi 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 
 
The recommended dose of Imraldi is an initial dose of 20 mg, followed by 20 mg one week later. 
Thereafter, the usual dose is 20 mg every other week. 
 
Children and adolescents from 4 to 17 years of age weighing 30 kg or more 
 
The recommended dose of Imraldi is an initial dose of 40 mg, followed by 40 mg one week later. 
Thereafter, the usual dose is 40 mg every other week. 
 



118 

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 dose 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 Imraldi 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 to 
Imraldi 40 mg every other week, 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 
 
The usual dose regimen is 40 mg initially followed by 20 mg two weeks later. If a faster response is 
required, your doctor may prescribe an initial dose of 80 mg (as two 40 mg injections in one day) 
followed by 40 mg two weeks later. 
 
Thereafter, the usual dose is 20 mg every other week. Depending on your response, your doctor may 
increase the dose frequency to 20 mg every week. 
 
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 Imraldi dose for adults with ulcerative colitis is 160 mg initially (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 and thereafter 40 mg every other week. If this dose does 
not work well enough, your doctor may increase the dose to 40 mg every week or 80 mg every other 
week. 
 
Adults with non-infectious uveitis 



119 

 
The usual dose for adults with non-infectious uveitis 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 Imraldi 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 Imraldi. Imraldi 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 
 
The usual dose of Imraldi is 20 mg every other week with methotrexate. 
 
Your child’s doctor may also prescribe an initial dose of 40 mg which may be administered one week 
prior to the start of the usual dose. 
 
Children and adolescents from 2 years of age weighing 30 kg or more 
 
The usual dose of Imraldi 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 
 
Imraldi is given by injection under the skin (by subcutaneous injection). For instructions for use, refer 
to section 7. 
 
If you use more Imraldi than you should 
 
If you accidentally inject Imraldi 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 Imraldi 
 
If you forget to give yourself an injection, you should inject the next dose of Imraldi 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 Imraldi 
 
The decision to stop using Imraldi 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 Imraldi injection. 
 
Seek medical attention urgently if you notice any of the following: 
• severe rash, hives or other signs of allergic reaction; 



120 

• 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); 



121 

• sensation of heart beating rapidly; 
• high blood pressure; 
• flushing; 
• haematoma (a solid swelling 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; 
• myocardial infarction; 
• 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; 



122 

• facial oedema; 
• gallbladder inflammation, gallbladder stones; 
• fatty liver (build up of fat in liver cells); 
• 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 (localized 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; 



123 

• 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; 
• 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 Imraldi 
 
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 of the 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 Imraldi pre-filled syringe may be stored 
at room temperature (up to 25°C) for a maximum period of 28 days – be sure to protect it from light. 
Once removed from the refrigerator for room temperature storage, the syringe must be used within 
28 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 Imraldi contains  
 
- The active substance is adalimumab. 

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


124 

- The other ingredients are sodium citrate, citric acid monohydrate, histidine, histidine 
hydrochloride monohydrate, sorbitol, polysorbate 20 and water for injections. 

 
What Imraldi looks like and contents of the pack 
 
Imraldi 40 mg solution for injection in pre-filled syringe is supplied as a 0.8 ml clear and colourless 
solution. 
 
Imraldi is available in packs containing 1, 2, 4 or 6 pre-filled syringe(s) (type I glass) with a stainless 
steel needle, a rigid needle shield, a rubber plunger, a plunger rod, a safe-shield body, a finger flange 
and 2, 2, 4 or 6 alcohol pads enclosed in packs respectively. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616 LR Delft 
The Netherlands 
 
 
Manufacturer 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
3400 Hillerød 
Denmark 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien  
Biogen Belgium NV/S.A  
Tél/Tel: + 32 (0)2 808 5947 

Lietuva  
Ewopharma AG Atstovybė 
Tel: +370 52 14 02 60 
 

България  
Ewopharma AG Representative Office 
Teл.: + 359 249 176 81 
 

Luxembourg/Luxemburg  
Biogen Belgium NV/SA  
Tél/Tel: +35 227 772 038 
 

Česká republika  
Biogen (Czech Republic) s.r.o.  
Tel: + 420 228 884 152 
 

Magyarország  
Biogen Hungary Kft.  
Tel.: + 36 (0)6 1 848 04 64 
 

Danmark  
Biogen (Denmark) A/S  
Tlf: + 45 78 79 37 53 
 

Malta  
Pharma.MT Ltd 
Tel: + 356 27 78 15 79 
 

Deutschland  
Biogen GmbH  
Tel: + 49 (0)30 223 864 72 

Nederland  
Biogen Netherlands B.V.  
Tel: + 31 (0)20 808 02 70 
 

Eesti  
Ewopharma AG Eesti filiaal 
Tel: + 372 6 68 30 56 
 

Norge  
Biogen Norway AS  
Tlf: + 47 21 93 95 87 
 

Ελλάδα  
Genesis Pharma S.A. 
Τηλ: + 30 211 176 8555 

Österreich  
Biogen Austria GmbH  
Tel: + 43 (0)1 267 51 42 



125 

 

España  
Biogen Spain, S.L.  
Tel: + 34 931 790 519 
 

Polska  
Biogen Poland Sp. z o.o.  
Tel.: + 48 22 116 86 94 
 

France  
Biogen France SAS  
Tél: + 33 (0)1 776 968 14 
 

Portugal  
Biogen Portugal Sociedade Farmacêutica,  
Unipessoal, Lda  
Tel: + 351 308 800 792 
 

Hrvatska  
Ewopharma d.o.o 
Tel: + 385 (0)1 777 64 37 
 

România  
Ewopharma AG Representative Office 
Tel: + 40 377 881 045 
 

Ireland  
Biogen Idec (Ireland) Ltd.  
Tel: +353 (0)1 513 33 33 
 

Slovenija  
Biogen Pharma d.o.o.  
Tel: + 386 (0)1 888 81 07 
 

Ísland  
Icepharma hf. 
Sími: + 354 800 9836 
 

Slovenská republika  
Biogen Slovakia s.r.o.  
Tel: + 421 (0)2 333 257 10 
 

Italia  
Biogen Italia s.r.l.  
Tel: + 39 (0)6 899 701 50 
 

Suomi/Finland  
Biogen Finland Oy  
Puh/Tel: + 358 (0)9 427 041 08 
 

Κύπρος  
Genesis Pharma (Cyprus) Ltd 
Τηλ: + 357 22 00 04 93 
 

Sverige  
Biogen Sweden AB  
Tel: +46 (0)8 525 038 36 

Latvija 
Ewopharma AG pārstāvniecība 
Tel: + 371 66 16 40 32 
 

United Kingdom  
Biogen Idec Limited (UK) 
Tel: +44 (0)20 360 886 22 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
 



126 

7. Instructions for use 
 
Follow this instruction guide carefully, and soon you will develop a routine for injecting confidently. 
• Before you inject, ask your doctor or nurse to show you how to use your pre-filled syringe. 

Your doctor or nurse should make sure you can use your syringe correctly. 
 
Your single-dose pre-filled syringe 
 

 
 
After you push the plunger all the way down, the needle will retract to help prevent needle stick injury. 
 
Caring for your pre-filled syringe 
 
Syringe storage 
• Store your syringe in the refrigerator, but do not freeze it. 
• Keep your syringe in its carton, and away from light. 
• Keep the syringe out of the sight and reach of children. 
 
Syringe disposal 
• Use each syringe only once. Never reuse a syringe. 
• Throw away your used syringe in a special container as instructed by your doctor, nurse or 

pharmacist. 
 

Cautions 
• If you dropped your syringe with the cap ON, it is okay to use the syringe. 

If you dropped your syringe with the cap OFF, do not use it. The needle might be dirty or 
damaged. 

• Do not use a damaged syringe. 
 
Injection site care 
 
• Choose a fatty area for injection: 

Fatty areas, like your stomach, are generally the best injection sites. Fatty areas are easier to 
pinch and are good for inserting the needle correctly. 

• Use a different injection site every time: 
When choosing an injection site, select an area that has not recently been used to avoid soreness 
and bruises. 



127 

• Press plunger slowly: 
Sometimes, fast injections can be painful. If you press the syringe plunger slowly, it may make 
your injection more comfortable. 
 

How to inject with your pre-filled syringe 
 

1. Gather supplies 

 
Place your pre-filled syringe and alcohol pads on a clean, dry surface.  
 Remember to wash your hands! 
 Do not remove the cap just yet! 
 
2. Wait 15-30 minutes 

 
Wait 15-30 minutes for your pre-filled syringe to reach to room temperature, which helps reduce your 
pain during injection. 
 Do not remove the cap just yet! 

 
3. Inspect medicine & expiration date 

 
Always make sure your medicine is clear, free of particles, and has not expired. If your medication is 
not clear, free of particles, or expired, do not use it. 
You may see an air bubble, and that is okay. There is no reason to remove it. 
 Do not remove the cap just yet! 

 
4. Choose an injection site & clean skin 



128 

 
Choose an injection site on your body. Your abdomen (except the area around the navel) or thighs are 
best.  
Clean your injection site with an alcohol pad. Do not touch the area again before the injection. 
 Avoid skin that’s sore, bruised, scarred, scaly, or has red patches. 

 
5. Pull off needle cap 

 
 
Carefully pull off the needle cap. 
It is normal to see a few drops of liquid come out of the needle. 
If you take off the needle cap before you are ready to inject, do not put the needle cap back on. This 
could bend or damage the needle. You might accidentally stick yourself or waste medication. 

 
6. Pinch skin & insert needle  

 
Gently pinch your skin and insert the needle all the way at about a 45-degree angle. 

 
7. Push plunger all the way  



129 

 
Hold the syringe steady and press the plunger all the way down.  
Then lift your thumb to let the needle retract into the body of the syringe. 
 
8. Remove syringe & dispose 

 
Pull the syringe away from your skin.  
After injecting Imraldi, confirm that the needle has retracted and immediately throw away the used 
syringe in a special container as instructed by your doctor, nurse or pharmacist. 
 Not sure if you received your dose? Contact your doctor, nurse or pharmacist. 



130 

Package leaflet: Information for the patient 
 

Imraldi 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 Reminder Card,which contains important safety 

information that you need to be aware of before you are given Imraldi and during treatment with 
Imraldi. Keep this Patient Reminder Card with you during your treatment and for 4 months after 
your (or your child’s) last injection of Imraldi. 

- If you have any further questions, please 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 Imraldi is and what it is used for 
2. What you need to know before you use Imraldi 
3. How to use Imraldi 
4. Possible side effects 
5. How to store Imraldi 
6. Contents of the pack and other information 
7. Instructions for use 
 
 
1. What Imraldi is and what it is used for 
 
Imraldi contains the active substance adalimumab, a medicine that acts on your body’s immune 
(defence) system. 
 
Imraldi is intended for treatment of: 
• 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 Imraldi, adalimumab, is a monoclonal antibody. Monoclonal antibodies are 
proteins that attach to a specific target. 
 



131 

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, Imraldi decreases 
the process of inflammation in these diseases. 
 
Rheumatoid arthritis 
 
Rheumatoid arthritis is an inflammatory disease of the joints. 
 
Imraldi 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 Imraldi to treat your rheumatoid arthritis. 
 
Imraldi can also be used to treat severe, active and progressive rheumatoid arthritis without previous 
methotrexate treatment. 
 
Imraldi can slow down the damage to the cartilage and bone of the joints caused by the disease and 
improve physical function. 
 
Usually, Imraldi is used with methotrexate. If your doctor considers that methotrexate is inappropriate, 
Imraldi 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. 
 
Imraldi 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 Imraldi 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. 
 
Imraldi 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 Imraldi to reduce the signs 
and symptoms of your disease. 
 
Psoriatic arthritis 
 
Psoriatic arthritis is an inflammatory disease of the joints associated with psoriasis. 
 
Imraldi is used to treat psoriatic arthritis in adults. Imraldi can slow down the damage to the cartilage 
and bone of the joints caused by the disease and to 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 



132 

caused by a problem with the body’s immune system that leads to an increased production of skin 
cells. 
 
Imraldi is used to treat moderate to severe plaque psoriasis in adults. Imraldi is also used to treat 
severe plaque psoriasis in children and adolescents weighing 30 kg or greater for whom topical 
therapy and phototherapies have either not worked very well or are not suitable. 
 
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. 
 
Imraldi is used to treat hidradenitis suppurativa in adults and adolescents from 12 years of age. Imraldi 
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 Imraldi. 
 
Crohn’s disease in adults and children 
 
Crohn’s disease is an inflammatory disease of the digestive tract. 
 
Imraldi 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 Imraldi to reduce the signs and symptoms of your Crohn’s disease. 
 
Ulcerative colitis 
 
Ulcerative colitis is an inflammatory disease of the bowel. 
 
Imraldi 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 Imraldi 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.  
 
Imraldi 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). Imraldi works by reducing this inflammation. 
 
 
2. What you need to know before you use Imraldi 
 
Do not use Imraldi 
- 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. 



133 

- 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”). 

 
Warnings and precautions 
 
Talk to your doctor or pharmacist before using Imraldi. 
 
Allergic reaction 
 
• If you have allergic reactions with symptoms such as chest tightness, wheezing, dizziness, 

swelling or rash do not inject more Imraldi 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 Imraldi. If you are unsure, contact your doctor. 
• You might get infections more easily while you are receiving Imraldi 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 Imraldi. 

 
Tuberculosis 
 
• As cases of tuberculosis have been reported in patients treated with Imraldi, your doctor will 

check you for signs and symptoms of tuberculosis before starting Imraldi. 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 Reminder 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 active HBV 

infection or if you think you might be at risk of contracting HBV. Your doctor should test you 
for HBV. Imraldi 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 Imraldi. You 

and your doctor should pay special attention to signs of infection while you are being treated 



134 

with Imraldi. It is 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 surgery or dental procedures tell your doctor that you are taking 

Imraldi. Your doctor may recommend temporary discontinuation of Imraldi. 
 
Demyelinating disease 
 
• If you have or develop 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 Imraldi. 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 disease-causing bacteria or viruses, and 

these vaccines should not be given while receiving Imraldi. 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 Imraldi. If you receive Imraldi 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 Imraldi 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 Imraldi, 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 Imraldi. 

 
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 Imraldi 

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 Imraldi 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 
Imraldi. Some of those patients were also treated with the medicines azathioprine or 
mercaptopurine. Tell your doctor if you are taking azathioprine or mercaptopurine with Imraldi. 

• In addition, cases of non-melanoma skin cancer have been observed in patients taking Imraldi. 
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 



135 

blocker. If you have 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 Imraldi 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 
 
• Do not give Imraldi 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 Imraldi 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Imraldi 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 Imraldi 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 Imraldi injection.  
• 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. 
• Imraldi 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. 

• Imraldi can be used during breast-feeding. 
• If you received Imraldi 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 

Imraldi 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 
 
Imraldi 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 Imraldi. 
 
Imraldi contains sodium and sorbitol 
 
This medicinal product contains 20 mg sorbitol in each pre-filled pen. If you have been told by your 
doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal 
product. 
 
Also this medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8 ml dose, i.e. 
essentially ‘sodium-free’. 



136 

 
 
3. How to use Imraldi 
 
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 
 
Imraldi is injected under the skin (subcutaneous use). 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 two weeks as a 
single dose. 
 
In rheumatoid arthritis, methotrexate is continued while using Imraldi. If your doctor determines that 
methotrexate is inappropriate, Imraldi can be given alone. 
 
If you have rheumatoid arthritis and you do not receive methotrexate with your Imraldi 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 
 
The recommended dose of Imraldi is 20 mg every other week. 
 
Children, adolescents and adults from 2 years of age weighing 30 kg or more 
 
The recommended dose of Imraldi 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 
 
The recommended dose of Imraldi is 20 mg every other week. 
 
Children, adolescents and adults from 6 years of age weighing 30 kg or more 
 
The recommended dose of Imraldi 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 Imraldi 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 
 
The recommended dose of Imraldi is an initial dose of 20 mg, followed by 20 mg one week later. 
Thereafter, the usual dose is 20 mg every other week. 
 
Children and adolescents from 4 to 17 years of age weighing 30 kg or more 



137 

 
The recommended dose of Imraldi 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 Imraldi 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 to 
Imraldi 40 mg every other week, 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 
 
The usual dose regimen is 40 mg initially followed by 20 mg two weeks later. If a faster response is 
required, your doctor may prescribe an initial dose of 80 mg (as two 40 mg injections in one day) 
followed by 40 mg two weeks later. 
 
Thereafter, the usual dose is 20 mg every other week. Depending on your response, your doctor may 
increase the dose frequency to 20 mg every week. 
 
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 Imraldi dose for adults with ulcerative colitis is 160 mg initially (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 and thereafter 40 mg every other week. If this dose does 



138 

not work well enough, your doctor may increase the dosage to 40 mg every week or 80 mg every other 
week. 
 
Adults with non-infectious uveitis 
 
The usual dose for adults with non-infectious uveitis 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 Imraldi 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 Imraldi. Imraldi 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 
 
The usual dose of Imraldi is 20 mg every other week with methotrexate. 
 
Your child’s doctor may also prescribe an initial dose of 40 mg which may be administered one week 
prior to the start of the usual dose. 
 
Children and adolescents from 2 years of age weighing 30 kg or more 
 
The usual dose of Imraldi 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 
 
Imraldi is given by injection under the skin (by subcutaneous injection). For instructions for use, refer 
to section 7. 
 
If you use more Imraldi than you should 
 
If you accidentally inject Imraldi 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 Imraldi 
 
If you forget to give yourself an injection, you should inject the next dose of Imraldi 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 Imraldi 
 
The decision to stop using Imraldi 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 
 



139 

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



140 

• 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; 
• haematoma (a solid swelling 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; 
• myocardial infarction; 
• a sac in the wall of a major artery, inflammation and clot of a vein; blockage of a blood vessel; 



141 

• 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); 
• 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 (localized 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; 



142 

• 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; 
• low blood potasium. 
 
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 Imraldi 
 
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 of the 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 Imraldi pre-filled pen may be stored at 
room temperature (up to 25°C) for a maximum period of 28 days – be sure to protect it from light. 
Once removed from the refrigerator for room temperature storage, the pen must be used within 
28 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 

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


143 

 
What Imraldi contains  
 
- The active substance is adalimumab. 
- The other ingredients are sodium citrate, citric acid monohydrate, histidine, histidine 

hydrochloride monohydrate, sorbitol, polysorbate 20, and water for injections. 
 
What Imraldi looks like and contents of the pack 
 
Imraldi 40 mg solution for injection in pre-filled pen is supplied as a 0.8 ml clear and colourless 
solution. 
 
Imraldi is available in packs containing 1, 2, 4 or 6 pre-filled pen(s) containing a pre-filled syringe 
(type I glass) with a stainless steel needle, a rigid needle shield, a rubber plunger for patient use and 2, 
2, 4 or 6 alcohol pads are enclosed in packs respectively. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616 LR Delft 
The Netherlands 
 
 
Manufacturer 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
3400 Hillerød 
Denmark 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien  
Biogen Belgium NV/S.A  
Tél/Tel: + 32 (0)2 808 5947 

Lietuva  
Ewopharma AG Atstovybė 
Tel: +370 52 14 02 60 
 

България  
Ewopharma AG Representative Office  
Teл.: + 359 249 176 81 
 

Luxembourg/Luxemburg  
Biogen Belgium NV/SA  
Tél/Tel: +35 227 772 038 
 

Česká republika  
Biogen (Czech Republic) s.r.o.  
Tel: + 420 228 884 152 
 

Magyarország  
Biogen Hungary Kft.  
Tel.: + 36 (0)6 1 848 04 64 
 

Danmark  
Biogen (Denmark) A/S  
Tlf: + 45 78 79 37 53 
 

Malta  
Pharma.MT Ltd 
Tel: + 356 27 78 15 79 
 

Deutschland  
Biogen GmbH  
Tel: + 49 (0)30 223 864 72 

Nederland  
Biogen Netherlands B.V.  
Tel: + 31 (0)20 808 02 70 
 

Eesti  
Ewopharma AG Eesti filiaal 
Tel: + 372 6 68 30 56 

Norge  
Biogen Norway AS  
Tlf: + 47 21 93 95 87 



144 

  

Ελλάδα  
Genesis Pharma S.A. 
Τηλ: + 30 211 176 8555 

Österreich  
Biogen Austria GmbH  
Tel: + 43 (0)1 267 51 42 
 

España  
Biogen Spain, S.L.  
Tel: + 34 931 790 519 
 

Polska  
Biogen Poland Sp. z o.o.  
Tel.: + 48 22 116 86 94 
 

France  
Biogen France SAS  
Tél: + 33 (0)1 776 968 14 
 

Portugal  
Biogen Portugal Sociedade Farmacêutica,  
Unipessoal, Lda  
Tel: + 351 308 800 792 
 

Hrvatska  
Ewopharma d.o.o  
Tel: + 385 (0)1 777 64 37 
 

România  
Ewopharma AG Representative Office  
Tel: + 40 377 881 045 
 

Ireland  
Biogen Idec (Ireland) Ltd.  
Tel: +353 (0)1 513 33 33 
 

Slovenija  
Biogen Pharma d.o.o.  
Tel: + 386 (0)1 888 81 07 
 

Ísland  
Icepharma hf.  
Sími: + 354 800 9836 
 

Slovenská republika  
Biogen Slovakia s.r.o.  
Tel: + 421 (0)2 333 257 10 
 

Italia  
Biogen Italia s.r.l.  
Tel: + 39 (0)6 899 701 50 
 

Suomi/Finland  
Biogen Finland Oy  
Puh/Tel: + 358 (0)9 427 041 08 
 

Κύπρος  
Genesis Pharma (Cyprus) Ltd 
Τηλ: + 357 22 00 04 93 
 

Sverige  
Biogen Sweden AB  
Tel: +46 (0)8 525 038 36 

Latvija 
Ewopharma AG pārstāvniecība 
Tel: + 371 66 16 40 32 
 

United Kingdom  
Biogen Idec Limited (UK) 
Tel: +44 (0)20 360 886 22 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 



145 

7. Instructions for use 
 
Follow this instruction guide carefully, and soon you will develop a routine for injecting confidently. 
• Before you inject, ask your doctor or nurse to show you how to use your pre-filled pen. Your 

doctor or nurse should make sure you can use your pen correctly. 
 
Your single-dose pre-filled pen 
 

 
 
There is no button on your pre-filled pen. 
The needle is hidden below the green base. When you push the pre-filled pen firmly onto your skin, 
the injection will start automatically. 
 
Caring for your pre-filled pen 
 
Pen storage 
• Store your pen in the refrigerator, but do not freeze it. 
• Keep your pen in its carton, and away from light. 
• Keep the pen out of the sight and reach of children. 
 
Pen disposal 
• Use each pen only once. Never reuse a pen. 
• Throw away your used pen in a special container as instructed by your doctor, nurse or 

pharmacist. 
 

Cautions 
• If you dropped your pen with the cap ON, it is okay to use the pen. 

If you dropped your pen with the cap OFF, do not use it. The needle might be dirty or damaged.  
• Do not use a damaged pen. 



146 

Injection site care 
 
• Choose a fatty area for injection: 

Fatty areas, like your stomach, are generally the best injection sites. Fatty areas are good for 
inserting the needle correctly. 

• Use a different injection site every time: 
When choosing an injection site, select an area that has not recently been used to avoid soreness 
and bruises. 

 
How to inject with your pre-filled pen 

 
1. Gather supplies 

 
Place your pre-filled pen and alcohol pads on a clean, dry surface.  
• Remember to wash your hands! 
• Do not remove the cap just yet! 
 
2. Wait 15-30 minutes 

 
Wait 15-30 minutes for your pre-filled pen to reach to room temperature, which helps reduce your 
pain during injection. 
• Do not remove the cap just yet!  
 
3. Inspect medicine & expiration date 



147 

 
Always make sure your medicine is clear, free of particles, and has not expired. If your medication is 
not clear, free of particles, or expired, do not use it. 
You may see an air bubble, and that is okay. There is no reason to remove it. 
• Do not remove the cap just yet! 
 
4. Choose an injection site & clean skin 

 
Choose an injection site on your body. Your abdomen (except the area around the navel) or thighs are 
best.  
Clean your injection site with an alcohol pad. Do not touch the area again before the injection. 
• Avoid skin that is sore, bruised, scarred, scaly, or has red patches. 
 
5. Pull off the clear needle cap 

 
Carefully pull off the clear needle cap with a metal center from the pen.  
It is normal to see a few drops of liquid come out of the needle. 
If you take off the needle cap before you are ready to inject, do not put the needle cap back on. This 
could bend or damage the needle. You might accidentally stick yourself or waste medication. 
 
6. Place greenbase, press down, and hold 



148 

 
Place the greenbase straight (90 degrees) on your skin, and push the entire pre-filled pen down firmly 
to start the injection. 
• When you push down, the injection starts. You may hear a 1st click. 
 
7. Continue to hold 

 
Hold the pen against your skin until the yellow indicator fills the medication window and stops 
moving. 
• Several seconds later you may hear a 2nd click. 
 
8. Confirm completion & dispose 

 
After injecting Imraldi, confirm that the entire medication window is yellow. 
Throw away the used pen in a special container as instructed by your doctor, nurse or pharmacist. 
•  Not sure if you received your dose? Contact your doctor, nurse or pharmacist. 



149 

Package leaflet: Information for the patient 
 

Imraldi 40 mg/0.8 ml solution for injection 
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 your child starts using this medicine because it contains 
important information. 
- Keep this leaflet. You may need to read it again.  
- Your doctor will also give you a Patient Reminder Card, which contains important safety 

information that you need to be aware of before your child is given Imraldi and during treatment 
with Imraldi. Keep this Patient Reminder Card with you or your child during his/her treatment 
and for 4 months after your child’s last injection of Imraldi. 

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

them, even if their signs of illness are the same as your child's.  
- If your child gets any side effects, talk to your child’s doctor or pharmacist. This includes any 

possible side effects not listed in this leaflet (See section 4). 
 
What is in this leaflet 
 
1. What Imraldi is and what it is used for  
2. What you need to know before your child uses Imraldi 
3. How to use Imraldi  
4. Possible side effects  
5. How to store Imraldi  
6. Contents of the pack and other information 
7. Instructions for use 
 
 
1. What Imraldi is and what it is used for 
 
Imraldi contains the active substance adalimumab, a medicine that acts on your body’s immune 
(defence) system. 
 
Imraldi is intended for treatment of: 
• polyarticular juvenile idiopathic arthritis, 
• enthesitis-related arthritis,  
• paediatric plaque psoriasis,  
• adolescent hidradenitis suppurativa,  
• paediatric Crohn’s disease, 
• paediatric uveitis. 
 
The active ingredient in Imraldi, 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, Imraldi decreases 
the process of inflammation in these diseases. 
 
Polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis 
 



150 

Polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis are inflammatory diseases of 
the joints that usually first appear in childhood. 
 
Imraldi is used to treat polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis. 
Patients may first be given other disease-modifying medicines, such as methotrexate. If these 
medicines do not work well enough, patients will be given Imraldi to treat their polyarticular juvenile 
idiopathic arthritis or enthesitis-related arthritis. 
 
Paediatric plaque psoriasis 
 
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. 
 
Imraldi is used to treat severe plaque psoriasis in children and adolescents aged 4 to 17 years in whom 
topical therapy and phototherapies have either not worked very well or are not suitable. 
 
Adolescent hidradenitis suppurativa 
 
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. 
 
Imraldi is used to treat hidradenitis suppurativa in adolescents from 12 years of age. Imraldi 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 Imraldi. 
 
Paediatric Crohn’s disease 
 
Crohn’s disease is an inflammatory disease of the digestive tract. 
 
Imraldi is indicated for the treatment of Crohn’s disease in children aged 6 to 17 years. Patients may 
first be given other medicines. If these medicines do not work well enough, patients will be given 
Imraldi to reduce the signs and symptoms of your disease. 
 
Paediatric uveitis 
 
Non-infectious uveitis is an inflammatory disease affecting certain parts of the eye. 
 
Imraldi is used to treat 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). 
Imraldi works by reducing this inflammation. 
 
2. What you need to know before your child uses Imraldi 
 
Do not use Imraldi 
- If your child is allergic to adalimumab or any of the other ingredients of this medicine (listed in 

section 6). 
- If your child has a severe infection, including tuberculosis (see “Warnings and precautions”). It 

is important that you tell your doctor if your child has symptoms of infections, e.g. fever, 
wounds, feeling tired, dental problems.  



151 

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

 
Warnings and precautions 
 
Talk to your child’s doctor or pharmacist before using Imraldi. 
 
Allergic reaction 
 
• If your child has allergic reactions with symptoms such as chest tightness, wheezing, dizziness, 

swelling or rash do not inject more Imraldi and contact your doctor immediately since, in rare 
cases, these reactions can be life-threatening. 

 
Infection 
 
• If your child has an infection, including long-term or localised infection (for example, leg ulcer) 

consult your doctor before starting Imraldi. If you are unsure, contact your doctor.  
• Your child might get infections more easily while receiving Imraldi treatment. This risk may 

increase if his/her 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 your child gets symptoms such as fever, wounds, feeling tired or dental problems. 
Your doctor may recommend temporary discontinuation of Imraldi. 

 
Tuberculosis 
 
• As cases of tuberculosis have been reported in patients treated with Imraldi, your doctor will 

check your child for signs and symptoms of tuberculosis before starting Imraldi. This will 
include a thorough medical evaluation including your child’s 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 child’s Patient Reminder Card. It is very important that you tell your 
doctor if your child has ever had tuberculosis, or if he/she has been in close contact with 
someone who has had tuberculosis. Tuberculosis can develop during therapy even if your child 
has 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 your child resides or travels in regions where fungal infections such as 

histoplasmosis, coccidioidomycosis or blastomycosis are endemic. 
• Tell your doctor if your child has a history of recurrent infections or other conditions that 

increase the risk of infections. 
 
Hepatitis B virus 
 
• Tell your doctor if your child is a carrier of the hepatitis B virus (HBV), if he/she has active 

HBV infection or if you think he/she might be at risk of contracting HBV. Your child’s doctor 
should test your child for HBV. Imraldi can reactivate HBV infection in people who carry this 
virus. In some rare cases, especially if your child is taking other medicines that suppress the 
immune system, reactivation of HBV infection can be life-threatening. 

 
Surgery or dental procedure 
 
• If your child is about to have surgery or dental procedures tell your doctor that he/she is 

taking Imraldi. Your doctor may recommend temporary discontinuation. 



152 

 
Demyelinating disease 
 
• If your child has or develops a demyelinating disease (a disease that affects the insulating layer 

around the nerves, such as multiple sclerosis), your doctor will decide if he/she should receive 
or continue to receive Imraldi. Tell your doctor immediately if your child gets symptoms like 
changes in vision, weakness in arms or legs or numbness or tingling in any part of the body. 

 
Vaccine 
 
• Certain vaccines contain weakened but live forms of disease-causing bacteria or viruses, and 

these vaccines should not be given while receiving Imraldi. Check with your doctor before your 
child receives any vaccines. It is recommended that children, if possible, be given all the 
scheduled vaccinations for their age before they start treatment with Imraldi. If you receive 
Imraldi 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 Imraldi use during your 
pregnancy so they can decide when your baby should receive any vaccine. 

 
Heart Failure 
 
• If your child has mild heart failure and is being treated with Imraldi, his/her heart failure status 

must be closely monitored by your doctor. It is important to tell your doctor if your child has 
had or has a serious heart condition. If he/she develops new or worsening symptoms of heart 
failure (e.g. shortness of breath, or swelling of his/her feet), you must contact your doctor 
immediately. Your doctor will decide if your child should receive Imraldi. 

 
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 him/her to stop bleeding. If your child develops a fever that does not go away, or he/she 
bruises or bleeds very easily or looks 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 Imraldi 

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 
your child takes Imraldi 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 
Imraldi. Some of those patients were also treated with the medicines azathioprine or 
mercaptopurine. Tell your doctor if your child is taking azathioprine or mercaptopurine with 
Imraldi. 

• In addition, cases of non-melanoma skin cancer have been observed in patients taking Imraldi. 
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 your child has COPD, or is a heavy smoker, you should discuss with your doctor 
whether treatment with a TNFα blocker is appropriate for your child. 

 
Lupus-like syndrome 
 
• On rare occasions, treatment with Imraldi could result in lupus-like syndrome. Contact your 

doctor if symptoms such as persistent unexplained rash, fever, joint pain or tiredness occur 



153 

 
Other medicines and Imraldi 
 
Tell your child’s doctor or pharmacist if your child is taking, has recently taken or might take any 
other medicines. 
 
Imraldi 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). 
 
Your child should not take Imraldi 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 Imraldi injection.  
• 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. 
• Imraldi 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. 

• Imraldi can be used during breast-feeding. 
• If you received Imraldi 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 Imraldi 
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 
 
Imraldi may have a minor influence on the ability to drive, cycle or use machines. Room spinning 
sensation (vertigo) and vision disturbances may occur after taking Imraldi. 
 
Imraldi contains sodium and sorbitol 
 
This medicinal product contains 20 mg sorbitol in each vial. If your child has been told by doctor that 
he/she has an intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
Also this medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8 ml dose, i.e. 
essentially ‘sodium-free’. 
 
 
3. How to use Imraldi 
 
Always use this medicine exactly as your child’s doctor or pharmacist has instructed. Check with your 
child’s doctor or pharmacist if you are not sure about any of the instructions or if you have any 
questions. Your doctor may prescribe another strength of Imraldi if your child needs a different dose. 
 
Children and adolescents with polyarticular juvenile idiopathic arthritis 
 
Children and adolescents from 2 years of age weighing 10 kg to less than 30 kg 
 
The recommended dose of Imraldi is 20 mg every other week. 
 
Children and adolescents from 2 years of age weighing 30 kg or more 



154 

 
The recommended dose of Imraldi is 40 mg every other weeks. 
 
Children, adolescents and adults with enthesitis-related arthritis 
 
Children and adolescents from 6 years of age weighing 15 kg to less than 30 kg 
 
The recommended dose of Imraldi is 20 mg every other week. 
 
Children, adolescents and adults from 6 years of age weighing 30 kg or more 
 
The recommended dose of Imraldi is 40 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 
 
The recommended dose of Imraldi is an initial dose of 20 mg, followed by 20 mg one week later. 
Thereafter, the usual dose is 20 mg every other week. 
 
Children and adolescents from 4 to 17 years of age weighing 30 kg or more 
 
The recommended dose of Imraldi is an initial dose of 40 mg, followed by 40 mg one week later. 
Thereafter, the usual dose is 40 mg every other week. 
 
Adolescents with hidradenitis suppurativa from 12 to 17 years of age weighing 30 kg or more 
 
The recommended dose of Imraldi 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 to 
Imraldi 40 mg every other week, 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. 
 
Children and adolescents with Crohn's disease 
 
Children and adolescents from 6 to 17 years of age weighing less than 40 kg 
 
The usual dose regimen is 40 mg initially followed by 20 mg two weeks later. If a faster response is 
required, your child’s doctor may prescribe an initial dose of 80 mg (as two 40-mg injections in 1 day) 
followed by 40 mg two weeks later. 
 
Thereafter, the usual dose is 20 mg every other week. If this dose does not work well enough, your 
child’s doctor may increase the dose frequency to 20 mg every week. 
 
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 child’s doctor may prescribe an initial dose of 
160 mg initially (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. 
 
Thereafter, the usual dose is 40 mg every other week. If this dose does not work well enough, your 
child’s doctor may increase the dosage to 40 mg every week or 80 mg every other week. 
 
Children and adolescents with chronic non-infectious uveitis from 2 years of age 
 



155 

Children and adolescents from 2 years of age weighing less than 30 kg 
 
The usual dose of Imraldi is 20 mg every other week with methotrexate. 
Your child’s doctor may also prescribe an initial dose of 40 mg which may be administered one week 
prior to the start of the usual dose. 
 
Children and adolescents from 2 years of age weighing 30 kg or more 
 
The usual dose of Imraldi is 40 mg every other week with methotrexate. 
Your child’s 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 
 
Imraldi is given by injection under the skin (by subcutaneous injection). For instructions for use, refer 
to section 7. 
 
If you use more Imraldi than you should 
 
If you accidentally inject a larger amount of Imraldi liquid, or if you inject Imraldi more frequently 
than you should, call your child’s doctor or pharmacist and explain that your child has taken more. 
Always take the outer carton or the vial of the medicine with you, even if it is empty. 
 
If you use less Imradi than you should 
 
If you accidentally inject a smaller amount of Imraldi liquid, or if you inject Imraldi less frequently 
than you should, call your child’s doctor or pharmacist and explain that your child has taken less. 
Always take the outer carton or the vial of the medicine with you, even if it is empty. 
 
If you forget to use Imraldi 
 
If you forget to give your child an injection, you should inject the Imraldi dose as soon as you 
remember. Then administer your child’s next dose as you would have on the originally scheduled day, 
had you not forgotten a dose. 
 
If you stop using Imraldi 
 
The decision to stop using Imraldi should be discussed with your child’s doctor. Your child’s 
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 Imraldi injection. 
 
Seek medical attention urgently if you notice any of the following: 
• severe rash, hives or other signs of allergic reaction; 
• 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: 



156 

• 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; 
• haematoma (a solid swelling with clotted blood); 
• cough; 



157 

• 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; 
• myocardial infarction; 
• 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); 
• night sweats; 
• scar;  



158 

• 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 (localized 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; 



159 

• high blood sugar; 
• high blood measurements for lactate dehydrogenase; 
• autoantibodies present in the blood; 
• 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 your child gets any side effects, talk to your child’s 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 Imraldi 
 
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 of the 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 vial in the outer carton in order to protect from light. 
 
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 Imraldi contains  
 
- The active substance is adalimumab. 
- The other ingredients are sodium citrate, citric acid monohydrate, histidine, histidine 

hydrochloride monohydrate, sorbitol, polysorbate 20 and water for injections. 
 
What Imraldi looks like and contents of the pack 
 
Imraldi 40 mg solution for injection in vial is supplied as a 0.8 ml clear and colourless solution. 
 
The Imraldi vial is a glass vial containing a solution of adalimumab. One pack contains 2 boxes, each 
containing 1 vial, 1 empty sterile syringe, 1 needle, 1 vial adapter and 2 alcohol pads. 
 
Imraldi may be available as a vial, a pre-filled syringe and/or a pre-filled pen. 
 
Marketing Authorisation Holder 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 

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


160 

2616LR Delft 
The Netherlands 
 
Manufacturer 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
3400 Hillerød 
Denmark 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien  
Biogen Belgium NV/S.A  
Tél/Tel: + 32 (0)2 808 5947 

Lietuva  
Ewopharma AG Atstovybė 
Tel: +370 52 14 02 60 
 

България  
Ewopharma AG Representative Office 
Teл.: + 359 249 176 81 
 

Luxembourg/Luxemburg  
Biogen Belgium NV/SA  
Tél/Tel: +35 227 772 038 
 

Česká republika  
Biogen (Czech Republic) s.r.o.  
Tel: + 420 228 884 152 
 

Magyarország  
Biogen Hungary Kft.  
Tel.: + 36 (0)6 1 848 04 64 
 

Danmark  
Biogen (Denmark) A/S  
Tlf: + 45 78 79 37 53 
 

Malta  
Pharma.MT Ltd 
Tel: + 356 27 78 15 79 
 

Deutschland  
Biogen GmbH  
Tel: + 49 (0)30 223 864 72 

Nederland  
Biogen Netherlands B.V.  
Tel: + 31 (0)20 808 02 70 
 

Eesti  
Ewopharma AG Eesti filiaal 
Tel: + 372 6 68 30 56 
 

Norge  
Biogen Norway AS  
Tlf: + 47 21 93 95 87 
 

Ελλάδα  
Genesis Pharma S.A. 
Τηλ: + 30 211 176 8555 

Österreich  
Biogen Austria GmbH  
Tel: + 43 (0)1 267 51 42 
 

España  
Biogen Spain, S.L.  
Tel: + 34 931 790 519 
 

Polska  
Biogen Poland Sp. z o.o.  
Tel.: + 48 22 116 86 94 
 

France  
Biogen France SAS  
Tél: + 33 (0)1 776 968 14 
 

Portugal  
Biogen Portugal Sociedade Farmacêutica,  
Unipessoal, Lda  
Tel: + 351 308 800 792 
 

Hrvatska  
Ewopharma d.o.o 
Tel: + 385 (0)1 777 64 37 
 

România  
Ewopharma AG Representative Office 
Tel: + 40 377 881 045 
 

Ireland  
Biogen Idec (Ireland) Ltd.  
Tel: +353 (0)1 513 33 33 
 

Slovenija  
Biogen Pharma d.o.o.  
Tel: + 386 (0)1 888 81 07 
 



161 

Ísland  
Icepharma hf. 
Sími: + 354 800 9836 
 

Slovenská republika  
Biogen Slovakia s.r.o.  
Tel: + 421 (0)2 333 257 10 
 

Italia  
Biogen Italia s.r.l.  
Tel: + 39 (0)6 899 701 50 
 

Suomi/Finland  
Biogen Finland Oy  
Puh/Tel: + 358 (0)9 427 041 08 
 

Κύπρος  
Genesis Pharma (Cyprus) Ltd 
Τηλ: + 357 22 00 04 93 
 

Sverige  
Biogen Sweden AB  
Tel: +46 (0)8 525 038 36 

Latvija 
Ewopharma AG pārstāvniecība 
Tel: + 371 66 16 40 32 
 

United Kingdom  
Biogen Idec Limited (UK) 
Tel: +44 (0)20 360 886 22 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
 



162 

7. Instructions for use 
 
The following instructions explain how to inject Imraldi. Please read the instructions carefully and 
follow them step by step. You will be instructed by your child's doctor or his/her assistant on the 
technique of injection and the amount to give to your child. Do not attempt to give your child an 
injection until you are sure that you understand how to prepare and give the injection. After proper 
training, the injection can be self-administered or given by another person, for example a family 
member or friend. 
 
Failure to perform the following steps as described may cause contamination which may lead to 
infection of your child. 
 
This injection should not be mixed in the same syringe or vial with any other medicine. 
 
Caring for your vial  
 
Vial storage 
• Store your vial in the refrigerator, but do not freeze it. 
• Keep your vial in its carton, and away from light. 
• Keep the vial out of the sight and reach of children. 
 
Vial disposal 
• Use each vial only once. Never reuse a vial and other components. 
• Throw away your used vial in a special container as instructed by your doctor, nurse or 

pharmacist. 
 
Injection site care 
 
• Choose a fatty area for injection: 

Fatty areas, like your stomach, are generally the best injection sites. Fatty areas are easier to 
pinch and are good for inserting the needle correctly. 

• Use a different injection site every time: 
When choosing an injection site, select an area that has not recently been used to avoid soreness 
and bruises. 

• Press plunger slowly: 
Sometimes, fast injections can be painful. If you press the syringe plunger slowly, it may make 
your injection more comfortable. 

 
How to inject with your vial 
 
1)  Setting up  
 
• Make sure you know the proper amount (volume) needed for dosing. If you don’t know the 

amount, STOP HERE and contact your doctor for further instruction. 
• You will need a special container for waste, such as a sharps container or as instructed by your 

nurse, doctor or pharmacist. Place the container on your work surface. 
• Wash your hands thoroughly 
• Remove one box containing, one syringe, one vial adapter, one vial, two alcohol pads and one 

needle from the carton. If there is a second box in the carton for a future injection, place it back 
in the refrigerator immediately. 

• Look at the expiry date on the box to be used. DO NOT use any item after the date shown on 
the box. 

• Set up the following items on a clean surface, DO NOT take them out of their individual 
packaging yet. 

 
o 1) One 1 ml syringe 



163 

o 2) One vial adapter  
o 3) One vial for paediatric use of Imraldi for injection 
o 4) Two alcohol swabs  
o 5) One needle 
 

 
 
• Imraldi is a liquid that is clear and colourless. DO NOT use if the liquid is not clear or not free 

of particles. 
 
2)  Preparing the Imraldi dose for injection 
 
General handling: DO NOT dispose of any waste items until after the injection is completed. 
 
• Prepare the needle by partially peeling the package open from the end closest to the yellow 

syringe connector. Peel the package just far enough to expose the yellow syringe connector.  
Set the package down with the clear side of the package facing up. 

 

 
 
• Pop off the white plastic cap from the vial to see the top of the vial stopper. 
 

 
 
• Use one of the alcohol pads to wipe the vial stopper. DO NOT touch the vial stopper after 

wiping with the alcohol pad. 



164 

• Peel the cover off the vial adapter package but do not take out the vial adapter. 
 

 
 
• Hold the vial with the vial stopper facing up. 
• With the vial adapter still in the clear package, attach it to the vial stopper by pushing down 

until the vial adapter snaps in place. 
• When you are sure the adapter is attached to the vial, lift off the package from the vial adapter.  
• Gently set the vial with vial adapter down on your clean work surface. Be careful that it does 

not fall over. DO NOT touch the vial adapter.  
 

 
 
• Prepare the syringe by partially peeling the package open from the end closest to white plunger 

rod. 
• Peel the clear package just far enough to expose the white plunger rod, but do not take the 

syringe out of the package. 
• Hold the syringe package and SLOWLY pull the white plunger rod out to 0.1 ml beyond the 

prescribed dose (For example, if the prescribed dose is 0.5 ml, pull the white plunger rod to 0.6 
ml). NEVER pull past the 0.9 ml position regardless of prescribed dose. 

• You will set the volume to the prescribed dose in a later step. 
• DO NOT pull the white plunger rod completely out of the syringe. 
 
NOTE:  
 
If the white plunger rod is pulled completely out of the syringe, discard the syringe and contact your 
Imraldi provider for a replacement. DO NOT try to reinsert the white plunger rod. 
 



165 

 

 
 
 
 
 
 
Dose + 0.1 ml 

 
• DO NOT use the white plunger rod to remove the syringe from the package. Hold the syringe 

on the graduated area and pull the syringe from its package. DO NOT set the syringe down at 
any time. 

• While holding the vial adapter firmly, insert the syringe tip into the vial adapter and twist the 
syringe clockwise with one hand until firm. DO NOT over-tighten.  

 

 
 
• While holding the vial, push the white plunger rod all the way down. This step is important to 

get the proper dose. Hold the white plunger rod in and turn the vial and syringe upside down. 
 

 
 
• SLOWLY pull the white plunger rod out to 0.1 ml beyond the prescribed dose. This is 

important to get the proper dose. You will set the volume to the prescribed dose in step 4 (Dose 
Preparation). If the prescribed dose is 0.5 ml, pull the white plunger rod out to 0.6 ml. You will 
see the liquid medication from the vial go into the syringe. 

 



166 

 
 
• Push the white plunger rod all the way back in to push the liquid medication back into the vial. 

Again, SLOWLY pull the white plunger rod out to 0.1 ml beyond the prescribed dose, this is 
important to get the proper dose and important in order to prevent air bubbles or air gaps in the 
liquid medication. You will set the volume to the prescribed dose in step 4 (Dose Preparation). 

 

 
 
• If you see remaining air bubbles or air gaps in the liquid medication in the syringe, you may 

repeat this process up to 3 times. DO NOT shake the syringe. 
 
NOTE:  
 
If the white plunger rod is pulled completely out of the syringe, discard the syringe and contact your 
Imraldi provider for a replacement. DO NOT try to reinsert the white plunger rod. 
 
• While still holding the syringe upright at the graduated area, remove the vial adapter with the 

vial by twisting the vial adapter off with the other hand. Be sure to remove the vial adapter with 
the vial from the syringe. DO NOT touch the tip of the syringe. 

 

 
 
• If a large air bubble or air gap can be seen near the syringe tip, SLOWLY push the white 

plunger rod into the syringe until fluid begins to enter the syringe tip. DO NOT push the white 
plunger rod past the dose position. 



167 

• For example, if the prescribed dose is 0.5 ml, DO NOT push the white plunger rod past the 0.5 
ml position. 

• Check to see that the fluid remaining in the syringe is at least the prescribed dose volume. If the 
remaining volume is less than the prescribed dose volume, DO NOT use the syringe and 
contact your healthcare provider. 

• With your free hand, pick up the needle package with the yellow syringe connector facing down. 
• Keeping the syringe up, insert the syringe tip into the yellow syringe connector and twist the 

syringe as indicated by the arrow in the picture until firm. The needle is now attached to the 
syringe. 

 

 
 
• Pull the needle package off, but DO NOT remove the clear needle cap. 
• Place the syringe on your clean work surface. Continue with injection site and dose preparation 

immediately. 
 
3)  Choosing and preparing an injection site 
 
• Choose a site on your thigh or abdomen (except the area around the navel). DO NOT use the 

same site that was used for the last injection. 
• The new injection site should be given at least 3 cm from the last injection site. 
 

 
 
• DO NOT inject in an area where the skin is sore, bruised, scarred, scaly, or has red patches. 

This may mean there is an infection and therefore you should contact your doctor. 
• To reduce the chance of infection, wipe the injection site with the other alcohol pad. DO NOT 

touch the area again before injecting. 
 
4)  Dose Preparation  
 
• Pick up the syringe with the needle pointing up. 
• Use your other hand to flip the pink needle cover down toward the syringe. 
 



168 

 
 
• Remove the clear needle cap by pulling it straight up with your other hand. 
 

 
 
• The needle is clean. 
• DO NOT touch the needle. 
• DO NOT set the syringe down at any time after the clear needle cap is off. 
• DO NOT try to put the clear needle cap back on the needle. 
• Hold the syringe at eye-level with the needle pointing up to see the amount clearly. Be careful 

not to squirt the liquid medication into your eye. 
• Recheck the prescribed medication amount. 
• Push the white plunger rod gently into the syringe until the syringe contains the prescribed 

amount of liquid. Excess liquid may come out of the needle while the white plunger rod is being 
pushed. DO NOT wipe off the needle or the syringe. 

 
5)  Injecting Imraldi 
 
• With the free hand, gently grasp the cleaned area of skin and hold firmly.  
• With the other hand, hold syringe at 45-degree angle to skin.  
• With one quick, short motion, push needle all the way into skin. 
• Let go of the skin in your hand. 
• Push the white plunger rod to inject the liquid medication until the syringe is empty. 
• When the syringe is empty, remove the needle from skin, being careful to pull it out at the same 

angle as when it was inserted. 
 



169 

 
 
• Gently flip the pink needle cover up, over the needle and snap into place and set the syringe 

with needle on the work surface. DO NOT put the clear needle cap back on the needle. 
 

 
 
• Using a piece of gauze, apply pressure over the injection site for 10 seconds. A little bleeding 

may occur. DO NOT rub the injection site. Use a plaster if you want to.  
 
6)  Throwing away supplies 
 
• You will need a special container for waste, such as a sharps container or as instructed by your 

nurse, doctor or pharmacist. 
• Put the syringe with needle, vial and vial adapter into a special sharps container. DO NOT put 

these items into regular household waste. 
• The syringe, needle, vial and vial adapter MUST NEVER be reused. 
• Keep the special container out of the sight and reach of children at all times. 
• Throw away all other used items into your regular household waste. 
 
 


	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