Kromeya

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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 

 

Kromeya 40 mg solution for injection in pre-filled syringe 

Kromeya 40 mg solution for injection in pre-filled pen 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Kromeya 40 mg solution for injection in pre-filled syringe 

 

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

 

Kromeya 40 mg solution for injection in pre-filled pen 

 

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

 

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

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Solution for injection (injection). 

 

Clear, colourless solution. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Rheumatoid arthritis 

 

Kromeya 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. 

 

Kromeya 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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Kromeya 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). Kromeya 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 

 

Kromeya 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) 

 

Kromeya 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 

 

Kromeya 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 

 

Kromeya 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 

 

Kromeya is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients 

who are candidates for systemic therapy. 

 

Paediatric plaque psoriasis 

 

Kromeya 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. 

 

Crohn’s disease 

 

Kromeya is indicated for treatment of moderately to severely active Crohn’s disease, in adult patients 

who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an 

immunosuppressant; or who are intolerant to or have medical contraindications for such therapies. 

 

Paediatric Crohn's disease 

 

Kromeya 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. 

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Ulcerative colitis 

 

Kromeya 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 

 

Kromeya 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 

 

Kromeya 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 

 

Kromeya treatment should be initiated and supervised by specialist physicians experienced in the 

diagnosis and treatment of conditions for which Kromeya is indicated. Ophthalmologists are advised 

to consult with an appropriate specialist before initiation of treatment with Kromeya (see section 4.4). 

Patients treated with Kromeya should be given the patient reminder card. 

 

After proper training in injection technique, patients may self-inject with Kromeya if their physician 

determines that it is appropriate and with medical follow-up as necessary. 

 

During treatment with Kromeya, other concomitant therapies (e.g. corticosteroids and/or 

immunomodulatory agents) should be optimised. 

 

Posology 

 

Rheumatoid arthritis 

 

The recommended dose of Kromeya 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 Kromeya. 

 

Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics can be continued 

during treatment with Kromeya. 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 Kromeya 40 mg every 

other week may benefit from an increase in dosage to 40 mg adalimumab every week or 80 mg every 

other week. 

 

Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. 

Continued therapy should be reconsidered in a patient not responding within this time period. 

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

 

Dose interruption 

 

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

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Available data suggest that re-introduction of adalimumab after discontinuation for 70 days or longer 

resulted in the same magnitudes of clinical response and similar safety profile as before dose 

interruption. 

 

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

arthritis 

 

The recommended dose of Kromeya 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 Kromeya 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 Kromeya 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. 

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

 

Crohn’s disease 

 

The recommended Kromeya induction dose regimen for adult patients with moderately to severely 

active Crohn’s disease is 80 mg at week 0 followed by 40 mg at week 2. In case there is a need for a 

more rapid response to therapy, the regimen 160 mg at week 0 (given as four 40 mg injections in one 

day or as two 40 mg injections per day for two consecutive days), 80 mg at week 2 (given as two 40 mg 

injections in one day), can be used with the awareness that the risk for adverse events is higher during 

induction. 

 

After induction treatment, the recommended dose is 40 mg every other week via subcutaneous 

injection. Alternatively, if a patient has stopped Kromeya and signs and symptoms of disease recur, 

Kromeya 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 Kromeya 40 mg every other week may 

benefit from an increase in dosage to 40 mg Kromeya 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. 

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

 

Ulcerative colitis 

 

The recommended Kromeya 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 Kromeya 40 mg every other week may 

benefit from an increase in dosage to 40 mg Kromeya every week or 80 mg every other week. 

 

Available data suggest that clinical response is usually achieved within 2-8 weeks of treatment. 

Kromeya therapy should not be continued in patients failing to respond within this time period. 

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

 

Uveitis 

 

The recommended dose of Kromeya for adult patients with uveitis is an initial dose of 80 mg, 

followed by 40 mg given every other week starting one week after the initial dose. There is limited 

experience in the initiation of treatment with adalimumab alone. Treatment with Kromeya 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 Kromeya. 

 

It is recommended that the benefit and risk of continued long-term treatment should be evaluated on a 

yearly basis (see section 5.1). 

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

 

Special populations 

 

Elderly 

 

No dose adjustment is required. 

 

Renal and/or hepatic impairment 

 

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

made. 

 

Paediatric population 

 

Juvenile idiopathic arthritis 

 

Polyarticular juvenile idiopathic arthritis from 2 years of age 

 

The recommended dose of Kromeya for patients with polyarticular juvenile idiopathic arthritis from 2 

years of age is based on body weight (Table 1). Kromeya is administered every other week via 

subcutaneous injection.  

 

 

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Table 1. Kromeya dose for patients with polyarticular juvenile idiopathic arthrtis 

 

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. 

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

 

Enthesitis-related arthritis 

 

The recommended dose of Kromeya for patients with enthesitis-related arthritis from 6 years of age is 

based on body weight (Table 2). Kromeya is administered every other week via subcutaneous 

injection. 

 

Table 2. Kromeya 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. 

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

 

Paediatric plaque psoriasis 

 

The recommended Kromeya dose for patients with plaque psoriasis from 4 to 17 years of age is based 

on body weight (Table 3). Kromeya is administered via subcutaneous injection. 

 

Table 3. Kromeya 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 Kromeya 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. 

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

 

Paediatric Crohn's disease 

 

The recommended dose of Kromeya for patients with Crohn’s disease from 6 to 17 years of age is 

based on body weight (Table 4). Kromeya is administered via subcutaneous injection.  

 

Table 4. Kromeya dose for paediatric patients with Crohn’s disease 

 

Patient 

weight 

Induction dose Maintenance 

dose starting 

at week 4 

< 40 

kg 

• 40 mg at week 0 and 20 mg at week 2 

 

In case there is a need for a more rapid response to therapy with the 

awareness that the risk for adverse events may be higher with use of 

the higher induction dose, the following dose may be used: 

• 80 mg at week 0 and 40 mg at week 2 

20 mg every 

other week 

≥ 40 kg • 80 mg at week 0 and 40 mg at week 2 

 

In case there is a need for a more rapid response to therapy with the 

awareness that the risk for adverse events may be higher with use of 

the higher induction dose, the following dose may be used: 

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

40 mg every 

other week 

 

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

• < 40 kg: 20 mg every week 

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

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

 

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

 

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

 

Paediatric Uveitis 

 

The recommended dose of Kromeya for paediatric patients with uveitis from 2 years of age is based 

on body weight (Table 5). Kromeya is administered via subcutaneous injection. 

 

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

treatment with methotrexate. 

 

 Table 5. Kromeya 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 Kromeya 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). 

 

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There is no relevant use of Kromeya 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). 

 

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

 

Paediatric ulcerative colitis 

 

The safety and efficacy of adalimumab in children aged 4-17 years have not yet been established. No 

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

indication. 

 

Psoriatic arthritis and axial spondyloarthritis including ankylosing spondylitis 

 

There is no relevant use of adalimumab in the paediatric population for the indications of ankylosing 

spondylitis and psoriatic arthritis. 

 

Method of administration 

 

Kromeya is administered by subcutaneous injection. Full instructions for use are provided in the 

package leaflet. 

 

Kromeya is available in other presentations. 

 

4.3 Contraindications 

 

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

 

Active tuberculosis or other severe infections such as sepsis, and opportunistic infections (see section 

4.4). 

 

Moderate to severe heart failure (NYHA class III/IV) (see section 4.4). 

 

4.4 Special warnings and precautions for use 

 

Traceability 

 

In order to improve traceability of biological medicinal products, the name and the batch number of 

the administered product should be clearly recorded. 

 

Infections 

 

Patients taking TNF-antagonists are more susceptible to serious infections. Impaired lung function 

may increase the risk for developing infections. Patients must therefore be monitored closely for 

infections, including tuberculosis, before, during and after treatment with Kromeya. Because the 

elimination of adalimumab may take up to four months, monitoring should be continued throughout 

this period. 

 

Treatment with Kromeya 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 

Kromeya should be considered prior to initiating therapy (see Other opportunistic infections). 

 

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Patients who develop a new infection while undergoing treatment with Kromeya, should be monitored 

closely and undergo a complete diagnostic evaluation. Administration of Kromeya 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 Kromeya 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 Kromeya, 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, Kromeya 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 Kromeya, and in accordance with local 

recommendations. 

 

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

Kromeya 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. 

 

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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 Kromeya. 

 

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 Kromeya 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 Kromeya. 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 Kromeya 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, Kromeya 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 Kromeya in patients with pre-existing or recent-onset central or peripheral nervous system 

demyelinating disorders; discontinuation of Kromeya 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 Kromeya 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 Kromeya should be 

discontinued immediately and appropriate therapy initiated. 

 

Immunosuppression 

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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 Kromeya 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 Kromeya 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 Kromeya. 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. 

 

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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, leucopenia) 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 Kromeya. Discontinuation of Kromeya 

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. Kromeya should be used with 

caution in patients with mild heart failure (NYHA class I/II). Kromeya is contraindicated in moderate 

to severe heart failure (see section 4.3). Treatment with Kromeya must be discontinued in patients who 

develop new or worsening symptoms of congestive heart failure. 

 

Autoimmune processes 

 

Treatment with Kromeya 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 Kromeya and is 

positive for antibodies against double-stranded DNA, further treatment with Kromeya 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 

 

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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 Kromeya should be closely monitored for infections, and 

appropriate actions should be taken. There is limited safety experience in patients undergoing 

arthroplasty while receiving adalimumab. 

 

Small bowel obstruction 

 

Failure to respond to treatment for Crohn’s disease may indicate the presence of fixed fibrotic stricture 

that may require surgical treatment. Available data suggest that adalimumab does not worsen or cause 

strictures. 

 

Elderly 

 

The frequency of serious infections among adalimumab treated subjects over 65 years of age (3.7%) 

was higher than for those under 65 years of age (1.5%). Some of those had a fatal outcome. Particular 

attention regarding the risk for infection should be paid when treating the elderly. 

 

Paediatric population 

 

See Vaccinations above. 

 

Excipients with known effects 

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8  ml dose, i.e. essentially 

'sodium-free'. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and 

psoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitant 

methotrexate. Antibody formation was lower when adalimumab was given together with methotrexate 

in comparison with use as monotherapy. Administration of adalimumab without methotrexate resulted 

in increased formation of antibodies, increased clearance and reduced efficacy of adalimumab (see 

section 5.1). 

 

The combination of Kromeya and anakinra is not recommended (see section 4.4 “Concurrent 

administration of biologic DMARDs or TNF-antagonists”). 

 

The combination of Kromeya 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 Kromeya treatment. 

 

Pregnancy 

 

A large number (approximately 2100) of prospectively collected pregnancies exposed to adalimumab 

resulting in live birth with known outcomes, including more than 1500 exposed during the first 

trimester, does not indicate an increase in the rate of malformation in the newborn. 

In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn’s disease (CD) 

treated with adalimumab at least during the first trimester and 120 women with RA or CD not treated 

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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, Kromeya can be used during breast-feeding. 

 

Fertility 

 

Preclinical data on fertility effects of adalimumab are not available. 

 

4.7 Effects on ability to drive and use machines 

 

Kromeya may have a minor influence on the ability to drive and use machines. Vertigo and visual 

impairment may occur following administration of Kromeya (see section 4.8). 

 

4.8 Undesirable effects 

 

Clinical studies in patients suffering hidradenitis suppurativa in this section are merely included for 

public health reasons. However, please note that Kromeya is neither intended nor authorized for 

treatment of hidradenitis suppurativa. 

 

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, 

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hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients 

receiving adalimumab and 3,801 patients receiving placebo or active comparator during the controlled 

period. 

 

The proportion of patients who discontinued treatment due to adverse events during the double-blind, 

controlled portion of pivotal studies was 5.9% for patients taking adalimumab and 5.4% for control 

treated patients. 

 

The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper 

respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain 

or swelling), headache and musculoskeletal pain. 

 

Serious adverse reactions have been reported for adalimumab. TNF-antagonists, such as adalimumab 

affect the immune system and their use may affect the body’s defence against infection and cancer. 

 

Fatal and life-threatening infections (including sepsis, opportunistic infections and TB), HBV 

reactivation and various malignancies (including leukaemia, lymphoma and HSTCL) have also been 

reported with use of adalimumab. 

 

Serious haematological, neurological and autoimmune reactions have also been reported. These 

include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events 

and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome. 

 

Paediatric population 

 

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

adult patients. 

 

Tabulated list of adverse reactions 

 

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

postmarketing experience and are displayed by system organ class and frequency in Table 6 below: 

very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 

1/10,000 to < 1/1,000); and not known (cannot be estimated from the available data). Within each 

frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest 

frequency seen among the various indications has been included. An asterisk (*) appears in the 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), 

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System Organ Class Frequency Adverse reaction 

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,  

diverticulitis 1) 

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 lymphatic 

system disorders* 

Very common Leucopaenia (including neutropaenia and 

agranulocytosis), 

anaemia 

Common Leucocytosis, 

thrombocytopenia 

Uncommon Idiopathic thrombocytopenic purpura 

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System Organ Class Frequency Adverse reaction 

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, 

hypophosphataemia, 

dehydration 

Psychiatric disorders Common Mood alterations (including depression), 

anxiety, 

insomnia 

Nervous system disorders* Very common Headache 

Common Paraesthesias (including hypoaesthesia), 

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 

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System Organ Class Frequency Adverse reaction 

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 

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System Organ Class Frequency Adverse reaction 

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, 

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 

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System Organ Class Frequency Adverse reaction 

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 7.2% of patients receiving placebo or active control. Injection site reactions generally did not 

necessitate discontinuation of the medicinal product. 

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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 a 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). 

 

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Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated 

with adalimumab (see section 4.4). 

 

Autoantibodies 

 

Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis 

studies I - V. In these trials, 11.9% of patients treated with adalimumab and 8.1% of placebo and 

active control − treated patients that had negative baseline anti-nuclear antibody titres reported 

positive titres at week 24. Two patients out of 3,441 treated with adalimumab in all rheumatoid 

arthritis and psoriatic arthritis studies developed clinical signs suggestive of new-onset lupus-like 

syndrome. The patients improved following discontinuation of therapy. No patients developed lupus 

nephritis or central nervous system symptoms. 

 

Hepato-biliary events 

 

In controlled Phase 3 trials of adalimumab in patients with rheumatoid arthritis and psoriatic arthritis 

with a control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 

3.7% of adalimumab-treated patients and 1.6% of control-treated patients. 

 

In controlled Phase 3 trials of adalimumab in patients with polyarticular juvenile idiopathic arthritis 

who were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations ≥ 3 x 

ULN occurred in 6.1% of adalimumab-treated patients and 1.3% of control-treated patients. Most ALT 

elevations occurred with concomitant methotrexate use. No ALT elevations ≥ 3 x ULN occurred in the 

Phase 3 trial of adalimumab in patients with polyarticular juvenile idiopathic arthritis who were 2 to 

<4 years. 

 

In controlled Phase 3 trials of adalimumab in patients with Crohn’s disease and ulcerative colitis with 

a control period ranging from 4 to 52 weeks. ALT elevations ≥ 3 x ULN occurred in 0.9% of 

adalimumab- treated patients and 0.9% of controlled-treated patients. 

 

In the Phase 3 trial of adalimumab in patients with paediatric Crohn’s disease which evaluated 

efficacy and safety of two body weight adjusted maintenance dose regimens following body weight 

adjusted induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% 

(5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline. 

 

In controlled Phase 3 trials of adalimumab in patients with plaque psoriasis with a control period 

duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumab-

treated patients and 1.8% of control-treated patients. 

 

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

plaque psoriasis. 

 

In controlled trials of adalimumab (initial doses of 160 mg at week 0 and 80 mg at week 2, followed 

by 40 mg every week starting at week 4), in patients with hidradenitis suppurativa with a control 

period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of 

adalimumab-treated patients and 0.6% of control-treated patients. 

 

In controlled trials of adalimumab (initial doses of 80 mg at week 0 followed by 40 mg every other 

week starting at week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 

days and 105.0 days in Adalimumab-treated and control-treated patients, respectively, ALT elevations 

≥ 3 x ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control-treated patients. 

Across all indications in clinical trials patients with raised ALT were asymptomatic and in most cases 

elevations were transient and resolved on continued treatment. However, there have also been post- 

marketing reports of liver failure as well as less severe liver disorders that may precede liver failure, 

such as hepatitis including autoimmune hepatitis in patients receiving adalimumab. 

 

Concurrent treatment with azathioprine/6-mercaptopurine 

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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 

 

Kromeya 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 and ulcerative colitis 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 

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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 

percentage 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. 

 

 

 

 

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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 NA NA NA NA 24.0% 58.9% 

ACR 50 
      

6 months 6.7% 52.4% 8.2% 22.1% 9.5% 39.1% 

12 months NA NA NA NA 9.5% 41.5% 

ACR 70 
      

6 months 3.3% 23.8% 1.8% 12.4% 2.5% 20.8% 

12 months NA NA NA NA 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 

 

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 

40mg 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). 

 

 

 

 

 

 

 

 

 

 

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Table 8 

ACR responses in RA study V 

(percent of patients) 

 

Response MTX 

n=257 

Adalimumab 

n=274 

Adalimumab/MTX 

n=268 
p-value

a
 p-value

b p-value
c
 

ACR 20       

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

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

ACR 50       

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

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

ACR 70       

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

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

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

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

c. p-value is from the pairwise comparison of adalimumab monotherapy and methotrexate 

monotherapy using the Mann-Whitney U test 

 

In the open-label extension for RA study V, ACR response rates were maintained when followed for 

up to 10 years. Of 542 patients who were randomised to adalimumab 40 mg every other week, 170 

patients continued on adalimumab 40 mg every other week for 10 years. Among those, 154 patients 

(90.6%) had ACR 20 responses; 127 patients (74.7%) had ACR 50 responses; and 102 patients 

(60.0%) had ACR 70 responses. 

 

At week 52, 42.9% of patients who received adalimumab/methotrexate combination therapy achieved 

clinical remission (DAS28 (CRP) < 2.6) compared to 20.6% of patients receiving methotrexate 

monotherapy and 23.4% of patients receiving adalimumab monotherapy. Adalimumab/methotrexate 

combination therapy was clinically and statistically superior to methotrexate (p < 0.001) and 

adalimumab monotherapy (p < 0.001) in achieving a low disease state in patients with recently 

diagnosed moderate to severe rheumatoid arthritis. The response for the two monotherapy arms was 

similar (p = 0.447). 

Of 342 subjects originally randomised to adalimumab monotherapy or adalimumab/methotrexate 

combination therapy who entered the open-label extension study, 171 subjects completed 10 years of 

adalimumab treatment. Among those, 109 subjects (63.7%) were reported to be in remission at 

10 years. 

 

Radiographic response 

 

In RA study III, where adalimumab treated patients had a mean duration of rheumatoid arthritis of 

approximately 11 years, structural joint damage was assessed radiographically and expressed as 

change in modified Total Sharp Score (TSS) and its components, the erosion score and joint space 

narrowing score. Adalimumab/methotrexate patients demonstrated significantly less radiographic 

progression than patients receiving methotrexate alone at 6 and 12 months (see Table 9). 

 

In the open-label extension of RA study III, the reduction in rate of progression of structural damage is 

maintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated 

with 40 mg adalimumab every other week were evaluated radiographically. Among those, 48 patients 

showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or 

less. At 10 years, 79 of 207 patients originally treated with 40 mg adalimumab every other week were 

evaluated radiographically. Among those, 40 patients showed no progression of structural damage 

defined by a change from baseline in the mTSS of 0.5 or less. 

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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 
amethotrexate 
b95% confidence intervals for the differences in change scores between methotrexate and 

adalimumab. 
cBased on rank analysis 
dJoint Space Narrowing 

 

In RA study V, structural joint damage was assessed radiographically and expressed as change in 

modified Total Sharp Score (see Table 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 randomised to methotrexate 

monotherapy, adalimumab monotherapy and adalimumab/methotrexate combination therapy, 

respectively. The corresponding proportions of patients with no radiographic progression were 31.3%, 

23.7% and 36.7% respectively. 

 

Quality of life and physical function 

 

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Health-related quality of life and physical function were assessed using the disability index of the 

Health Assessment Questionnaire (HAQ) in the four original adequate and well-controlled trials, 

which was a pre-specified primary endpoint at week 52 in RA study III. All doses/schedules of 

adalimumab in all four studies showed statistically significantly greater improvement in the disability 

index of the HAQ from baseline to Month 6 compared to placebo and in RA study III the same was 

seen at week 52. Results from the Short Form Health Survey (SF 36) for all doses/schedules of 

adalimumab in all four studies support these findings, with statistically significant physical component 

summary (PCS) scores, as well as statistically significant pain and vitality domain scores for the 

40 mg every other week dose. A statistically significant decrease in fatigue as measured by functional 

assessment of chronic illness therapy (FACIT) scores was seen in all three studies in which it was 

assessed (RA studies I, III, IV). 

 

In RA study III, most subjects who achieved improvement in physical function and continued 

treatment maintained improvement through week 520 (120 months) of open-label treatment. 

Improvement in quality of life was measured up to week 156 (36 months) and improvement was 

maintained through that time. 

 

In RA study V, the improvement in the HAQ disability index and the physical component of the SF 36 

showed greater improvement (p < 0.001) for adalimumab/methotrexate combination therapy versus 

methotrexate monotherapy and adalimumab monotherapy at week 52, which was maintained through 

week 104. Among the 250 subjects who completed the open-label extension study, improvements in 

physical function were maintained through 10 years of treatment. 

 

Juvenile idiopathic arthritis (JIA) 

 

Polyarticular juvenile idiopathic arthritis (pJIA) 

 

The safety and efficacy of adalimumab was assessed in two studies (pJIA I and II) in children with 

active polyarticular or polyarticular course juvenile idiopathic arthritis, who had a variety of JIA onset 

types (most frequently rheumatoid-factor negative or positive polyarthritis and extended 

oligoarthritis). 

 

pJIA I 

 

The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind, 

parallel − group study in 171 children (4-17 years old) with polyarticular JIA. In the open-label lead in 

phase (OL LI) patients were stratified into two groups, MTX (methotrexate)-treated or non-MTX- 

treated. Patients who were in the non-MTX stratum were either naïve to or had been withdrawn from 

MTX at least two weeks prior to study drug administration. Patients remained on stable doses of 

NSAIDs and or prednisone (≤ 0.2 mg /kg/day or 10 mg/day maximum). In the OL LI phase all patients 

received 24 mg/m2 up to a maximum of 40 mg adalimumab every other week for 16 weeks. The 

distribution of patients by age and minimum, median and maximum dose received during the OL LI 

phase is presented in Table 11. 

 

Table 11 

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

 

Age group Number of patients at baseline  

n (%) 

Minimum, median and maximum 

dose 

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

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

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

 

Patients demonstrating a Pediatric 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 

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defined as a worsening of ≥ 30% from baseline in ≥ 3 of 6 Pediatric ACR core criteria, ≥ 2 active 

joints, and improvement of ≥ 30% in no more than 1 of the 6 criteria. After 32 weeks or at disease 

flare, patients were eligible to enrol into the open label extension phase. 

 

Table 12 

Ped ACR 30 responses in the JIA study 

 

Stratum MTX Without MTX 

Phase   

OL-LI 16 weeks   

Ped ACR 30 

response (n/N) 

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

Efficacy outcomes 

Double blind 32 weeks Adalimumab 

/MTX (N = 38) 

Placebo /MTX 

(N = 37) 

Adalimumab 

(N = 30) 

Placebo (N = 28) 

Disease flares at the end of 

32 weeksa (n/N) 

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

Median time to disease 

flare 

> 32 weeks 20 weeks > 32 weeks 14 weeks 

 
a Ped ACR 30/50/70 responses week 48 significantly greater than those of placebo treated patients 
b p = 0.015 
c p = 0.031 

 

Amongst those who responded at week 16 (n=144), the Pediatric ACR 30/50/70/90 responses were 

maintained for up to six years in the OLE phase in patients who received adalimumab throughout the 

study. 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, Kromeya 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, multicenter study in 32 children 

(2 - < 4 years old or aged 4 and above weighing < 15 kg) with moderately to severely active 

polyarticular JIA. The patients received 24 mg/m2 body surface area (BSA) of adalimumab up to a 

maximum of 20 mg every other week as a single dose via SC injection for at least 24 weeks. During 

the study, most subjects used concomitant MTX, with fewer reporting use of corticosteroids or 

NSAIDs. 

 

At week 12 and week 24, PedACR30 response was 93.5% and 90.0%, respectively, using the observed 

data approach. The proportions of subjects with PedACR50/70/90 at week 12 and week 24 were 

90.3%/61.3%/38.7% and 83.3%/73.3%/36.7%, respectively. Amongst those who responded (Pediatric 

ACR 30) at week 24 (n=27 out of 30 patients), the Pediatric ACR 30 responses were maintained for up 

to 60 weeks in the OLE phase in patients who received adalimumab throughout this time period. 

Overall, 20 subjects were treated for 60 weeks or longer. 

 

Enthesitis-related arthritis 

 

The safety and efficacy of adalimumab were assessed in a multicenter, randomised, double-blind study 

in 46 paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients were 

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randomised to receive either 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of 

40 mg, or placebo every other week for 12 weeks. The double-blind period is followed by an open-

label (OL) period during which patients received 24 mg/m2 BSA of adalimumab up to a maximum of 

40 mg every other week subcutaneously for up to an additional 192 weeks. The primary endpoint was 

the percent change from Baseline to week 12 in the number of active joints with arthritis (swelling not 

due to deformity or joints with loss of motion plus pain and/or tenderness), which was achieved with 

mean percent decrease of -62.6% (median percent change -88.9%) in patients in the adalimumab 

group compared to -11.6% (median percent change -50.0%) in patients in the placebo group. 

Improvement in number of active joints with arthritis was maintained during the OL period through 

week 156 for the 26 of 31 (84%) patients in the adalimumab group who remained in the study. 

Although not statistically significant, the majority of patients demonstrated clinical improvement in 

secondary endpoints such as number of sites of enthesitis, tender joint count (TJC), swollen joint count 

(SJC), Pediatric ACR 50 response, and Pediatric ACR 70 response. 

 

Axial spondyloarthritis  

 

Ankylosing spondylitis (AS) 

 

Adalimumab 40 mg every other week was assessed in 393 patients in two randomised, 24 week 

double−blind, placebo−controlled studies in patients with active ankylosing spondylitis (mean baseline 

score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.3 in 

all groups) who have had an inadequate response to conventional therapy. Seventy-nine (20.1%) 

patients were treated concomitantly with disease modifying anti−rheumatic drugs, and 37 (9.4%) 

patients with glucocorticoids. The blinded period was followed by an open−label period during which 

patients received adalimumab 40 mg every other week subcutaneously for up to an additional 28 

weeks. Subjects (n=215, 54.7%) who failed to achieve ASAS 20 at weeks 12, or 16 or 20 received 

early escape open-label adalimumab 40 mg every other week subcutaneously and were subsequently 

treated as non-responders in the double-blind statistical analyses. 

 

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). 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Table 13 

Efficacy responses in placebo-controlled AS Study – Study I 

reduction of signs and symptoms 

 

Response Placebo 

N=107 

Adalimumab 

N=208 

ASASa 20   

Week 2 16% 42%*** 

Week 12 21% 58%*** 

Week 24 19% 51%*** 

ASAS 50   

Week 2 3% 16%*** 

Week 12 10% 38%*** 

Week 24 11% 35%*** 

ASAS 70   

Week 2 0% 7%** 

Week 12 5% 23%*** 

Week 24 8% 24%*** 

BASDAIb 50   

Week 2 4% 20%*** 

Week 12 16% 45%*** 

Week 24 15% 42%*** 

***,** Statistically significant at p < 0.001, < 0.01 for all comparisons between 

adalimumab and placebo at weeks 2, 12 and 24 
a Assessments in Ankylosing Spondylitis 
b Bath Ankylosing Spondylitis Disease Activity Index 

 

Adalimumab treated patients had significantly greater improvement at week 12 which was maintained 

through week 24 in both the SF36 and Ankylosing Spondylitis Quality of Life Questionnaire 

(ASQoL). 

 

Similar trends (not all statistically significant) were seen in the smaller randomised, double−blind, 

placebo−controlled AS study II of 82 adult patients with active ankylosing spondylitis. 

 

Axial spondyloarthritis without radiographic evidence of AS 

The safety and efficacy of adalimumab were assessed in two 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 one 

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 

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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 

ASAS
a 

40 15% 36%*** 

ASAS 20 31% 52%** 

ASAS 5/6 6% 31%*** 

ASAS partial remission 5% 16%* 

BASDAI
b 

50 15% 35%** 

ASDASc,d,e -0.3 -1.0*** 

ASDAS inactive disease 4% 24%*** 

hs-CRP
d,f,g

 -0.3 -4.7*** 

SPARCC
h 
MRI sacroiliac joints

d,i
 -0.6 -3.2** 

SPARCC MRI spine
d,j

 -0.2 -1.8** 
a 

Assessment of Spondyloarthritis International Society 
b 

Bath Ankylosing Spondylitis Disease Activity Index 
c 

Ankylosing Spondylitis Disease Activity Score 
d 

mean change from baseline 
e 

n=91 placebo and n=87 adalimumab 
f 

high sensitivity C-Reactive Protein (mg/L) 
g 

n=73 placebo and n=70 adalimumab 
h 

Spondyloarthritis Research Consortium of Canada 
i 

n=84 placebo and adalimumab 
j 

n=82 placebo and n=85 adalimumab 

***, **, * Statistically significant at p < 0.001, < 0.01, and < 0.05, respectively, for all 

comparisons between adalimumab and placebo. 

 

In the open-label extension, improvement in the signs and symptoms was maintained with 

adalimumab therapy through week 156.  

 

Inhibition of inflammation 

 

Significant improvement of signs of inflammation as measured by hs-CRP and MRI of both Sacroiliac 

Joints and the Spine was maintained in adalimumab-treated patients through week 156 and week 104, 

respectively. 

 

Quality of life and physical function 

 

Health-related quality of life and physical function were assessed using the HAQ-S and the SF-36 

questionnaires. Adalimumab showed statistically significantly greater improvement in the HAQ-S 

total score and the SF-36 Physical Component Score (PCS) from baseline to week 12 compared to 

placebo. Improvement in health-related quality of life and physical function was maintained during the 

open-label extension through week 156. 

 

Study nr-axSpA II 

 

673 patients with active nr-axSpA (mean baseline disease activity [BASDAI] was 7.0) who had an 

inadequate response to ≥ 2 NSAIDs, or an intolerance to or a contraindication for NSAIDs enrolled 

into the open-label period of Study nr-axSpA II during which they received adalimumab 40 mg eow 

for 28 weeks. 

 

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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 

TIME (WEEKS) 

Treatment    Placebo    Adalimumab ∆ Censored 

Note: P = Placebo (number at risk (flared)); A = Adalimumab (number at risk (flared)). 

 

Among the 68 patients who flared in the group allocated to treatment withdrawal, 65 completed 

12 weeks of rescue therapy with adalimumab, out of which 37 (56.9%) had regained remission 

(ASDAS < 1.3) after 12 weeks of restarting the open-label treatment. 

 

By Week 68, patients receiving continuous Kromeya 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). 

 

 

 

 

 

 

 

 

 

 

 

P
R

O
B

A
B

IL
IT

Y
 O

F
 N

O
 F

L
A

R
E

 

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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%*** 
aAssessment of SpondyloArthritis international Society 
bBaseline is defined as open label baseline when patients have active disease. 
cAnkylosing Spondylitis Disease Activity Score 
dPartial 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 Kromeya 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%*** N/A N/A 

ACR 50  
    

Week 12 4% 36%*** 2% 25%*** 

Week 24 6% 39%*** N/A N/A 

ACR 70  
    

Week 12 1% 20%*** 0% 14% * 

Week 24 1% 23%*** N/A N/A 

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

* p < 0.05 for all comparisons between adalimumab and placebo  

N/A not applicable 

 

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

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

 

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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 and 18). 

 

 

 

 

 

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Table 17 

Ps Study I (REVEAL) efficacy results at 16 weeks 

 

 Placebo 

N=398 

n (%) 

Adalimumab 40 mg eow 
N=814 

n (%) 

PASI 75
a
 26 (6.5) 578 (70.9)

b
 

PASI 100 3 (0.8) 163 (20.0)
b
 

PGA: Clear/minimal 17 (4.3) 506 (62.2)
b
 

a 
Percent of patients achieving PASI75 response was calculated as center- 

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 

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38 

 

 

 

88.8% [95/107] for patients who relapsed and who did not relapse during the withdrawal period, 

respectively). A similar safety profile was observed during retreatment as before withdrawal. 

 

Significant improvements at week 16 from baseline compared to placebo (Studies I and II) and MTX 

(study II) were demonstrated in the DLQI (Dermatology Life Quality Index). In study I, improvements 

in the physical and mental component summary scores of the SF-36 were also significant compared to 

placebo. 

 

In an open-label extension study, for patients who dose escalated from 40 mg every other week to 40 

mg weekly due to a PASI response below 50%, 26.4% (92/349) and 37.8% (132/349) of patients 

achieved PASI 75 response at week 12 and 24, respectively. 

 

Psoriasis study III (REACH) compared the efficacy and safety of adalimumab versus placebo in 72 

patients with moderate to severe chronic plaque psoriasis and hand and/or foot psoriasis. Patients 

received an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week 

after the initial dose) or placebo for 16 weeks. At week 16, a statistically significantly greater 

proportion of patients who received adalimumab achieved PGA of 'clear' or 'almost clear' for the hands 

and/or feet compared to patients who received placebo (30.6% versus 4.3%, respectively [p = 0.014]). 

 

Psoriasis study IV compared efficacy and safety of adalimumab versus placebo in 217 adult patients 

with moderate to severe nail psoriasis. Patients received an initial dose of 80 mg adalimumab followed 

by 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followed 

by open-label adalimumab treatment for an additional 26 weeks. Nail psoriasis assessments included 

the Modified Nail Psoriasis Severity Index (mNAPSI), the Physician’s Global Assessment of 

Fingernail Psoriasis (PGA-F) and the Nail Psoriasis Severity Index (NAPSI) (see Table 19). 

Adalimumab demonstrated a treatment benefit in nail psoriasis patients with different extents of skin 

involvement (BSA  ≥  10% (60% of patients) and BSA  <  10% and ≥  5% (40% of patients)). 

 

Table 19 

Ps Study IV efficacy results at 16, 26 and 52 weeks 

Endpoint Week 16 

placebo-controlled 

Week 26 

placebo-controlled 

Week 52 

open-label 

Placebo 

N=108 

Adalimumab 

40 mg eow 

N=109 

Placebo 

N=108 

Adalimumab 

40 mg eow 

N=109 

Adalimumab 

40 mg eow 

N=80 

≥ mNAPSI 75 (%) 2.9 26.0a 3.4 46.6a 65.0 

PGA-F clear/minimal and 

≥  2-grade improvement 

(%) 

2.9 29.7a 6.9 48.9a 61.3 

Percent change in total 

fingernail NAPSI (%) 

-7.8 -44.2 a -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. 

 

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Patients received adalimumab 0.8 mg/kg eow (up to 40 mg), 0.4 mg/kg eow (up to 20 mg), or 

methotrexate 0.1 – 0.4 mg/kg weekly (up to 25 mg). At week 16, more patients randomised to 

adalimumab 0.8 mg/kg had positive efficacy responses (e.g. PASI 75) than those randomised to 

0.4 mg/kg eow or MTX. 

 

Table 20: Paediatric plaque psoriasis efficacy results at 16 weeks 

 MTX
a 

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. 

 

Crohn’s disease 

 

The safety and efficacy of adalimumab were assessed in over 1500 patients with moderately to 

severely active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in 

randomised, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, 

corticosteroids, and/or immunomodulatory agents were permitted and 80% of patients continued to 

receive at least one of these medications. 

 

Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies, CD study I 

(CLASSIC I) and CD study II (GAIN). In CD study I, 299 TNF-antagonist naive patients were 

randomised to one of four treatment groups; placebo at weeks 0 and 2, 160 mg adalimumab at week 0 

and 80 mg at week 2, 80 mg at week 0 and 40 mg at week 2, and 40 mg at week 0 and 20 mg at week 

2. In CD study II, 325 patients who had lost response or were intolerant to infliximab were randomised 

to receive either 160 mg adalimumab at week 0 and 80 mg at week 2 or placebo at weeks 0 and 2. The 

primary non-responders were excluded from the studies and therefore these patients were not further 

evaluated. 

 

Maintenance of clinical remission was evaluated in CD study III (CHARM). In CD study III, 854 

patients received open-label 80 mg at week 0 and 40 mg at week 2. At week 4 patients were 

randomised to 40 mg every other week, 40 mg every week, or placebo with a total study duration of 

56 weeks. Patients in clinical response (decrease in CDAI ≥ 70) at week 4 were stratified and analysed 

separately from those not in clinical response at week 4. Corticosteroid taper was permitted after week 

8. 

 

CD study I and CD study II induction of remission and response rates are presented in Table 21. 

 

 

 

 

 

 

 

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Table 21 

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 22. 

 

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 22 

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 

 

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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 multicenter, 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 23. 

 

Table 23 

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 24. Rates of discontinuation of corticosteroids or 

immunomodulators are presented in Table 25. 

 

 

 

 

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Table 24 

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 25 

Paediatric CD study 

Discontinuation of corticosteroids or immunomodulators and fistula remission 

 Standard dose 

40/20 mg eow 

Low dose 

20/10 mg eow 

p value1 

Discontinued corticosteroids N= 33 N=38  

Week 26 84.8% 65.8% 0.066 

Week 52 69.7% 60.5% 0.420 

Discontinuation of immunomodulators2 N=60 N=57  

Week 52 30.0% 29.8% 0.983 

Fistula remission3 N=15 N=21  

Week 26 46.7% 38.1% 0.608 

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

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

Baseline visits 

 

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

and height velocity were observed for both treatment groups. 

 

Statistically and clinically significant improvements from Baseline were also observed in both 

treatment groups for quality of life parameters (including IMPACT III). 

 

One hundred patients (n=100) from the Paediatric CD study continued in an open-label long-term 

extension study. After 5 years of adalimumab therapy, 74.0% (37/50) of the 50 patients remaining in 

the study continued to be in clinical remission, and 92.0% (46/50) of patients continued to be in 

clinical response per PCDAI. 

 

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. 

 

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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 26. 

 

Table 26 

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 days a 6% 

(N=140) 

13% * 

(N=150) 

Week 8 and 52   

Sustained response  12% 24%** 

Sustained remission  4% 8%* 

Sustained mucosal healing  11% 19%* 

Clinical remission is Mayo score ≤ 2 with no subscore > 1; 

Clinical response is decrease from baseline in Mayo score ≥ 3 points and ≥ 30% plus a decrease in the 

rectal bleeding subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1; 
*p < 0.05 for adalimumab vs. placebo pairwise comparison of proportions  

**p < 0.001 for adalimumab vs. placebo pairwise comparison of proportions 
a Of those receiving corticosteroids at baseline 

 

 

Of those patients who had a response at week 8, 47% were in response, 29% were in remission, 41% 

had mucosal healing, and 20% were in steroid-free remission for ≥ 90 days at week 52. 

 

Approximately 40% of patients in study UC-II had failed prior anti-TNF treatment with infliximab. 

The efficacy of adalimumab in those patients was reduced compared to that in anti-TNF naïve 

patients. Among patients who had failed prior anti-TNF treatment, week 52 remission was achieved by 

3% on placebo and 10% on adalimumab. 

 

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. 

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Quality of life 

 

In study UC-II, treatment with adalimumab resulted in improvements in the Inflammatory Bowel 

Disease Questionnaire (IBDQ) score. 

 

Uveitis 

 

The safety and efficacy of adalimumab were assessed in adult patients with non-infectious 

intermediate, posterior, and panuveitis, excluding patients with isolated anterior uveitis, in two 

randomised, double- masked, placebo-controlled studies (UV I and II). Patients received placebo or 

adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week after 

the initial dose. Concomitant stable doses of one non-biologic immunosuppressant were permitted. 

 

Study UV I evaluated 217 patients with active uveitis despite treatment with corticosteroids (oral 

prednisone at a dose of 10 to 60 mg/day). All patients received a 2-week standardised dose of 

prednisone 60 mg/day at study entry followed by a mandatory taper schedule, with complete 

corticosteroid discontinuation by week 15. 

 

Study UV II evaluated 226 patients with inactive uveitis requiring chronic corticosteroid treatment 

(oral prednisone 10 to 35 mg/day) at baseline to control their disease. Patients subsequently underwent 

a mandatory taper schedule, with complete corticosteroid discontinuation by week 19. 

 

The primary efficacy endpoint in both studies was ´time to treatment failure´. Treatment failure was 

defined by a multi-component outcome based on inflammatory chorioretinal and/or inflammatory 

retinal vascular lesions, anterior chamber (AC) cell grade, vitreous haze (VH) grade and best corrected 

visual acuity (BCVA). 

 

Clinical Response 

 

Results from both studies demonstrated statistically significant reduction of the risk of treatment 

failure in patients treated with adalimumab versus patients receiving placebo (See Table 27). Both 

studies demonstrated an early and sustained effect of adalimumab on the treatment failure rate versus 

placebo (see Figure 2). 

 

Table 27 

Time to treatment failure in studies UV I and UV II 

 

 

Analysis 

treatment 

N Failure 

N (%) 

Median 

time to 

failure 

(months) 

HRa CI 95% for 

HRa 

p Value b 

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 

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Note: Treatment failure at or after week 6 (study UV I), or at or after week 2 (study UV II), was 

counted as event. Drop outs due to reasons other than treatment failure were censored at the time of 

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

 
Figure 2: Kaplan-Meier curves summarizing time to treatment failure on or after week 6 

(study UV I) or week 2 (study UV II) 

 

TIME (MONTHS) 
Study UV I Treatment Placebo Adalimumab 
 

T
R

E
A

T
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N

T
 F

A
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U
R

E
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A
T

E
 (

%
)  

 TIME (MONTHS) 
Study UV II Treatment Placebo Adalimumab 

 

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

Events/Number at Risk). 

 

In study UV I statistically significant differences in favour of adalimumab versus placebo were 

observed for each component of treatment failure. In study UV II, statistically significant differences 

were observed for visual acuity only, but the other components were numerically in favour of 

adalimumab. 

 

Of the 417 subjects included in the uncontrolled long-term extension of studies UV I and UV II, 46 

subjects were regarded ineligible (e.g. developed complications secondary to diabetic retinopathy, due 

T
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A
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U
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 R

A
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 (

%
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to cataract surgery or vitrectomy) and were excluded from the primary analysis of efficacy. Of the 371 

remaining patients, 276 evaluable patients reached 78 weeks of open-label adalimumab treatment. 

Based on the observed data approach, 222 (80.4%) were in quiescence (no active inflammatory 

lesions, AC cell grade ≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose ≤ 7.5 mg per day, 

and 184 (66.7 %) were in steroid-free quiescence. BCVA was either improved or maintained (< 5 

letters deterioration) in 88.4% of the eyes at week 78. Among the patients who discontinued the study 

prior to week 78, 11% discontinued due to adverse events, and 5% due to insufficient response to 

adalimumab treatment. 

 

Quality of Life 

 

Patient reported outcomes regarding vision-related functioning were measured in both clinical studies, 

using the NEI VFQ-25. Adalimumab was numerically favoured for the majority of subscores with 

statistically significant mean differences for general vision, ocular pain, near vision, mental health, and 

total score in study UV I, and for general vision and mental health in study UV II. Vision related 

effects were not numerically in favour of adalimumab for colour vision in study UVI and for colour 

vision, peripheral vision and near vision in study UV II. 

 

Pediatric 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]). 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Figure 3: Kaplan-Meier curves summarizing time to treatment failure in the paediatric uveitis 

study 

 

 
TIME (WEEKS) 

Treatment     Placebo Adalimumab 

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

subcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg, 

P
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A
B

IL
IT

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F
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A
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IN
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 T
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A

T
M

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A 

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48 

 

 

 

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 patients with Crohn’s disease, the loading dose of 80 mg adalimumab on week 0 followed by 40 mg 

adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 

5.5 µg/mL during the induction period. A loading dose of 160 mg adalimumab on week 0 followed by 

80 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 

12 µg/mL during the induction period. Mean steady-state trough levels of approximately 7 µg/mL 

were observed in Crohn’s disease patients who received a maintenance dose of 40 mg adalimumab 

every other week. 

 

In paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was 

160/80 mg or 80/40 mg at weeks 0 and 2, respectively, dependent on a body weight cut-off of 40 kg. 

At week 4, patients were randomised 1:1 to either the Standard Dose (40/20 mg eow) or Low Dose 

(20/10 mg eow) maintenance treatment groups based on their body weight. The mean (±SD) serum 

adalimumab trough concentrations achieved at week 4 were 15.7±6.6 µg/mL for patients ≥ 40 kg 

(160/80 mg) and 10.6±6.1 µg/mL for patients < 40 kg (80/40 mg). 

 

For patients who stayed on their randomised therapy, the mean (±SD) adalimumab trough 

concentrations at week 52 were 9.5±5.6 µg/mL for the Standard Dose group and 3.5±2.2 µg/mL for 

the Low Dose group. The mean trough concentrations were maintained in patients who continued to 

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49 

 

 

 

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 adult 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 1300 RA patients revealed a trend toward 

higher apparent clearance of adalimumab with increasing body weight. After adjustment for weight 

differences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum 

levels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be lower 

in patients with measurable AAA. 

 

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. 

 

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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 neutralizing 

antibodies in rodents. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Sodium dihydrogen phosphate dihydrate 

Disodium phosphate dihydrate 

Mannitol 

Sodium chloride 

Citric acid monohydrate 

Sodium citrate 

Polysorbate 80 

Sodium hydroxide (for pH adjustment) 

Water for injections 

 

6.2 Incompatibilities 

 

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

products. 

 

6.3 Shelf life 

 

2 years 

 

6.4 Special precautions for storage 

 

Store in a refrigerator (2°C – 8°C).  

Do not freeze.  

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

 

A single 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 14 days. The pre-filled syringe or the pre-filled pen must be protected from light, 

and discarded if not used within the 14-day period. 

 

6.5 Nature and contents of container  

 

Kromeya 40 mg solution for injection in pre-filled syringe 

 

0.8 mL solution in pre-filled syringe (type I glass) with a 29G Thin-Wall, ½ inch needle with a 

latex-free needle cap, a plunger stopper (synthetic rubber), extended finger flanges and a passive 

needle shield. 

 

Pack sizes of: 

– 2 pre-filled syringes, with 2 alcohol pads 
– 6 pre-filled syringes, with 6 alcohol pads. 

 

Kromeya 40 mg solution for injection in pre-filled pen 

 

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0.8 mL solution in pre-filled PhysiojectTM pen containing a pre-filled syringe (type I glass) with a 29G 

Thin-Wall, ½ inch needle with latex-free needle cap and a plunger stopper (synthetic rubber). The pen 

is a single use, disposable, handheld, mechanical injection device. 

 

Pack sizes of: 

– 2 pre-filled pens, with 2 alcohol pads 
– 6 pre-filled pens, with 6 alcohol pads. 

 

Not all presentations 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 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1 

61352 Bad Homburg v.d.Höhe 

Germany 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

Kromeya 40 mg solution for injection in pre-filled syringe 

EU/1/19/1357/002 

EU/1/19/1357/004 

 

Kromeya 40 mg solution for injection in pre-filled pen 

EU/1/19/1357/003 

EU/1/19/1357/005 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

2 April 2019 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

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

 

  

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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 

 

Kromeya 40 mg/0.8 mL solution for injection for paediatric use 

 

 

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. 

 

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 

 

Kromeya 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). Kromeya 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 

 

Kromeya 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 

 

Kromeya 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 

 

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Kromeya is indicated for the treatment of moderately to severely active Crohn's disease in paediatric 

patients (from 6 years of age) who have had an inadequate response to conventional therapy including 

primary nutrition therapy and a corticosteroid and/or an immunomodulator, or who are intolerant to or 

have contraindications for such therapies. 

 

Paediatric Uveitis 

 

Kromeya 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 

 

Kromeya treatment should be initiated and supervised by specialist physicians experienced in the 

diagnosis and treatment of conditions for which Kromeya is indicated. Ophthalmologists are advised 

to consult with an appropriate specialist before initiation of treatment with Kromeya (see section 4.4). 

Patients treated with Kromeya should be given the patient reminder card. 

 

After proper training in injection technique, patients may self-inject with Kromeya if their physician 

determines that it is appropriate and with medical follow-up as necessary. 

 

During treatment with Kromeya, 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 Kromeya for patients with polyarticular juvenile idiopathic arthritis from 2 

years of age is based on body weight (Table 1). Kromeya is administered every other week via 

subcutaneous injection. 

 

Table 1. Kromeya dose for patients with polyarticular juvenile idiopathic arthrtis 

 

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. 

 

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

 

Enthesitis-related arthritis 

 

The recommended dose of Kromeya for patients with enthesitis-related arthritis from 6 years of age is 

based on body weight (Table 2). Kromeya is administered every other week via subcutaneous 

injection. 

 

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Table 2. Kromeya 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. 

 

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

 

Paediatric plaque psoriasis 

 

The recommended Kromeya dose for patients with plaque psoriasis from 4 to 17 years of age is based 

on body weight (Table 3). Kromeya is administered via subcutaneous injection. 

 

Table 3. Kromeya 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 Kromeya 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. 

 

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

 

Paediatric Crohn's disease 

 

The recommended dose of Kromeya for patients with Crohn’s disease from 6 to 17 years of age is 

based on body weight (Table 4). Kromeya is administered via subcutaneous injection. 

 

 

 

 

 

 

 

 

 

 

 

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Table 4. Kromeya dose for paediatric patients with Crohn’s disease 

 

Patient 

weight 

Induction dose Maintenance 

dose starting 

at week 4 

< 40 

kg 

• 40 mg at week 0 and 20 mg at week 2 

 

In case there is a need for a more rapid response to therapy with the 

awareness that the risk for adverse events may be higher with use of 

the higher induction dose, the following dose may be used: 

• 80 mg at week 0 and 40 mg at week 2 

20 mg every 

other week 

≥ 40 kg • 80 mg at week 0 and 40 mg at week 2 

 

In case there is a need for a more rapid response to therapy with the 

awareness that the risk for adverse events may be higher with use of 

the higher induction dose, the following dose may be used: 

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

40 mg every 

other week 

 

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

• < 40 kg: 20 mg every week 

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

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

 

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

 

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

 

Paediatric Uveitis 

 

The recommended dose of Kromeya for paediatric patients with uveitis from 2 years of age is based 

on body weight (Table 5). Kromeya is administered via subcutaneous injection. 

 

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

treatment with methotrexate. 

 

 Table 5. Kromeya 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 Kromeya 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 Kromeya 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). 

 

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

 

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Renal and/or hepatic impairment 

 

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

made. 

 

Method of administration 

 

Kromeya is administered by subcutaneous injection. Full instructions for use are provided in the 

package leaflet. 

 

Kromeya is available in other presentations. 

 

4.3 Contraindications 

 

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

 

Active tuberculosis or other severe infections such as sepsis, and opportunistic infections (see section 

4.4). 

 

Moderate to severe heart failure (NYHA class III/IV) (see section 4.4). 

 

4.4 Special warnings and precautions for use 

 

Traceability 

 

In order to improve traceability of biological medicinal products, the name and the batch number of 

the administered product should be clearly recorded. 

 

Infections 

 

Patients taking TNF-antagonists are more susceptible to serious infections. Impaired lung function 

may increase the risk for developing infections. Patients must therefore be monitored closely for 

infections, including tuberculosis, before, during and after treatment with Kromeya. Because the 

elimination of adalimumab may take up to four months, monitoring should be continued throughout 

this period. 

 

Treatment with Kromeya 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 

Kromeya should be considered prior to initiating therapy (see Other opportunistic infections). 

 

Patients who develop a new infection while undergoing treatment with Kromeya, should be monitored 

closely and undergo a complete diagnostic evaluation. Administration of Kromeya 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 Kromeya 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. 

 

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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 Kromeya, 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, Kromeya 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 Kromeya, and in accordance with local 

recommendations. 

 

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

Kromeya 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 Kromeya. 

 

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, 

dyspnea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant 

shock an invasive fungal infection should be suspected and administration of Kromeya should be 

promptly discontinued. Diagnosis and administration of empiric antifungal therapy in these patients 

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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 Kromeya. 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 Kromeya 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, Kromeya 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 Kromeya in patients with pre-existing or recent-onset central or peripheral nervous system 

demyelinating disorders; discontinuation of Kromeya 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 Kromeya 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 Kromeya 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. 

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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 Kromeya 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 Kromeya 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 Kromeya. 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, leucopenia) 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 Kromeya. Discontinuation of Kromeya 

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. 

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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. Kromeya should be used with 

caution in patients with mild heart failure (NYHA class I/II). Kromeya is contraindicated in moderate 

to severe heart failure (see section 4.3). Treatment with Kromeya must be discontinued in patients who 

develop new or worsening symptoms of congestive heart failure. 

 

Autoimmune processes 

 

Treatment with Kromeya 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 Kromeya 

and is positive for antibodies against double-stranded DNA, further treatment with Kromeya 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 Kromeya 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 

 

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The frequency of serious infections among adalimumab treated subjects over 65 years of age (3.7%) 

was higher than for those under 65 years of age (1.5%). Some of those had a fatal outcome. Particular 

attention regarding the risk for infection should be paid when treating the elderly. 

 

Paediatric population 

 

See Vaccinations above. 

 

Excipients with known effects 

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8  ml dose, i.e. essentially 

'sodium-free'. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and 

psoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitant 

methotrexate. Antibody formation was lower when adalimumab was given together with methotrexate 

in comparison with use as monotherapy. Administration of adalimumab without methotrexate resulted 

in increased formation of antibodies, increased clearance and reduced efficacy of adalimumab (see 

section 5.1). 

 

The combination of Kromeya and anakinra is not recommended (see section 4.4 “Concurrent 

administration of biologic DMARDs or TNF-antagonists”). 

 

The combination of Kromeya 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 Kromeya treatment. 

 

Pregnancy 

 

A large number (approximately 2100) of prospectively collected pregnancies exposed to adalimumab 

resulting in live birth with known outcomes, including more than 1500 exposed during the first 

trimester, does not indicate an increase in the rate of malformation in the newborn. 

In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn’s disease (CD) 

treated with adalimumab at least during the first trimester and 120 women with RA or CD not treated 

with adalimumab were enrolled. The primary endpoint was the birth prevalence of major birth defects. 

The rate of pregnancies ending with at least one live born infant with a major birth defect was 6/69 

(8.7%) in the adalimumab-treated women with RA and 5/74 (6.8%) in the untreated women with RA 

(unadjusted OR 1.31, 95% CI 0.38-4.52) and 16/152 (10.5%) in the adalimumab-treated women with 

CD and 3/32 (9.4%) in the untreated women with CD (unadjusted OR 1.14, 95% CI 0.31-4.16). The 

adjusted OR (accounting for baseline differences) was 1.10 (95% CI 0.45-2.73) with RA and CD 

combined. There were no distinct differences between adalimumab-treated and untreated women for the 

secondary endpoints spontaneous abortions, minor birth defects, preterm delivery, birth size and serious 

or opportunistic infections and no stillbirths or malignancies were reported. The interpretation of data 

may be impacted due to methodological limitations of the study, including small sample size and non-

randomized design. 

 

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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, Kromeya can be used during breast-feeding. 

 

Fertility 

 

Preclinical data on fertility effects of adalimumab are not available. 

 

4.7 Effects on ability to drive and use machines 

 

Kromeya may have a minor influence on the ability to drive and use machines. Vertigo and visual 

impairment may occur following administration of Kromeya (see section 4.8). 

 

4.8 Undesirable effects 

 

Clinical studies in patients suffering hidradenitis suppurativa in this section are merely included for 

public health reasons. However, please note that Kromeya is neither intended nor authorized for 

treatment of hidradenitis suppurativa. 

 

Summary of the safety profile 

 

Adalimumab was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 

months or more. These trials included rheumatoid arthritis patients with short term and long standing 

disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related 

arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without 

radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, 

hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients 

receiving adalimumab and 3,801 patients receiving placebo or active comparator during the controlled 

period. 

 

The proportion of patients who discontinued treatment due to adverse events during the double-blind, 

controlled portion of pivotal studies was 5.9% for patients taking adalimumab and 5.4% for control 

treated patients. 

 

The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper 

respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain 

or swelling), headache and musculoskeletal pain. 

 

Serious adverse reactions have been reported for adalimumab. TNF-antagonists, such as adalimumab 

affect the immune system and their use may affect the body’s defence against infection and cancer. 

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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,  

joint infections 

Uncommon Neurological infections (including viral 

meningitis), 

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System Organ Class Frequency Adverse reaction 

opportunistic infections and tuberculosis 

(including coccidioidomycosis, histoplasmosis 

and mycobacterium avium complex infection), 

bacterial infections, 

eye infections,  

diverticulitis 1) 

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 lymphatic 

system disorders* 

Very common Leucopaenia (including neutropaenia and 

agranulocytosis), 

anaemia 

Common Leucocytosis, 

thrombocytopenia 

Uncommon Idiopathic thrombocytopenic purpura 

Rare Pancytopenia 

Immune system disorders* Common Hypersensitivity, 

allergies (including seasonal allergy) 

Uncommon Sarcoidosis1), 

vasculitis 

Rare Anaphylaxis1) 

Metabolism and nutrition 

disorders 

Very common Lipids increased 

Common Hypokalaemia, 

uric acid increased, 

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System Organ Class Frequency Adverse reaction 

blood sodium abnormal, 

hypocalcaemia, 

hyperglycaemia, 

hypophosphataemia, 

dehydration 

Psychiatric disorders Common Mood alterations (including depression), 

anxiety, 

insomnia 

Nervous system disorders* Very common Headache 

Common Paraesthesias (including hypoaesthesia), 

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, 

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System Organ Class Frequency Adverse reaction 

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) 

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System Organ Class Frequency Adverse reaction 

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, 

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System Organ Class Frequency Adverse reaction 

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 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, 

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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 a adalimumab trial in paediatric patients with chronic plaque psoriasis. No 

malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during an 

adalimumab trial in paediatric patients with uveitis. 

 

During the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in duration in 

patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial 

spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis 

suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and 

non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 

1,000 patient-years among 5,291 adalimumab treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 

patient-years among 3,444 control patients (median duration of treatment was 4.0 months for 

adalimumab and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-

melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among adalimumab-treated patients 

and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell 

carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among 

adalimumab- treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The 

rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among 

adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. 

 

When combining controlled portions of these trials and ongoing and completed open label extension 

studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 

patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma 

skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin 

cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is 

approximately 1.3 per 1,000 patient years. 

 

In post-marketing experience from January 2003 to December 2010, predominantly in patients with 

rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient treatment 

years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 

0.3 per 1,000 patient treatment years, respectively (see section 4.4). 

 

Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated 

with adalimumab (see section 4.4). 

 

Autoantibodies 

 

Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis 

studies I − V. In these trials, 11.9% of patients treated with adalimumab and 8.1% of placebo and 

active control − treated patients that had negative baseline anti-nuclear antibody titres reported 

positive titres at week 24. Two patients out of 3,441 treated with adalimumab in all rheumatoid 

arthritis and psoriatic arthritis studies developed clinical signs suggestive of new-onset lupus-like 

syndrome. The patients improved following discontinuation of therapy. No patients developed lupus 

nephritis or central nervous system symptoms. 

 

Hepato-biliary events 

 

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In controlled Phase 3 trials of adalimumab in patients with rheumatoid arthritis and psoriatic arthritis 

with a control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 

3.7% of adalimumab-treated patients and 1.6% of control-treated patients. 

 

In controlled Phase 3 trials of adalimumab in patients with polyarticular juvenile idiopathic arthritis 

who were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations ≥ 3 x 

ULN occurred in 6.1% of adalimumab-treated patients and 1.3% of control-treated patients. Most ALT 

elevations occurred with concomitant methotrexate use. No ALT elevations ≥ 3 x ULN occurred in the 

Phase 3 trial of adalimumab in patients with polyarticular juvenile idiopathic arthritis who were 2 to 

<4 years. 

 

In controlled Phase 3 trials of adalimumab in patients with Crohn’s disease and ulcerative colitis with 

a control period ranging from 4 to 52 weeks. ALT elevations ≥ 3 x ULN occurred in 0.9% of 

adalimumab- treated patients and 0.9% of controlled-treated patients. 

 

In the Phase 3 trial of adalimumab in patients with paediatric Crohn’s disease which evaluated 

efficacy and safety of two body weight adjusted maintenance dose regimens following body weight 

adjusted induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% 

(5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline. 

 

In controlled Phase 3 trials of adalimumab in patients with plaque psoriasis with a control period 

duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumab-

treated patients and 1.8% of control-treated patients. 

 

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

plaque psoriasis. 

 

In controlled trials of adalimumab (initial doses of 160 mg at week 0 and 80 mg at week 2, followed 

by 40 mg every week starting at week 4), in patients with hidradenitis suppurativa with a control 

period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of 

adalimumab-treated patients and 0.6% of control-treated patients. 

 

In controlled trials of adalimumab (initial doses of 80 mg at week 0 followed by 40 mg every other 

week starting at week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 

days and 105.0 days in Adalimumab-treated and control-treated patients, respectively, ALT elevations 

≥ 3 x ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control-treated patients. 

 

Across all indications in clinical trials patients with raised ALT were asymptomatic and in most cases 

elevations were transient and resolved on continued treatment. However, there have also been post- 

marketing reports of liver failure as well as less severe liver disorders that may precede liver failure, 

such as hepatitis including autoimmune hepatitis in patients receiving adalimumab. 

 

Concurrent treatment with azathioprine/6-mercaptopurine 

 

In adult Crohn’s disease studies, higher incidences of malignant and serious infection-related adverse 

events were seen with the combination of adalimumab and azathioprine/6-mercaptopurine compared 

with adalimumab alone. 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V.  

 

4.9 Overdose 

 

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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 

 

Kromeya 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 neutralizes the biological function of TNF by blocking its 

interaction with the p55 and p75 cell surface TNF receptors. 

 

Adalimumab also modulates biological responses that are induced or regulated by TNF, including 

changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, 

and ICAM-1 with an IC50 of 0.1-0.2 nM). 

 

Pharmacodynamic effects 

 

After treatment with 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 and ulcerative colitis 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 

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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 

dose 

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

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

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

 

Patients demonstrating a Pediatric 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 Pediatric ACR core criteria, ≥ 2 active 

joints, and improvement of ≥ 30% in no more than 1 of the 6 criteria. After 32 weeks or at disease 

flare, patients were eligible to enrol into the open label extension phase. 

 

Table 8 

Ped ACR 30 responses in the JIA study 

 

Stratum MTX Without MTX 

Phase   

OL-LI 16 weeks   

Ped ACR 30 

response (n/N) 

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

Efficacy outcome 

Double blind 32 weeks Adalimumab 

/MTX (N = 38) 

Placebo /MTX 

(N = 37) 

Adalimumab 

(N = 30) 

Placebo (N = 28) 

Disease flares at the end of 

32 weeksa (n/N) 

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

Median time to disease 

flare 

>32 weeks 20 weeks >32 weeks 14 weeks 

 
a Ped ACR 30/50/70 responses week 48 significantly greater than those of placebo treated patients 
b p = 0.015 
c p = 0.031 

 

Amongst those who responded at week 16 (n=144), the Pediatric ACR 30/50/70/90 responses were 

maintained for up to six years in the OLE phase in patients who received adalimumab throughout the 

study. 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, Kromeya 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 

 

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The safety and efficacy of adalimumab was assessed in an open-label, multicenter study in 32 children 

(2 - <4 years old or aged 4 and above weighing < 15 kg) with moderately to severely active 

polyarticular JIA. The patients received 24 mg/m2 body surface area (BSA) of adalimumab up to a 

maximum of 20 mg every other week as a single dose via SC injection for at least 24 weeks. During 

the study, most subjects used concomitant MTX, with fewer reporting use of corticosteroids or 

NSAIDs. 

 

At week 12 and week 24, PedACR30 response was 93.5% and 90.0%, respectively, using the observed 

data approach. The proportions of subjects with PedACR50/70/90 at week 12 and week 24 were 

90.3%/61.3%/38.7% and 83.3%/73.3%/36.7%, respectively. Amongst those who responded (Pediatric 

ACR 30) at week 24 (n=27 out of 30 patients), the Pediatric ACR 30 responses were maintained for up 

to 60 weeks in the OLE phase in patients who received adalimumab throughout this time period. 

Overall, 20 subjects were treated for 60 weeks or longer. 

 

Enthesitis-related arthritis 

 

The safety and efficacy of adalimumab were assessed in a multicenter, randomised, double-blind study 

in 46 paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients were 

randomised to receive either 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of 

40 mg, or placebo every other week for 12 weeks. The double-blind period is followed by an open-

label (OL) period during which patients received 24 mg/m2 BSA of adalimumab up to a maximum of 

40 mg every other week subcutaneously for up to an additional 192 weeks. The primary endpoint was 

the percent change from Baseline to week 12 in the number of active joints with arthritis (swelling not 

due to deformity or joints with loss of motion plus pain and/or tenderness), which was achieved with 

mean percent decrease of -62.6% (median percent change -88.9%) in patients in the adalimumab 

group compared to -11.6% (median percent change -50.0%) in patients in the placebo group. 

Improvement in number of active joints with arthritis was maintained during the OL period through 

week 156 for the 26 of 31 (84%) patients in the adalimumab group who remained in the study. 

Although not statistically significant, the majority of patients demonstrated clinical improvement in 

secondary endpoints such as number of sites of enthesitis, tender joint count (TJC), swollen joint count 

(SJC), Pediatric ACR 50 response, and Pediatric ACR 70 response. 

 

Adults with rheumatoid arthritis 

 

Adalimumab was evaluated in over 3000 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 

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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 

percentage 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 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 NA NA NA NA 24.0% 58.9% 

ACR 50 
      

6 months 6.7% 52.4% 8.2% 22.1% 9.5% 39.1% 

12 months NA NA NA NA 9.5% 41.5% 

ACR 70 
      

6 months 3.3% 23.8% 1.8% 12.4% 2.5% 20.8% 

12 months NA NA NA NA 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 

 

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) 

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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 

40mg 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). 

 

Table 10 

ACR responses in RA study V 

(percent of patients) 

 

Response MTX 

n=257 

Adalimumab 

n=274 

Adalimumab/MTX 

n=268 
p-value

a
 p-value

b p-value
c
 

ACR 20       

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

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

ACR 50       

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

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

ACR 70       

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

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

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

adalimumab/methotrexate combination therapy using the Mann-Whitney U test. 

b. p-value is from the pairwise comparison of adalimumab monotherapy and 

adalimumab/methotrexate combination therapy using the Mann-Whitney U test 

c. p-value is from the pairwise comparison of adalimumab monotherapy and methotrexate 

monotherapy using the Mann-Whitney U test 

 

In the open-label extension for RA study V, ACR response rates were maintained when followed for 

up to 10 years. Of 542 patients who were randomised to adalimumab 40 mg every other week, 170 

patients continued on adalimumab 40 mg every other week for 10 years. Among those, 154 patients 

(90.6%) had ACR 20 responses; 127 patients (74.7%) had ACR 50 responses; and 102 patients 

(60.0%) had ACR 70 responses. 

 

At week 52, 42.9% of patients who received adalimumab/methotrexate combination therapy achieved 

clinical remission (DAS28 (CRP) < 2.6) compared to 20.6% of patients receiving methotrexate 

monotherapy and 23.4% of patients receiving adalimumab monotherapy. Adalimumab/methotrexate 

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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. 

 

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 
amethotrexate 
b95% confidence intervals for the differences in change scores between methotrexate and 

adalimumab. 
cBased on rank analysis 
dJoint Space Narrowing 

 

In RA study V, structural joint damage was assessed radiographically and expressed as change in 

modified Total Sharp Score (see Table 12). 

 

 

 

 

 

 

 

 

 

 

 

 

 

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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 baseline to Month 6 compared to placebo and in RA study III the same was 

seen at week 52. Results from the Short Form Health Survey (SF 36) for all doses/schedules of 

adalimumab in all four studies support these findings, with statistically significant physical component 

summary (PCS) scores, as well as statistically significant pain and vitality domain scores for the 

40 mg every other week dose. A statistically significant decrease in fatigue as measured by functional 

assessment of chronic illness therapy (FACIT) scores was seen in all three studies in which it was 

assessed (RA studies I, III, IV). 

 

In RA study III, most subjects who achieved improvement in physical function and continued 

treatment maintained improvement through week 520 (120 months) of open-label treatment. 

Improvement in quality of life was measured up to week 156 (36 months) and improvement was 

maintained through that time. 

 

In RA study V, the improvement in the HAQ disability index and the physical component of the SF 36 

showed greater improvement (p < 0.001) for adalimumab/methotrexate combination therapy versus 

methotrexate monotherapy and adalimumab monotherapy at week 52, which was maintained through 

week 104. Among the 250 subjects who completed the open-label extension study, improvements in 

physical function were maintained through 10 years of treatment. 

 

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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 

adalimmab 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 

 MTX
a 

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, adalimumaa 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 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 1212 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 

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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 75
a
 26 (6.5) 578 (70.9)

b
 

PASI 100 3 (0.8) 163 (20.0)
b
 

PGA: Clear/minimal 17 (4.3) 506 (62.2)
b
 

a 
Percent of patients achieving PASI75 response was calculated as center- 

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 

 

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-randomization to placebo who then enrolled into the open-

label extension trial, 38% (25/66) and 55% (36/66) regained PASI 75 response after 12 and 24 weeks 

of re-treatment, respectively. 

 

A total of 233 PASI 75 responders at week 16 and week 33 received continuous 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, 

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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)). 

 

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 -44.2 a -11.5 -56.2a -72.2 

a p<0.001, adalimumab vs. placebo 

 

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Adalimumab treated patients showed statistically significant improvements at week 26 compared with 

placebo in the DLQI.  

 

Paediatric Crohn’s disease 

 

Adalimumab was assessed in a multicenter, 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 17. 

 

Table 17 

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 18. Rates of discontinuation of corticosteroids or 

immunomodulators are presented in Table 19. 

 

Table 18 

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. 

 

 

 

 

 

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Table 19 

Paediatric CD study 

Discontinuation of corticosteroids or immunomodulators and fistula remission 

 Standard dose 

40/20 mg eow 

Low dose 

20/10 mg eow 

p value1 

Discontinued corticosteroids N= 33 N=38  

Week 26 84.8% 65.8% 0.066 

Week 52 69.7% 60.5% 0.420 

Discontinuation of immunomodulators2 N=60 N=57  

Week 52 30.0% 29.8% 0.983 

Fistula remission3 N=15 N=21  

Week 26 46.7% 38.1% 0.608 

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

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

Baseline visits 

 

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

and height velocity were observed for both treatment groups. 

 

Statistically and clinically significant improvements from Baseline were also observed in both 

treatment groups for quality of life parameters (including IMPACT III). 

 

One hundred patients (n=100) from the Paediatric CD study continued in an open-label long-term 

extension study. After 5 years of adalimumab therapy, 74.0% (37/50) of the 50 patients remaining in 

the study continued to be in clinical remission, and 92.0% (46/50) of patients continued to be in 

clinical response per PCDAI. 

 

Adult Crohn’s disease 

 

The safety and efficacy of adalimumab were assessed in over 1500 patients with moderately to 

severely active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in 

randomised, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, 

corticosteroids, and/or immunomodulatory agents were permitted and 80% of patients continued to 

receive at least one of these medications. 

 

Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies, CD study I 

(CLASSIC I) and CD study II (GAIN). In CD study I, 299 TNF-antagonist naive patients were 

randomised to one of four treatment groups; placebo at weeks 0 and 2, 160 mg adalimumab at week 0 

and 80 mg at week 2, 80 mg at week 0 and 40 mg at week 2, and 40 mg at week 0 and 20 mg at week 

2. In CD study II, 325 patients who had lost response or were intolerant to infliximab were randomised 

to receive either 160 mg adalimumab at week 0 and 80 mg at week 2 or placebo at weeks 0 and 2. The 

primary non-responders were excluded from the studies and therefore these patients were not further 

evaluated. 

 

Maintenance of clinical remission was evaluated in CD study III (CHARM). In CD study III, 854 

patients received open-label 80 mg at week 0 and 40 mg at week 2. At week 4 patients were 

randomised to 40 mg every other week, 40 mg every week, or placebo with a total study duration of 

56 weeks. Patients in clinical response (decrease in CDAI ≥ 70) at week 4 were stratified and analysed 

separately from those not in clinical response at week 4. Corticosteroid taper was permitted after week 

8. 

 

CD study I and CD study II induction of remission and response rates are presented in Table 20. 

 

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Table 20 

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 21. 

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 21 

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 

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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. 

 

Pediatric 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 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]). 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Figure 1: Kaplan-Meier curves summarizing time to treatment failure in the paediatric uveitis 

study 

 

 
TIME (WEEKS) 

Treatment     Placebo Adalimumab 

Note: P = Placebo (number at risk); A = 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. 

 

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). 

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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 22). Both 

studies demonstrated an early and sustained effect of adalimumab on the treatment failure rate versus 

placebo (see Figure 2). 

 

Table 22 

Time to treatment failure in studies UV I and UV II 

 

 

Analysis 

treatment 

N Failure 

N (%) 

Median 

time to 

failure 

(months) 

HRa CI 95% for 

HRa 

p Value b 

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. 

 

 

 

 

 

 

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Figure 2: Kaplan-Meier curves summarizing time to treatment failure on or after week 6 
(study UV I) or week 2 (study UV II) 

TIME (MONTHS) 

Study UV I Treatment Placebo Adalimumab 
 

T
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A

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%
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 TIME (MONTHS) 
Study UV II Treatment Placebo Adalimumab 

 

Note: P# = Placebo (Number of events/Number at risk); A# = Adalimumab (number of events/Number 

at risk). 

 

In study UV I statistically significant differences in favour of adalimumab versus placebo were 

observed for each component of treatment failure. In study UV II, statistically significant differences 

were observed for visual acuity only, but the other components were numerically in favour of 

adalimumab. 

 

Of the 417 subjects included in the uncontrolled long-term extension of Studies UV I and UV II, 

46 subjects were regarded ineligible (e.g. developed complications secondary to diabetic retinopathy, 

due to cataract surgery or vitrectomy) and were excluded from the primary analysis of efficacy. Of the 

371 remaining patients, 276 evaluable patients reached 78 weeks of open-label adalimumab treatment. 

Based on the observed data approach, 222 (80.4%) were in quiescence (no active inflammatory 

lesions, AC cell grade ≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose ≤ 7.5 mg per day, 

and 184 (66.7 %) were in steroid-free quiescence. BCVA was either improved or maintained (< 

5 letters deterioration) in 88.4% of the eyes at week 78. Among the patients who discontinued the 

study prior to week 78, 11% discontinued due to adverse events, and 5% due to insufficient response 

to adalimumab treatment. 

 

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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 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). 

 

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 

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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 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. 

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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 1300 RA patients revealed a trend toward 

higher apparent clearance of adalimumab with increasing body weight. After adjustment for weight 

differences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum 

levels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be lower 

in patients with measurable AAA. 

 

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 neutralizing 

antibodies in rodents. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Sodium dihydrogen phosphate dihydrate 

Disodium phosphate dihydrate 

Mannitol 

Sodium chloride 

Citric acid monohydrate 

Sodium citrate 

Polysorbate 80 

Sodium hydroxide (for pH adjustment) 

Water for injections 

 

6.2 Incompatibilities 

 

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

products. 

 

6.3 Shelf life 

 

2 years 

 

6.4 Special precautions for storage 

 

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

from light. 

 

Kromeya 40 mg/0.8 mL solution for injection for paediatric use may be stored at temperatures up to a 

maximum of 25°C for a period of up to 14 days. The vial must be protected from light, and discarded 

if not used within the 14-day period. 

 

6.5 Nature and contents of container 

 

Kromeya 40 mg/0.8 mL solution for injection for paediatric use in single-use vial  

0.8 mL solution in vial (type I glass) with a rubber stopper (synthetic rubber) and aluminium crimp 

seal. 

Each box contains 1 vial, 1 sterile injection syringe, 1 sterile needle, 1 vial adaptor and 2 alcohol pads. 

 

6.6 Special precautions for disposal <and other handling> 

 

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

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1 

61352 Bad Homburg v.d.Höhe 

Germany 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/19/1357/001 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

2 April 2019 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

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

 

  

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ANNEX II 

 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 

MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 

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

 

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

Merck Serono S.A. 

Succursale de Corsier-sur-Vevey 

Chemin du Fenil  

Zone Industrielle B 

1804 Corsier-sur-Vevey 

Switzerland  

 

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

Fresenius Kabi Austria GmbH 

Hafnerstraße 36,  

8055 Graz 

Austria 

 

Merck Serono S.p.a. 

Via delle Magnolie 15 

Loc. frazione Zona Industriale 

70026 – Modugno (BA) 

Italy 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

 

• Periodic safety update reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

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

 

• Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 

updates of the RMP. 

An updated RMP should be submitted: 

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• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached.  

 

• Additional risk minimisation measures  
 

 

The Patient Reminder Cards (adult and paediatric) contain the following key elements: 

- infections, including tuberculosis 

- cancer 

- nervous system problems 

- vaccinations 

  

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ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  

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A. LABELLING 

  

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Kromeya 40 mg solution for injection in pre-filled syringe 

adalimumab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One 0.8 mL pre-filled syringe contains 40 mg adalimumab 

 

 

3. LIST OF EXCIPIENTS 

 

Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, mannitol, sodium 

chloride, citric acid monohydrate,  sodium citrate, polysorbate 80, sodium hydroxide and water for 

injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for injection 

2 pre-filled syringes 

2 alcohol pads 

6 pre-filled syringes 

6 alcohol pads 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

 

Subcutaneous use 

For single use only 

 

Open here 

 

 

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 

 

 

8. EXPIRY DATE 

 

EXP 

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9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator. Do not freeze. 

Refer to package leaflet for alternative storage details. 

 

Keep the pre-filled 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 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1 

61352 Bad Homburg v.d.Höhe 

Germany 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/19/1357/002 

EU/1/19/1357/004 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Kromeya 40 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

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PC: 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

SYRINGE/LABEL 

 

 

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

 

Kromeya 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 

 

0.8 mL 

 

 

6. OTHER 

 

 

  

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Kromeya 40 mg solution for injection in pre-filled pen 

adalimumab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One 0.8 mL pre-filled pen contains 40 mg adalimumab 

 

 

3. LIST OF EXCIPIENTS 

 

Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, mannitol, sodium 

chloride, citric acid monohydrate, sodium citrate, polysorbate 80, sodium hydroxide and water for 

injections.  

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for injection 

2 pre-filled pens 

2 alcohol pads 

6 pre-filled pens 

6 alcohol pads 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

 

Subcutaneous use 

For single use only 

 

Open here 

 

 

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 

 

 

8. EXPIRY DATE 

 

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EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator. Do not freeze. 

Refer to package leaflet for alternative storage details. 

 

Keep the pre-filled 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 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1 

61352 Bad Homburg v.d.Höhe 

Germany 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/19/1357/003 

EU/1/19/1357/005  

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Kromeya 40 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

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PC: 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

PEN LABEL 

 

 

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

 

Kromeya 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 

 

0.8 mL 

 

 

6. OTHER 

 

 

 

  

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105 

 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Kromeya 40 mg/0.8 mL solution for injection for paediatric use 

adalimumab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One 0.8 mL vial contains 40 mg adalimumab 

 

 

3. LIST OF EXCIPIENTS 

 

Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, mannitol, sodium 

chloride, citric acid monohydrate, sodium citrate, polysorbate 80, sodium hydroxide and water for 

injections.  

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for injection 

1 vial  

1 sterile injection syringe 

1 sterile needle 

1 vial adaptor 

2 alcohol pads 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

 

Subcutaneous use 

Each item for single use only 

 

Open here 

 

 

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 

 

 

8. EXPIRY DATE 

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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 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1 

61352 Bad Homburg v.d.Höhe 

Germany 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/19/1357/001  

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Kromeya 40 mg/0.8 mL 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

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

 

Kromeya 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 

 

 

  

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B. PACKAGE LEAFLET 

  

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Package leaflet: Information for the patient 

 

Kromeya 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 Kromeya and during treatment 

with Kromeya. Keep this patient reminder card with you during your treatment and for 4 months 

after your (or your child’s) last injection of Kromeya. 

- 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 Kromeya is and what it is used for 

2. What you need to know before you use Kromeya 

3. How to use Kromeya 

4. Possible side effects 

5. How to store Kromeya 

6. Contents of the pack and other information 

7. Instructions for use 

 

 

1. What Kromeya is and what it is used for 

 

Kromeya contains the active substance adalimumab, a medicine that acts on your body’s immune 

(defence) system.  

 

Kromeya is intended for the treatment of the following inflammatory diseases: 

• rheumatoid arthritis, 

• polyarticular juvenile idiopathic arthritis,  
• enthesitis-related arthritis,  
• ankylosing spondylitis,  
• axial spondyloarthritis without radiographic evidence of ankylosing spondylitis,  
• psoriatic arthritis,  
• psoriasis,  
• Crohn’s disease,  
• ulcerative colitis and  
• non-infectious uveitis  
 

The active ingredient in Kromeya, adalimumab, is a monoclonal antibody. Monoclonal antibodies are 

proteins that attach to a specific target in the body.   

 

The target of adalimumab is another protein called tumour necrosis factor (TNFα), which is present at 

increased levels in the inflammatory diseases listed above. By attaching to TNFα, Kromeya blocks its 

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action and reduces the inflammation in these diseases. 

 

Rheumatoid arthritis 

 

Rheumatoid arthritis is an inflammatory disease of the joints. 

 

Kromeya 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 Kromeya to treat your rheumatoid 

arthritis. 

 

Kromeya can also be used to treat severe, active and progressive rheumatoid arthritis without previous 

methotrexate treatment. 

 

Kromeya can slow down the damage to the cartilage and bone of the joints caused by the disease and 

improve physical function. 

 

Usually, Kromeya is used with methotrexate. If your doctor considers that methotrexate is 

inappropriate, Kromeya 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. 

 

Kromeya 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 Kromeya 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. 

 

Kromeya is used in adults to treat these conditions. 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 Kromeya to reduce the signs 

and symptoms of your disease. 

 

Psoriatic arthritis 

 

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

 

Kromeya is used to treat psoriatic arthritis in adults. Kromeya can slow down the damage to the 

cartilage and bone of the joints caused by the disease and improve physical function. 

 

Plaque psoriasis in adults and children 

 

Plaque psoriasis is an inflammatory skin condition that causes red, flaky, crusty patches of skin 

covered with silvery scales. Plaque psoriasis can also affect the nails, causing them to crumble, 

become thickened and lift away from the nail bed which can be painful. Psoriasis is believed to be 

caused by a problem with the body’s immune system that leads to an increased production of skin 

cells. 

 

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Kromeya is used to treat moderate to severe plaque psoriasis in adults. Kromeya is also used to treat 

severe plaque psoriasis in children and adolescents adolescents aged 4 to 17 years for whom medicines 

applied to the skin and treatment with UV light have either not worked very well or are not suitable. 

 

Crohn’s disease in adults and children 

 

Crohn’s disease is an inflammatory disease of the gut. 

 

Kromeya 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 you do not respond well enough to these 

medicines, you will be given Kromeya to reduce the signs and symptoms of your Crohn’s disease. 

 

Ulcerative colitis 

 

Ulcerative colitis is an inflammatory disease of the bowel. 

 

Kromeya 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 Kromeya 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. The inflammation 

leads 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). Kromeya works by reducing this inflammation. 

 

Kromeya 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. 

 

 

2. What you need to know before you use Kromeya  

 

Do not use Kromeya 

 

- 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, sepsis (blood poisoning) or other 

opportunistic infections (unusual infections associated with a weakened immune system). It is 

important that you tell your doctor if you have symptoms of infections, e.g. fever, wounds, 

feeling tired, dental problems (see “Warnings and precautions”). 

 

- 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 Kromeya 

 

Allergic reaction 

 

• If you have allergic reactions with symptoms such as chest tightness, wheezing, dizziness, 
swelling or rash do not inject more Kromeya and contact your doctor immediately since, in rare 

cases, these reactions can be life threatening. 

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Infection 

 

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

 

• You might get infections more easily while you are receiving Kromeya treatment. This risk may 
increase if your lung function is reduced. These infections may be more serious and include 

tuberculosis, infections caused by viruses, fungi, parasites or bacteria, or other unusual 

infectious organisms 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 temporarily stopping Kromeya. 

 

Tuberculosis (TB) 

 

• As cases of tuberculosis have been reported in patients treated with adalimumab, your doctor 
will check you for signs and symptoms of tuberculosis before starting Kromeya. 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 had 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 have lived or travelled in regions where fungal infections such as 
histoplasmosis, coccidioidomycosis or blastomycosis are common. 

 

• 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. Adalimumab 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 Kromeya. You 
and your doctor should pay special attention to signs of infection while you are being treated 

with Kromeya. 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 procedures 

 

• If you are about to have surgery or dental procedures tell your doctor that you are taking 
Kromeya. Your doctor may recommend temporarily stopping Kromeya. 

 

Demyelinating disease 

 

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• 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 Kromeya. 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 living but weakened forms of disease-causing bacteria or viruses and 
should not be given during treatment with Kromeya in case they cause infections. Check with 

your doctor before you receive any vaccines. It is recommended that, if possible, children be 

given all the scheduled vaccinations for their age before they start treatment with Kromeya. If 

you receive Kromeya 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 

Kromeya use during your pregnancy so they can decide when your baby should receive any 

vaccine. 

 

Heart failure 

 

• It is important to tell your doctor if you have had or have a serious heart condition. If you have 
mild heart failure and you are being treated with Kromeya, your heart failure status must be 

closely monitored by your doctor. 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.  

 

Fever, bruising, bleeding or looking pale 

 

• In some patients the body may fail to produce enough of the blood cells that fight off infections or 
help you to stop bleeding. If you develop a fever that does not go away, or you bruise or bleed 

very easily or look very pale, call your doctor right away. Your doctor may decide to stop 

treatment. 

 

Cancer 

 

• There have been very rare cases of certain kinds of cancer in children and adults taking 
adalimumab or other TNFα blockers. People with more serious rheumatoid arthritis who have 

had the disease for a long time may have a higher than average risk of getting lymphoma  and 

leukaemia (cancers that affect blood cells and bone marrow). If you take Kromeya the risk of 

getting lymphoma, leukaemia, or other cancers may increase. On rare occasions, a specific and 

severe type of lymphoma, has been observed in patients taking adalimumab. Some of those 

patients were also treated with the medicines azathioprine or mercaptopurine. Tell your doctor if 

you are taking azathioprine or mercaptopurine with Kromeya. 

  

• In addition cases of non-melanoma skin cancer have been observed in patients taking 
adalimumab. If new areas of damaged skin appear during or after treatment 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 are a heavy smoker, you should discuss with your doctor 

whether treatment with a TNFα blocker is appropriate for you. 

 

• On rare occasions, treatment with Kromeya 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 

 

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• Vaccinations: if possible children should be up to date with all vaccinations before using 
Kromeya. 

• Do not give Kromeya to children with polyarticular juvenile idiopathic arthritis below the age of 
2 years. 

• Do not use the 40 mg pre-filled syringe or 40 mg pre-filled pen if doses other than 40 mg are 
recommended. 

 

Other medicines and Kromeya 

 

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

medicines. 

 

Kromeya 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 Kromeya with medicines containing the active substances anakinra or abatacept 

due to increased risk of serious infection. The combination of adalimumab as well as other 

TNF-antagonists and anakinra or abatacept is not recommended based upon the possible increased risk 

for infections, including serious infections and other potential pharmacological interactions. If you 

have questions, please ask your doctor. 

 

Pregnancy and breast-feeding 

 

If you think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for 

advice before taking this medicine. 

 

You are advised to avoid becoming pregnant and must use adequate contraception while using 

Kromeya and for at least 5 months after the last Kromeya injection. If you become pregnant, you 

should see your doctor. 

 

Kromeya 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. 

 

Kromeya can be used during breast-feeding. 

 

If you receive Kromeya 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 Kromeya use during your pregnancy before the baby receives any vaccine (for more information 

see section on vaccination). 

 

Driving and using machines 

 

Kromeya 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 Kromeya. 

 

Kromeya contains sodium 

 

This medicine contains less than 1 mmol of sodium (23 mg) per 0.8 ml dose, that is to say essentially 

‘sodium-free’. 

 

 

3. How to use Kromeya 

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Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 

or pharmacist if you are not sure. 

 

Kromeya is injected under the skin (subcutaneous use). Patients requiring a dose less than 40 mg 

should use the 40 mg vial presentation of Kromeya. 

 

The recommended doses for Kromeya in each of the approved uses are shown in the following table. 

 

Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis 

without radiographic evidence of ankylosing spondylitis 

Age or body weight How much and how often to 

take? 

Notes 

Adults  40 mg every other week In rheumatoid arthritis, 

methotrexate is continued while 

using Kromeya. If your doctor 

decides that methotrexate is 

inappropriate, Kromeya can be 

given alone. 

 

If you have rheumatoid arthritis 

and you do not receive 

methotrexate with your 

Kromeya therapy, your doctor 

may decide to give Kromeya 40 

mg every week or 80 mg every 

other week.  

 

Polyarticular juvenile idiopathic arthritis 

Age or body weight How much and how often to 

take? 

Notes 

Children, adolescents and 

adults from 2 years of age 

weighing 30 kg or more 

40 mg every other week Not applicable 

Children and adolescents from 

2 years of age weighing 10 kg 

to less than 30 kg 

20 mg every other week  Not applicable 

 

Enthesitis-related arthritis 

Age or body weight How much and how often to 

take? 

Notes 

Children, adolescents and 

adults from 6 years of age 

weighing 30 kg or more 

40 mg every other week  Not applicable 

Children and adolescents from 

6 years of age weighing 15 kg 

to less than 30 kg 

20 mg every other week Not applicable 

 

Plaque psoriasis 

Age or body weight How much and how often to 

take? 

Notes 

Adults  

 

Initial dose of 80 mg (as two 

40 mg injections in one day), 

followed by 40 mg given every 

If this dose does not work well 

enough, your doctor may 

increase the dosage to 40 mg 

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other week starting one week 

after the initial dose. 

You should continue to inject 

Kromeya for as long as your 

doctor has told you. 

every week or 80 mg every 

other week. 

 

Children and adolescents from 

4 to 17  years of age weighing 

30 kg or more 

Initial dose of 40 mg, followed 

by 40 mg one week later. 

 

Thereafter, the usual dose is 40 

mg every other week. 

Not applicable 

Children and adolescents from 

4 to 17 years of age weighing 

15 kg to less than 30 kg 

Initial dose of 20 mg, followed 

by 20 mg one week later. 

 

Thereafter, the usual dose is 20 

mg every other week. 

Not applicable 

 

Crohn’s disease 

Age or body weight How much and how often to 

take? 

Notes 

Children, adolescents and 

adults from 6 years of age 

weighing 40 kg or more 

Initial dose of 80 mg (as two 40 

mg injections in one day), 

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 

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 dose frequency to 

40 mg every week or 80 mg 

every other week. 

 

Children and adolescents from 

6 to 17  years of age weighing 

less than 40 kg 

Initial dose of 40 mg, followed 

by 20 mg two weeks later.  

 

If a faster response is required, 

your doctor may prescribe a 

first dose of 80 mg (two 40 mg 

injections in one 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 doctor may 

increase the dose frequency to 

20 mg every week. 

 

 

Ulcerative colitis 

Age or body weight How much and how often to 

take? 

Notes 

Adults 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), 

If this dose does not work well 

enough, your doctor may 

increase the dosage to 40 mg 

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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. 

every week or 80 mg every 

other week. 

 

Non-infectious uveitis 

Age or body weight How much and how often to 

take? 

Notes 

Adults Initial dose of 80 mg (as two 

40 mg injections), followed by 

40 mg every other week 

starting one week after the 

initial dose. 

You should continue to inject 

Kromeya for as long as your 

doctor has told you. 

Corticosteroids or other 

medicines that influence the 

immune system may be 

continued while using 

Kromeya. Kromeya can also be 

given alone. 

Children and adolescents from 

2 years of age weighing less 

than 30 kg 

 

20 mg every other week Your doctor may prescribe an 

initial dose of 40 mg which 

may be administered one week 

prior to the start of the usual 

dose. 

Kromeya is recommended for 

use in combination with 

methotrexate. 

Children and adolescents from 

2 years of age weighing at least 

30 kg 

 

40 mg every other week  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. 

Kromeya is recommended for 

use in combination with 

methotrexate. 

 

Method and route of administration 

 

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

 

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

 

If you use more Kromeya than you should 

 

If you accidentally inject Kromeya more frequently than you should, call your doctor or pharmacist 

and explain that you have taken more than required. Always take the outer carton of the medicine with 

you, even if it is empty. 

 

If you forget to use Kromeya 

 

If you forget to give yourself an injection, you should inject the next dose of Kromeya 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 Kromeya 

 

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The decision to stop using Kromeya 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 Kromeya injection. 

 
Seek medical attention urgently, if you notice any of the following signs of allergic reaction or heart 
failure: 

• severe rash, hives; 

• 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 and symptoms of infection such as fever, feeling sick, wounds, dental problems, burning on 
urination, feeling weak or tired or coughing; 

• symptoms of nerve problems such as tingling, numbness, double vision or arm or leg weakness; 
• signs of skin cancer such as a bump or open sore that doesn't heal; 

• signs and symptoms suggestive of blood disorders such as persistent fever, bruising, 
bleeding, paleness. 

 

The following side effects 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; 

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• 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 eye lid and eye swelling; 

• vertigo (sensation of 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)  

• unusual 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 that affects 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; 

• double vision; 

• hearing loss, buzzing; 

• sensation of heart beating irregularly such as skipped beats; 

• heart problems that can cause shortness of breath or ankle swelling; 

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• heart attack; 

• a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel; 

• lung diseases causing shortness of breath (including inflammation); 

• pulmonary embolism (blockage in an artery of the lung); 

• pleural effusion (abnormal collection of fluid in the pleural space); 

• inflammation of the pancreas which causes severe pain in the abdomen and back; 

• difficulty in swallowing; 

• facial oedema (swelling); 

• gallbladder inflammation, gallbladder stones; 

• fatty liver (build-up of fat in liver cells); 

• night sweats; 

• scar; 

• abnormal muscle breakdown; 

• systemic lupus erythematosus (an immune disorder 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 (hole in the wall of the gut); 

• hepatitis (liver inflammation); 

• reactivation of hepatitis B infection; 

• 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 (life-threatening reaction with flu-like symptoms and blistering 
rash); 

• facial oedema (swelling) 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; 

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• increased lipids in the blood; 

• raised liver enzymes. 
 

Common (may affect up to 1 in 10 people)  

• high blood measurements for white blood cells; 

• low blood measurements for platelets; 

• increased uric acid in the blood; 

• abnormal blood measurements for sodium; 

• low blood measurements for calcium; 

• low blood measurements for phosphate; 

• high blood sugar; 

• high blood measurements for lactate dehydrogenase; 

• autoantibodies present in the blood; 

• low blood potassium. 
 

Uncommon (may affect up to 1 in 100 people)  

• raised 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 Kromeya 

 

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/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 Kromeya pre-filled syringe may be 

stored at room temperature (up to 25°C) for a maximum period of 14 days – be sure to protect it from 

light. 

Once removed from the refrigerator for room temperature storage, your pre-filled syringe must be 

used within 14 days or discarded, even if it is later 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. 

 

 

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6. Contents of the pack and other information 

 

What Kromeya contains  

 

- The active substance is adalimumab. Each pre-filled syringe contains 40 mg of adalimumab in 
0.8 ml of solution. 

- The other ingredients are sodium dihydrogen phosphate dihydrate, disodium phosphate 
dihydrate, mannitol, sodium chloride, citric acid monohydrate, sodium citrate, polysorbate 80, 

sodium hydroxide and water for injections.  

 

What Kromeya looks like and contents of the pack 

 

Kromeya 40 mg solution for injection (injection) in pre-filled syringe is supplied as a sterile 0.8 mL 

clear, colourless solution of 40 mg adalimumab. 

 

The Kromeya pre-filled syringe is supplied in a glass syringe with needleguard and finger flanges. 

Each pack contains 2 or 6 pre-filled syringes, and 2 or 6 alcohol pads. 

 

Kromeya is available as a vial, a pre-filled syringe and as a pre-filled pen. 

 

Marketing Authorisation Holder 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1 

61352 Bad Homburg v.d.Höhe 

Germany 

 

Manufacturer 

 

Fresenius Kabi Austria GmbH 

Hafnerstraße 36,  

8055 Graz 

Austria 

 

Merck Serono S.p.A. 

Via delle Magnolie 15 

I-70026 Modugno (Bari) 

Italy 

 

This leaflet was last revised in 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 

 

7. Instructions for use 

Be sure that you read, understand, and follow these Instructions for Use before injecting Kromeya. 

Your healthcare provider should show you how to prepare and inject Kromeya properly using the 

pre-filled syringe before you use it for the first time. Talk to your healthcare provider if you have any 

questions. 

  

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Note : images for illustration purposes only 

 

Read carefully these entire instructions before using your Kromeya pre-filled syringe. 

Important Information 

• Only use Kromeya pre-filled syringe if your healthcare professional has trained you on how to 

use the pre-filled syringe correctly.  

• Kromeya is a pre-filled syringe for single use only. 

• Kromeya pre-filled syringe has a clear needle guard that covers the needle after the injection is 

complete. 

• Children under 12 years of age are not allowed to inject themselves and injection must be done by 

a trained adult. 

• Keep Kromeya pre-filled syringe and the sharps disposal container out of reach and sight of 

children. 

• Do not shake. Shaking can damage the pre-filled syringe and the medicine. 

• Do not use the Kromeya pre-filled syringe if liquid appears cloudy or discolored, or has -particles 

or flakes in it. The liquid should be clear and colorless. 

• Do not try to activate the clear needle guard before injecting. 

• Do not insert your fingers into the opening of the clear needle guard. 

• Do not use an Kromeya pre-filled syringe that has been frozen or left in direct sunlight. 

• Do not use the Kromeya pre-filled syringe if it has been dropped or crushed, as the pre-filled 

syringe may be broken even if you cannot see the break.  

Use a new pre-filled syringe instead. 

Storage Information 

• Store the pre-filled syringe in its original box to protect it from light. 

• Store the pre-filled syringe in a refrigerator between 2°C to 8°C. 

• If needed, for example when traveling, a single pre-filled syringe can be stored at room 

temperature for up to 14 days. 

 

 

Instruction For Use 

Kromeya
® 

Single use pre-filled 
syringe (adalimumab) for 
subcutaneous injection 
40mg 

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Get Familiar with your Kromeya Pre-Filled Syringe 

Before Use  

Clear Needle Guard Plunger 

Front view  

 Needle cap  Liquid-filled syringe 
Barrel (inside) 

 

Back view 

 

 

After Use  
Clear Needle Guard 

Plunger 

 
 

 Needle covered Needle Guard Spring 

 

 

Each box of Kromeya pre-filled syringe comes with two or six syringes. 

1.1 Prepare a clean flat surface, such as a table or countertop, in a well-lit area. 

1.2 You will also need (Figure A):  

• an alcohol pad (included in the box) 

• a cotton ball or gauze, and 

• a sharps disposal container. 

Step 1       Prepare for your Injection 

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Open your sharps disposal container so it is ready to use. 

 

Figure A 

 

1.3 Remove the box from the refrigerator (Figure B). 

1.4 Check the expiration date on the side of the box (Figure B). 

Warning: Do not use if expiration date has passed. 

 

Figure B 

 

1.5 Caution: Do not pick up the syringe by the plunger or the needle cap. Doing so could damage the 

syringe or activate the clear needle guard. 

Take a syringe out of the original box: 

• place two fingers on middle of the clear needle guard  

• pull the syringe straight up and out of the packaging (Figure C). 

Put it on a clean flat surface.  

EXP : MM/YYYY 

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Figure C 

 

1.6 Place the remaining syringe(s) in its (their) original box back in the refrigerator (Figure D).  

Refer to Storage information for -how to store your unused syringe(s). 

 

Figure D 

 

1.7 Leave the syringe at room temperature for 30 minutes to allow the medicine to warm up.  

Injecting cold medicine can be painful (Figure E).  

 

 

Figure E 

 

Warning: Do not warm the syringe any other way, such as in a microwave, hot water, or direct 

sunlight. 

Warning: Do not remove the needle cap while allowing syringe to reach room temperature. 

 

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2.1 Wash your hands well with soap and water (Figure F) and dry them. 

Warning: Gloves will not replacethe need for washing hands. 

 

Figure F 

 

 

3.1 Check the syringe to make sure that: 

• The syringe, the clear needle guard, and the needle cap are not cracked or damaged (Figure G). 

 

Figure G 

 

• The needle cap is securely attached (Figure H).  

 

Figure H 

 

• The needle guard spring is not extended (Figure I).  

Step 2       Wash your Hands 

Step 3       Check the Syringe 

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Figure I 

Warning: Do not use the syringe if it shows any sign of damage.  

If so, throw away the syringe in a sharps disposal container and contact your healthcare 

professional or pharmacist.  

3.2 Check the liquid to make sure that:  

• The liquid is clear, colorless, and free of particles (Figure J). 

Warning: Do not use the syringe if liquid contains particles, or is cloudy or if it is colored or has 

flakes in it.  

 

Figure J 

 

3.3 Check the label to make sure that: 

• The name on the syringe says Kromeya (Figure K). 

• The expiration date on syringe has not passed (Figure K). 

 

 

Figure K 

 Warning: Do not use the syringe if: 

• The name on the syringe is not Kromeya. 

• The expiration date on the syringe has passed. 

EXP: MM/YYYY 

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 If so, throw away the syringe in a sharps disposal container and contact your healthcare 

professional or pharmacist. 

 

 

4.1 Choose an injection site (Figure L) on:   

• Top of the thighs. 

• Abdomen (inject at least 5 centimeters away from the belly button).  

 

Figure L 

 

4.2 Choose a different site (at least 2.5 centimeters away from the previous injection site) each time to 

reduce redness, irritation or other skin problems. 

Warning: Do not inject into an area that is sore (tender), bruised, red, hard, scarred or where you 

have stretch marks. 

Warning: If you have psoriasis, do not inject into any lesions or red, thick, raised or scaly 

patches.  

 

 

5.1 Wipe the skin of your injection site with an alcohol pad to clean it. (Figure M)  

Warning: Do not blow on or touch the injection site after cleaning.  

 

Figure M 

 

Step 4       Choose the Injection Site 

Step 5       Clean the Injection Site 

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6.1 Remove the needle cap 

• Always hold the syringe by the clear needle guard.  

• Hold the syringe upward and pull the needle cap straight off (Figure N). 

 

Figure N 

 

You may see drops of liquid at the needle tip. 

• Throw away the needle cap. 

Warning: Do not touch the needle. 

6.2 Pinch the skin 

• Hold the syringe like a pencil. 

• With your other hand gently pinch skin (without squeezing) to avoid injecting into a muscle 

(Figure O). 

 

Figure O 

 

6.3 Insert the needle  

• With a quick, short motion, push the needle all the way into the skin at an angle between 45° 

and 90° (Figure P).  

Step 6       Give your Injection 

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Figure P 

 

• After the needle is inserted, release the pinched skin.  

 

6.4 Inject 

• Use your thumb to gently push plunger all the way down (Figure Q).  

 

Figure Q 
 

• Give plunger a final push to ensure the full dose has been injected (Figure R).  

• Hold the syringe firmly without moving it, at the same angle (Figure R). 

 

Figure R 
 

Do not remove the needle from the skin when the plunger reaches the end. 

 

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 Slowly release your thumb up.  

This will allow the needle to move up into the clear needle guard and cover the entire needle 

(Figure S).  

 

Figure S 
 

Warning: Call your healthcare professional or pharmacist if: 

• You did not inject the full dose or 

• The clear needle guard does not activate after injecting. 

Warning: Do not reuse a syringe in case of partial injection. 

Do not try to recap needle as it could lead to needle stick injury. 

6.5 If there is blood or liquid on the injection site, gently press a cotton ball or gauze on the skin (Figure 

T).  

 

Figure T 
 

 

7.1 Throw away your used syringe in a sharps disposal container right away after use (Figure U).  

Step 7       Throw away your Syringe M
ed

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pro
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no

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au

tho
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ed



 

134 

 

 

 

 

Figure U 
 

Warning: Keep your sharps disposal container out of the reach of children. 

Warning: Do not throw away the syringe in your household trash. 

If you do not have a sharps disposal container, you may use a household container that is:   

• Made of a heavy-duty plastic;  

• Can be closed with a tight-fitting, puncture-resistant lid; that will keep sharps from coming out, 

• Upright and stable during use, 

• Leak-resistant and  

• Properly labeled to warn of hazardous waste inside the container. 

7.2 When your sharps disposal container is almost full, you will need to follow your local guidelines 

for the right way to dispose of your sharps disposal container.   

 Do not recycle your used sharps disposal container. 

 

 

8.1 To help you remember when and where to do your next injection, you should keep a record of the 

dates and injection sites used for your injections (Figure V). 

 

Step 8       Record your Injection Me
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135 

 

 

 

 

Figure V 

 

  

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Package leaflet: Information for the patient 

 

Kromeya 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 Kromeya and during treatment 

with Kromeya. Keep this patient reminder card with you during your treatment and for 4 months 

after your (or your child’s) last injection of Kromeya. 

- 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 Kromeya is and what it is used for 

2. What you need to know before you use Kromeya 

3. How to use Kromeya 

4. Possible side effects 

5. How to store Kromeya 

6. Contents of the pack and other information 

7. Instructions for use 

 

 

1. What Kromeya is and what it is used for 

 

Kromeya contains the active substance adalimumab, a medicine that acts on your body’s immune 

(defence) system. 

 

Kromeya is intended for the treatment of the following inflammatory diseases: 

• rheumatoid arthritis, 

• polyarticular juvenile idiopathic arthritis, 

• enthesitis-related arthritis, 

• ankylosing spondylitis, 

• axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, 

• psoriatic arthritis, 

• psoriasis, 

• Crohn’s disease, 

• ulcerative colitis and 

• non-infectious uveitis 
 

The active ingredient in Kromeya, adalimumab, is a monoclonal antibody. Monoclonal antibodies are 

proteins that attach to a specific target in the body.   

  

The target of adalimumab is another protein called tumour necrosis factor (TNFα), which is present at 

increased levels in the inflammatory diseases listed above. By attaching to TNFα, Kromeya blocks its 

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action and reduces the inflammation in these diseases. 

 

Rheumatoid arthritis 

 

Rheumatoid arthritis is an inflammatory disease of the joints. 

 

Kromeya 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 Kromeya to treat your rheumatoid 

arthritis. 

 

Kromeya can also be used to treat severe, active and progressive rheumatoid arthritis without previous 

methotrexate treatment. 

 

Kromeya can slow down the damage to the cartilage and bone of the joints caused by the disease and 

improve physical function. 

 

Usually, Kromeya is used with methotrexate. If your doctor considers that methotrexate is 

inappropriate, Kromeya 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. 

 

Kromeya 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 Kromeya 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. 

 

Kromeya is used in adults to treat these conditions. 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 Kromeya to reduce the signs 

and symptoms of your disease. 

 

Psoriatic arthritis 

 

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

 

Kromeya is used to treat psoriatic arthritis in adults. Kromeya can slow down the damage to the 

cartilage and bone of the joints caused by the disease and improve physical function. 

 

Plaque psoriasis in adults and children 

 

Plaque psoriasis is an inflammatory skin condition that causes red, flaky, crusty patches of skin 

covered with silvery scales. Plaque psoriasis can also affect the nails, causing them to crumble, 

become thickened and lift away from the nail bed which can be painful. Psoriasis is believed to be 

caused by a problem with the body’s immune system that leads to an increased production of skin 

cells. 

 

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Kromeya is used to treat moderate to severe plaque psoriasis in adults. Kromeya is also used to treat 

severe plaque psoriasis in children and adolescents adolescents aged 4 to 17 years for whom medicines 

applied to the skin and treatment with UV light have either not worked very well or are not suitable. 

 

Crohn’s disease in adults and children 

 

Crohn’s disease is an inflammatory disease of the gut. 

 

Kromeya 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 you do not respond well enough to these 

medicines, you will be given Kromeya to reduce the signs and symptoms of your Crohn’s disease. 

 

Ulcerative colitis 

 

Ulcerative colitis is an inflammatory disease of the bowel. 

 

Kromeya 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 Kromeya 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. The inflammation 

leads 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). Kromeya works by reducing this inflammation. 

 

Kromeya 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. 

 

 

2. What you need to know before you use Kromeya  

 

Do not use Kromeya 

 

- 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, sepsis (blood poisoning) or other 

opportunistic infections (unusual infections associated with a weakened immune system). It is 

important that you tell your doctor if you have symptoms of infections, e.g. fever, wounds, 

feeling tired, dental problems (see “Warnings and precautions”). 

 

- 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 Kromeya 

 

Allergic reaction 

 

• If you have allergic reactions with symptoms such as chest tightness, wheezing, dizziness, 
swelling or rash do not inject more Kromeya and contact your doctor immediately since, in rare 

cases, these reactions can be life threatening. 

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Infection 

 

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

 

• You might get infections more easily while you are receiving Kromeya treatment. This risk may 
increase if your lung function is reduced. These infections may be more serious and include 

tuberculosis, infections caused by viruses, fungi, parasites or bacteria, or other unusual 

infectious organisms 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 temporarily stopping Kromeya. 

 

Tuberculosis (TB) 

 

• As cases of tuberculosis have been reported in patients treated with adalimumab, your doctor 
will check you for signs and symptoms of tuberculosis before starting Kromeya. 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 had 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 have lived or travelled in regions where fungal infections such as 
histoplasmosis, coccidioidomycosis or blastomycosis are common. 

 

• 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. Adalimumab 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 Kromeya. You 
and your doctor should pay special attention to signs of infection while you are being treated 

with Kromeya. 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 procedures 

 

• If you are about to have surgery or dental procedures tell your doctor that you are taking 
Kromeya. Your doctor may recommend temporarily stopping Kromeya. 

 

Demyelinating disease 

 

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• 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 Kromeya. 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 living but weakened forms of disease-causing bacteria or viruses and 
should not be given during treatment with Kromeya in case they cause infections. Check with 

your doctor before you receive any vaccines. It is recommended that, if possible, children be 

given all the scheduled vaccinations for their age before they start treatment with Kromeya. If 

you receive Kromeya 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 

Kromeya use during your pregnancy so they can decide when your baby should receive any 

vaccine. 

 

Heart failure 

 

• It is important to tell your doctor if you have had or have a serious heart condition. If you have 
mild heart failure and you are being treated with Kromeya, your heart failure status must be 

closely monitored by your doctor. 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.  

 

Fever, bruising, bleeding or looking pale 

 

• In some patients the body may fail to produce enough of the blood cells that fight off infections or 
help you to stop bleeding. If you develop a fever that does not go away, or you bruise or bleed 

very easily or look very pale, call your doctor right away. Your doctor may decide to stop 

treatment. 

 

Cancer 

 

• There have been very rare cases of certain kinds of cancer in children and adults taking 
adalimumab or other TNFα blockers. People with more serious rheumatoid arthritis who have 

had the disease for a long time may have a higher than average risk of getting lymphoma  and 

leukaemia (cancers that affect blood cells and bone marrow). If you take Kromeya the risk of 

getting lymphoma, leukaemia, or other cancers may increase. On rare occasions, a specific and 

severe type of lymphoma, has been observed in patients taking adalimumab. Some of those 

patients were also treated with the medicines azathioprine or mercaptopurine. Tell your doctor if 

you are taking azathioprine or mercaptopurine with Kromeya. 

  

• In addition cases of non-melanoma skin cancer have been observed in patients taking 
adalimumab. If new areas of damaged skin appear during or after treatment 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 are a heavy smoker, you should discuss with your doctor 

whether treatment with a TNFα blocker is appropriate for you. 

 

• On rare occasions, treatment with Kromeya 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 

 

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• Vaccinations: if possible children should be up to date with all vaccinations before using 
Kromeya. 

• Do not give Kromeya to children with polyarticular juvenile idiopathic arthritis below the age of 
2 years. 

• Do not use the 40 mg pre-filled syringe or 40 mg pre-filled pen if doses other than 40 mg are 
recommended. 

 

Other medicines and Kromeya 

 

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

medicines. 

 

Kromeya 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 Kromeya with medicines containing the active substances anakinra or abatacept 

due to increased risk of serious infection. The combination of adalimumab as well as other 

TNF-antagonists and anakinra or abatacept is not recommended based upon the possible increased risk 

for infections, including serious infections and other potential pharmacological interactions. If you 

have questions, please ask your doctor. 

 

Pregnancy and breast-feeding 

 

If you think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for 

advice before taking this medicine. 

 

You are advised to avoid becoming pregnant and must use adequate contraception while using 

Kromeya and for at least 5 months after the last Kromeya injection. If you become pregnant, you 

should see your doctor. 

 

Kromeya 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. 

 

Kromeya can be used during breast-feeding. 

 

If you receive Kromeya 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 Kromeya use during your pregnancy before the baby receives any vaccine (for more information 

see section on vaccination). 

 

Driving and using machines 

 

Kromeya 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 Kromeya. 

 

Kromeya contains sodium 

 

This medicine contains less than 1 mmol of sodium (23 mg) per 0.8 ml dose, that is to say essentially 

‘sodium-free’. 

 

 

3. How to use Kromeya 

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Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 

or pharmacist if you are not sure. 

 

Kromeya is injected under the skin (subcutaneous use). Patients requiring a dose less than 40 mg 

should use the 40 mg vial presentation of Kromeya. 

 

The recommended doses for Kromeya in each of the approved uses are shown in the following table. 

 

Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis 

without radiographic evidence of ankylosing spondylitis 

Age or body weight How much and how often to 

take? 

Notes 

Adults  40 mg every other week In rheumatoid arthritis, 

methotrexate is continued while 

using Kromeya. If your doctor 

decides that methotrexate is 

inappropriate, Kromeya can be 

given alone. 

 

If you have rheumatoid arthritis 

and you do not receive 

methotrexate with your 

Kromeya therapy, your doctor 

may decide to give Kromeya 40 

mg every week or 80 mg every 

other week.  

 

Polyarticular juvenile idiopathic arthritis 

Age or body weight How much and how often to 

take? 

Notes 

Children, adolescents and 

adults from 2 years of age 

weighing 30 kg or more 

40 mg every other week Not applicable 

Children and adolescents from 

2 years of age weighing 10 kg 

to less than 30 kg 

20 mg every other week  Not applicable 

 

Enthesitis-related arthritis 

Age or body weight How much and how often to 

take? 

Notes 

Children, adolescents and 

adults from 6 years of age 

weighing 30 kg or more 

40 mg every other week  Not applicable 

Children and adolescents from 

6 years of age weighing 15 kg 

to less than 30 kg 

20 mg every other week Not applicable 

 

Plaque psoriasis 

Age or body weight How much and how often to 

take? 

Notes 

Adults  

 

Initial dose of 80 mg (as two 

40 mg injections in one day), 

followed by 40 mg given every 

If this dose does not work well 

enough, your doctor may 

increase the dosage to 40 mg 

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other week starting one week 

after the initial dose. 

You should continue to inject 

Kromeya for as long as your 

doctor has told you. 

every week or 80 mg every 

other week. 

 

Children and adolescents from 

4 to 17  years of age weighing 

30 kg or more 

Initial dose of 40 mg, followed 

by 40 mg one week later. 

 

Thereafter, the usual dose is 40 

mg every other week. 

Not applicable 

Children and adolescents from 

4 to 17 years of age weighing 

15 kg to less than 30 kg 

Initial dose of 20 mg, followed 

by 20 mg one week later. 

 

Thereafter, the usual dose is 20 

mg every other week. 

Not applicable 

 

Crohn’s disease 

Age or body weight How much and how often to 

take? 

Notes 

Children, adolescents and 

adults from 6 years of age 

weighing 40 kg or more 

Initial dose of 80 mg (as two 40 

mg injections in one day), 

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 

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 dose frequency to 

40 mg every week or 80 mg 

every other week. 

 

Children and adolescents from 

6 to 17  years of age weighing 

less than 40 kg 

Initial dose of 40 mg, followed 

by 20 mg two weeks later.  

 

If a faster response is required, 

your doctor may prescribe a 

first dose of 80 mg (two 40 mg 

injections in one 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 doctor may 

increase the dose frequency to 

20 mg every week. 

 

 

Ulcerative colitis 

Age or body weight How much and how often to 

take? 

Notes 

Adults 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), 

If this dose does not work well 

enough, your doctor may 

increase the dosage to 40 mg 

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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. 

every week or 80 mg every 

other week. 

 

Non-infectious uveitis 

Age or body weight How much and how often to 

take? 

Notes 

Adults Initial dose of 80 mg (as two 

40 mg injections), followed by 

40 mg every other week 

starting one week after the 

initial dose. 

You should continue to inject 

Kromeya for as long as your 

doctor has told you. 

Corticosteroids or other 

medicines that influence the 

immune system may be 

continued while using 

Kromeya. Kromeya can also be 

given alone. 

Children and adolescents from 

2 years of age weighing less 

than 30 kg 

 

20 mg every other week Your doctor may prescribe an 

initial dose of 40 mg which 

may be administered one week 

prior to the start of the usual 

dose. 

Kromeya is recommended for 

use in combination with 

methotrexate. 

Children and adolescents from 

2 years of age weighing at least 

30 kg 

 

40 mg every other week  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. 

Kromeya is recommended for 

use in combination with 

methotrexate. 

 

Method and route of administration 

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

 

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

 

If you use more Kromeya than you should 

If you accidentally inject Kromeya more frequently than you should, call your doctor or pharmacist 

and explain that you have taken more than required. Always take the outer carton of the medicine with 

you, even if it is empty. 

 

If you forget to use Kromeya 

If you forget to give yourself an injection, you should inject the next dose of Kromeya 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 Kromeya 

The decision to stop using Kromeya 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. 

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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 Kromeya injection. 

 
Seek medical attention urgently, if you notice any of the following signs of allergic reaction or heart 
failure: 

• severe rash, hives; 

• 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 and symptoms of infection such as fever, feeling sick, wounds, dental problems, burning on 
urination, feeling weak or tired or coughing; 

• symptoms of nerve problems such as tingling, numbness, double vision or arm or leg weakness; 
• signs of skin cancer such as a bump or open sore that doesn't heal; 

• signs and symptoms suggestive of blood disorders such as persistent fever, bruising, 
bleeding, paleness. 

 

The following side effects 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); 

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• vision disturbances; 

• eye inflammation; 

• inflammation of the eye lid and eye swelling; 

• vertigo (sensation of 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)  

• unusual 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 that affects 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; 

• double vision; 

• hearing loss, buzzing; 

• sensation of heart beating irregularly such as skipped beats; 

• heart problems that can cause shortness of breath or ankle swelling; 

• heart attack; 

• a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel; 

• lung diseases causing shortness of breath (including inflammation); 

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• 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 (swelling); 

• gallbladder inflammation, gallbladder stones; 

• fatty liver (build-up of fat in liver cells); 

• night sweats; 

• scar; 

• abnormal muscle breakdown; 

• systemic lupus erythematosus (an immune disorder 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 (hole in the wall of the gut); 

• hepatitis (liver inflammation); 

• reactivation of hepatitis B infection; 

• 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 (life-threatening reaction with flu-like symptoms and blistering 
rash); 

• facial oedema (swelling) 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. 
 

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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 potassium. 
 

Uncommon (may affect up to 1 in 100 people)  

• raised 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 Kromeya 

 

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/ 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 Kromeya pre-filled pen may be stored at 

room temperature (up to 25°C) for a maximum period of 14 days – be sure to protect it from light. 

Once removed from the refrigerator for room temperature storage, your pre-filled pen must be used 

within 14 days or discarded, even if it is later returned to the refrigerator. 

 

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

should be discarded. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Kromeya contains  

 

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- The active substance is adalimumab. Each pre-filled pen contains 40 mg of adalimumab in 0.8 
ml of solution. 

- The other ingredients are sodium dihydrogen phosphate dihydrate, disodium phosphate 
dihydrate, mannitol, sodium chloride, citric acid monohydrate, sodium citrate, polysorbate 80, 

sodium hydroxide and water for injections.  

 

What Kromeya looks like and contents of the pack 

 

Kromeya 40 mg solution for injection (injection) in pre-filled pen is supplied as a sterile 0.8 mL clear, 

colourless solution of 40 mg adalimumab. 

 

The Kromeya pre-filled pen contains a pre-filled syringe with Kromeya. Each pack contains 2 or 6 

pre-filled pens with 2 or 6 alcohol pads. 

 

Kromeya is available as a vial, a pre-filled syringe and a pre-filled pen. 

 

Marketing Authorisation Holder 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1 

61352 Bad Homburg v.d.Höhe 

Germany 

 

Manufacturer 

 

Fresenius Kabi Austria GmbH 

Hafnerstraße 36,  

8055 Graz 

Austria 

 

Merck Serono S.p.A. 

Via delle Magnolie 15 

I-70026 Modugno (Bari) 

Italy. 

 

This leaflet was last revised in  

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 

 

7. Instructions for use 

Be sure that you read, understand, and follow these Instructions for Use before injecting Kromeya. 

Your healthcare provider should show you how to prepare and inject Kromeya properly using the 

pre-filled pen before you use it for the first time. Talk to your healthcare provider if you have any 

questions. 

  

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Note : images for illustration purposes only 

 

Read carefully these entire instructions before using your Kromeya pre-filled pen. 

Important Information 

• Only use Kromeya pre-filled pen if your healthcare professional has trained you how to use it 
correctly. 

• The Kromeya pre-filled pen comes as a ready to use single-use pre-filled pen to give a full dose 

of adalimumab. 

• Always inject using the technique your healthcare professional taught you. 

• Children under 12 years of age are not allowed to inject themselves and injection must be done by 

a trained adult. 

• Keep the Kromeya pre-filled pen out of the reach of children. 

• Do not insert your fingers into the opening of the safety guard.  

• Do not use an Kromeya pre-filled pen that has been frozen or left in direct sunlight. 

• Talk to your healthcare professional if you have any questions or concerns.  

Storage Information  

• Store the pre-filled pen in its original box to protect it from light. 

• Store the pre-filled pen in a refrigerator between 2°C to 8°C. 

• If needed, for example when traveling, a single pre-filled pen can be stored at room temperature 

for up to 14 days. 

 

 

 

Instruction For Use 

Kromeya
® 

Single use pre-filled pen 
(adalimumab) for 
subcutaneous injection 
40mg 

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Get Familiar with your Kromeya Pre-filled pen 

Before Use Transparent syringe 
housing 

Label area 
(Kromeya, dose, expiration date)  

 

Injection  
button 
 

Needle cap              Syringe plunger Injector body 

 

 

After Use 

 

 
 

Needle cap 

Needle 

 

Safety guard 
extended 

Syringe plunger final position 

 

 

Each box of Kromeya pre-filled pen comes with two or six pre-filled pens. 

1.1 Prepare a clean flat surface, such as a table or countertop, in a well-lit area. 

1.2 You will also need (Figure A):  

• an alcohol pad (included in the box) 

• a cotton ball or gauze, and 

• a sharps disposal container. 

 

Step 1       Prepare for your injection 

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Figure A 

 

1.3 Remove the box from the refrigerator (Figure B). 

 

Figure B 

 

1.4 Check the expiration date on the side of the box (Figure C). 

 

Figure C 

 

Warning: Do not use if expiration date has passed. 

 

1.5 Take a pre-filled pen out of the original box: 

• place two fingers on the label area   

• pull the pre-filled pen straight up and out of the packaging (Figure D). 

 

Figure D 

EXP: MM/YYYY 

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Put it on a clean flat surface. 

1.6 Place the remaining pre-filled pen(s) in its (their) original box back in the refrigerator (Figure E).  

 

 

Figure E 

 

Refer to Storage Information for how to store your unused pre-filled pen(s). 

1.7 Leave the pre-filled pen at room temperature for at least 30 minutes to allow the medicine to warm 

up (Figure F).  

 

Figure F 

 

Injecting cold medicine may be painful. 

Warning: Do not warm the pre-filled pen any other way, such as in a microwave, hot water, or 

direct sunlight. 

Warning: Do not remove the needle cap until you are ready to inject. 

 

2.1 Wash your hands with soap and water (Figure G) and dry them well. 

Warning: Gloves do not replace the need for washing hands. 

 

Figure G 

 

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3.1 Check the transparent syringe housing to make sure that: 

• The liquid is clear, colorless, and free of particles (Figure H).  

• The glass syringe is not cracked or broken (Figure H). 

 

 

Transparent syringe housing 

Figure H 

 

Warning: Do not use the pre-filled pen if the liquid contains particles, or is cloudy or if it is 

colored, or has flakes in it or shows any sign of damage.  

If so, throw it away in a sharps disposal container and contact your healthcare professional or 

pharmacist.  

3.2 Check the label to make sure that: 

• The name on the pre-filled pen says Kromeya (Figure I). 

• The expiration date on the pre-filled pen has not passed (Figure I). 

 

 

Figure I 

 

Warning: Do not use the pre-filled pen if the name on the label is not Kromeya and/or the 

expiration date on the label has passed. 

Step 3       Check the Pre-filled Pen 

EXP: MM/YYYY 

 

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If so, throw away the pre-filled pen in a sharps disposal container and contact your healthcare 

professional or pharmacist. 

 

 

4.1 Choose an injection site (Figure J) on:   

• Top of the thighs.  

• Abdomen (inject at least 5 centimeters away from the belly button). 

 

 

Figure J 

4.2 Choose a different site (at least 2.5 centimeters away from the previous injection site) each time to 

reduce redness, irritation or other skin problems.  

Warning: Do not inject into an area that is sore (tender), bruised, red, hard, scarred or where you 

have stretch marks. 

Warning: If you have psoriasis, do not inject into any lesions or red, thick, raised or scaly 

patches. 

 

 

5.1 Wipe the skin of your injection site with an alcohol pad to clean it (Figure K). 

Warning: Do not blow on or touch the injection site after cleaning.  

 

 

Figure K 

 

Step 4       Choose the injection Site 

Step 5       Clean the Injection Site 

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6.1 Remove the needle cap 

• Hold the pre-filled pen upwards and pull the needle cap straight off (Figure L). 

 

Figure L 

 

You may see drops of liquid at the needle tip. 

• Throw away the needle cap. 

Warning: Do not twist the cap. 

Warning: Do not recap the pre-filled pen. 

6.2 Position the pre-filled pen 

• Hold the -pre-filled pen so that you can see the transparent syringe housing. 

• Place your thumb above (not touching) the yellow injection button (Figure M). 

 

Figure M 

 

• Place the pre-filled pen against your skin at a 90° angle (Figure N). 

 

Step 6       Give your Injection 

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Figure N 

Before Injection 

 

• Push and hold the pre-filled pen firmly against your skin until the safety guard is fully 

depressed. This will unlock the injection button (Figure O). 

 
 
 
 

 

Figure O 

Before Injection 

 

6.3 Administer the Injection 

• Push the injection button (Figure P).  

You will hear a loud click, which means the injection has started. 

• Continue to HOLD the pre-filled pen firmly. 

• WATCH the syringe plunger to make sure it moves all the way down to the bottom (Figure P). 

 

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Figure P 

After Injection 

 

Warning: Do not lift the pre-filled pen from the skin until the plunger has moved all the way 

down and all the liquid has been injected.  

• When the syringe plunger has moved to the bottom and has stopped moving, continue holding it 

for 5 seconds. 

• Lift the pre-filled pen from your skin (Figure Q).  

The safety guard will slide down and lock into place to protect you from the needle (Figure Q). 

 

Figure Q 

Warning: Call your healthcare professional or pharmacist if you have any problem. 

6.4 If there is blood or liquid on the skin, treat the injection site by gently pressing a cotton ball or 

gauze on the site (Figure R). 

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Figure R 

 

 

 

7.1 Throw away your used pre-filled pen in a sharps disposal container right away after use (Figure S). 

 

Figure S 

Warning: Keep your sharps disposal container out of the reach of children.  

Warning: Do not throw away the pre-filled pen in your household trash. 

If you do not have a sharps disposal container, you may use a household container that is:   

• Made of a heavy-duty plastic;  

• Can be closed with a tight-fitting, puncture-resistant lid; that will keep sharps from coming out, 

• Upright and stable during use, 

• Leak-resistant and  

• Properly labeled to warn of hazardous waste inside the container. 

 

7.2 When your sharps disposal container is almost full, you will need to follow your local guidelines 

for the right way to dispose of your sharps disposal container.  

Step 7       Throw away your Pre-filled pen 

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Do not recycle your used sharps disposal container. 

 

 

8.1 To help you remember when and where to do your next injection, you should keep a record of the dates 

and injection sites used for your injections (Figure T). 

  

 

Figure T 

 

  

Step 8       Record your Injection 

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Package leaflet: Information for the patient 

 

Kromeya 40 mg/0.8 mL solution for injection for paediatric use 

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 Kromeya and during 

treatment with Kromeya. Keep this patient reminder card with you or your child during 

treatment and for 4 months after your (or your child’s) last injection of Kromeya. 

- 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 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 Kromeya is and what it is used for 

2. What you need to know before your child uses Kromeya 

3. How to use Kromeya 

4. Possible side effects 

5. How to store Kromeya 

6. Contents of the pack and other information 

7. Instructions for use 

 

 

1. What Kromeya is and what it is used for 

 

Kromeya contains the active substance adalimumab, a medicine that acts on your body’s immune 

(defence) system. 

 

Kromeya is intended for the treatment of the following inflammatory diseases: 

• polyarticular juvenile idiopathic arthritis 

• enthesitis-related arthritis 

• paediatric plaque psoriasis 

• paediatric Crohn’s disease 

• paediatric uveitis 
 

The active ingredient in Kromeya, adalimumab, is a monoclonal antibody. Monoclonal antibodies are 

proteins that attach to a specific target in the body.   

 

The target of adalimumab is another protein called tumour necrosis factor (TNFα), which is present at 

increased levels in the inflammatory diseases listed above. By attaching to TNFα, Kromeya blocks its 

action and reduces the inflammation in these diseases. 

 

Polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis 

 

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Polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis are inflammatory diseases of 

the joints that usually first appear in childhood. 

 

Kromeya is used to treat polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis. Your 

child may first be given other disease-modifying medicines, such as methotrexate. If these medicines 

do not work well enough, your child will be given Kromeya to treat his/her polyarticular juvenile 

idiopathic arthritis or enthesitis-related arthritis. 

 

Paediatric plaque psoriasis 

 

Plaque psoriasis is a 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. 

 

Kromeya is used to treat severe plaque psoriasis in children and adolescents aged 4 to 17 years for 

whom medicines applied to the skin and treatment with UV light have either not worked very well or 

are not suitable. 

 

Paediatric Crohn's disease 

 

Crohn’s disease is an inflammatory disease of the gut. 

 

Kromeya is indicated for the treatment of Crohn's disease in children aged 6 to 17 years. Your child 

may first be given other medicines. If these medicines do not work well enough, your child will be 

given Kromeya to reduce the signs and symptoms of his/her disease. 

 

Paediatric uveitis 

 

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

 

Kromeya is used to treat children from 2 years of age with chronic non-infectious uveitis with 

inflammation affecting the front of the eye.  

 

 

2. What you need to know before your child uses Kromeya  

 

Do not use Kromeya 

 

- 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, sepsis (blood poisoning) or other 

opportunistic infections (unusual infections associated with a weakened immune system). It is 

important that you tell your doctor if your child has symptoms of infections, e.g. fever, wounds, 

feeling tired, dental problems (see “Warnings and precautions”). 

 

- 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 Kromeya 

 

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Allergic reaction 

 

• If your child experiences allergic reactions with symptoms such as chest tightness, wheezing, 
dizziness, swelling or rash do not inject more Kromeya 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 Kromeya. If you are unsure, contact your doctor. 

 

• Your child might get infections more easily while receiving Kromeya treatment. This risk may 
increase if his/her lung function is reduced. These infections may be more serious and include 

tuberculosis, infections caused by viruses, fungi, parasites or bacteria, or other unusual 

infectious organisms 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 temporarily stopping 

Kromeya. 

 

Tuberculosis (TB) 

 

• As cases of tuberculosis have been reported in patients treated with adalimumab, your doctor 
will check your child for signs and symptoms of tuberculosis before starting Kromeya. 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 had 

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 has lived or travelled in regions where fungal infections such as 
histoplasmosis, coccidioidomycosis or blastomycosis are common. 

 

• 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. Adalimumab 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. 

 

Symptoms of infections 

 

• It is important to tell your doctor if your child gets symptoms of infections, such as fever, 
wounds, feeling tired or dental problems. 

 

Surgery or dental procedures 

 

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• If your child is about to have surgery or dental procedures tell your doctor that he/she is taking 
Kromeya. Your doctor may recommend temporarily stopping Kromeya. 

 

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 Kromeya. 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 living but weakened forms of bacteria or disease-causing bacteria or 
viruses and should not be given during treatment with Kromeya in case they cause infections. 

Check with your doctor before your child receives any vaccines. It is recommended that, if 

possible, children be given all the scheduled vaccinations for their age before they start 

treatment with Kromeya. If you receive Kromeya 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 Kromeya use during your pregnancy so they can decide when your 

baby should receive any vaccine. 

 

Heart failure 

 

• It is important to tell your doctor if your child has had or has a serious heart condition. If your 
child has mild heart failure and is being treated with Kromeya, his/her heart failure status must 

be closely monitored by your doctor. 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 Kromeya. 

 

Fever, bruising, bleeding or looking pale 

 

• In some patients the body may fail to produce enough of the blood cells that help your child's 
body fight off infections or help him/her to stop bleeding. If your child develops a fever that 

does not go away, 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 
adalimumab or other TNFα blockers. People with more serious rheumatoid arthritis who have 

had the disease for a long time may have a higher than average risk of getting lymphoma and 

leukaemia (cancers that affect blood cells and bone marrow). If your child takes Kromeya the 

risk of getting lymphoma, leukaemia, or other cancers may increase. On rare occasions, a 

specific and severe type of lymphoma, has been observed in patients taking adalimumab. Some 

of those patients were also treated with the medicines azathioprine or mercaptopurine. Tell your 

doctor if your child is taking azathioprine or mercaptopurine with Kromeya.  

 

• In addition cases of non-melanoma skin cancer have been observed in patients taking 
adalimumab. If new areas of damaged skin appear during or after treatment 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. 

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

 

Other medicines and Kromeya 

 

Tell your child’s doctor or pharmacist if your child is taking, has recently taken or might take any 

other medicines. 

 

Kromeya 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 Kromeya with medicines containing the active substances anakinra or 

abatacept due to increased risk of serious infection. The combination of adalimumab as well as other 

TNF-antagonists and anakinra or abatacept is not recommended based upon the possible increased risk 

for infections, including serious infections and other potential pharmacological interactions.If you 

have questions, please ask your doctor. 

 

Pregnancy and breast-feeding 

 

If you think your child may be pregnant or is planning to have a baby, ask your doctor or pharmacist 

for advice before they use this medicine. 

 

Your child is advised to avoid becoming pregnant and must use adequate contraception while using 

Kromeya and for at least 5 months after the last Kromeya injection. If your child becomes pregnant, 

you should see your child’s doctor. 

 

Kromeya 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. 

 

Kromeya can be used during breast-feeding. 

 

If your child received Kromeya during her pregnancy, her baby may have a higher risk for getting an 

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

Kromeya use during her pregnancy before the baby receives any vaccine (for more information see 

section on vaccination). 

 

 

Driving and using machines 

 

Kromeya 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 Kromeya. 

 

Kromeya contains sodium  

 

This medicine contains less than 1 mmol of sodium (23 mg) per 0.8 ml dose, that is to say essentially 

‘sodium-free’. 

 

3. How to use Kromeya 

 

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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 Kromeya if your child needs a different dose. 

 

Kromeya is injected under the skin (subcutaneous use). A 40 mg pre-filled syringe and a 40 mg pre-

filled pen are also available for use. 

 

The recommended doses for Kromeya in each of the approved uses are shown in the following table. 

 

Polyarticular juvenile idiopathic arthritis 

Age or body weight How much and how often to 

take? 

Notes 

Children, adolescents and 

adults from 2 years of age 

weighing 30 kg or more 

40 mg every other week Not applicable 

Children and adolescents from 

2 years of age weighing 10 kg 

to less than 30 kg 

20 mg every other week Not applicable 

 

Enthesitis-related arthritis 

Age or body weight How much and how often to 

take? 

Notes 

Children, adolescents and 

adults from 6 years of age 

weighing 30 kg or more 

40 mg every other week Not applicable 

Children and adolescents from 

6 years of age weighing 15 kg 

to less than 30 kg 

20 mg every other week Not applicable 

 

Paediatric plaque psoriasis 

Age or body weight How much and how often to 

take? 

Notes 

Children and adolescents from 

4 to 17 years of age weighing 

30 kg or more 

Initial dose of 40 mg, followed 

by 40 mg one week later. 

 

Thereafter, the usual dose is 40 

mg every other week. 

Not applicable 

Children and adolescents from 

4 to 17 years of age weighing 

15 kg to less than 30 kg 

Initial dose of 20 mg, followed 

by 20 mg one week later. 

 

Thereafter, the usual dose is 20 

mg every other week. 

Not applicable 

 

Paediatric Crohn’s disease 

Age or body weight How much and how often to 

take? 

Notes 

Children and adolescents from 

6 to 17 years of age weighing 

40 kg or more 

 

 

Initial dose of 80 mg (as two 40 

mg injections in one day), 

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 (as four 40 mg injections in 

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. 

 

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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. 

Children and adolescents from 

6 to 17 years of age weighing 

less than 40 kg 

Initial dose of 40 mg, 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 

one 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. 

 

 

Paediatric uveitis 

Age or body weight How much and how often to 

take? 

Notes 

Children and adolescents from 

2 years of age weighing less 

than 30 kg 

 

20 mg every other week Your child’s doctor may 

prescribe an initial dose of 

40 mg which may be 

administered one week prior to 

the start of the usual dose.  

Kromeya is recommended for 

use in combination with 

methotrexate. 

Children and adolescents from 

2 years of age weighing 30 kg 

or more 

 

40 mg every other week  Your child’s doctor may 

prescribe an initial dose of 

80 mg which may be 

administered one week prior to 

the start of the usual dose.  

Kromeya is recommended for 

use in combination with 

methotrexate. 

 

Method and route of administration 

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

 

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

 

If you use more Kromeya than you should 

 

If you accidentally inject a larger amount of Kromeya liquid, or if you inject Kromeya more frequently 

than told to by your doctor, call your doctor and tell him/her 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 Kromeya than you should 

 

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If you accidentally inject a smaller amount of Kromeya liquid, or if you inject Kromeya less 

frequently than told to by your child’s doctor or pharmacist, you should call your child’s doctor or 

pharmacist and tell him/her 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 Kromeya 

 

If you forget to give your child a Kromeya injection, you should inject the Kromeya 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 your child stops using Kromeya 

 

The decision to stop using Kromeya 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 Kromeya injection. 

 
Seek medical attention urgently, if you notice any of the following signs of allergic reaction or heart 
failure: 

• severe rash, hives; 

• 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 and symptoms of infection such as fever, feeling sick, wounds, dental problems, burning on 
urination, feeling weak or tired or coughing; 

• symptoms of nerve problems such as tingling, numbness, double vision or arm or leg weakness; 
• signs of skin cancer such as a bump or open sore that doesn't heal; 

• signs and symptoms suggestive of blood disorders such as persistent fever, bruising, 
bleeding, paleness. 

 

The following side effects 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); 

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• 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 eye lid and eye swelling; 

• vertigo (sensation of 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)  

• unusual infections (which include tuberculosis and other infections) that occur when resistance 
to disease is lowered; 

• neurological infections (including viral meningitis); 

• eye infections; 

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• bacterial infections; 

• diverticulitis (inflammation and infection of the large intestine); 

• cancer, including cancer that affects 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; 

• double vision; 

• hearing loss, buzzing; 

• sensation of heart beating irregularly such as skipped beats; 

• heart problems that can cause shortness of breath or ankle swelling; 

• heart attack; 

• a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel; 

• lung diseases causing shortness of breath (including inflammation); 

• pulmonary embolism (blockage in an artery of the lung); 

• pleural effusion (abnormal collection of fluid in the pleural space); 

• inflammation of the pancreas which causes severe pain in the abdomen and back; 

• difficulty in swallowing; 

• facial oedema (swelling); 

• gallbladder inflammation, gallbladder stones; 

• fatty liver (build-up of fat in liver cells); 

• night sweats; 

• scar; 

• abnormal muscle breakdown; 

• systemic lupus erythematosus (an immune disorder 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 (hole in the wall of the gut); 

• hepatitis (liver inflammation); 

• reactivation of hepatitis B infection; 

• 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 (life-threatening reaction with flu-like symptoms and blistering 
rash); 

• facial oedema (swelling) 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). 

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Not known (frequency cannot be estimated from available data)  

• hepatosplenic T-cell lymphoma (a rare blood cancer that is often fatal); 

• Merkel cell carcinoma (a type of skin cancer); 

• liver failure; 

• worsening of a condition called dermatomyositis (seen as a skin rash accompanying muscle 
weakness). 

 

Some side effects observed with adalimumab may not have symptoms and may only be discovered 

through blood tests. These include: 

 

Very common (may affect more than 1 in 10 people) 

• low blood measurements for white blood cells; 

• low blood measurements for red blood cells; 

• increased lipids in the blood; 

• raised liver enzymes. 
 

Common (may affect up to 1 in 10 people)  

• high blood measurements for white blood cells; 

• low blood measurements for platelets; 

• increased uric acid in the blood; 

• abnormal blood measurements for sodium; 

• low blood measurements for calcium; 

• low blood measurements for phosphate; 

• high blood sugar; 

• high blood measurements for lactate dehydrogenase; 

• autoantibodies present in the blood; 

• low blood potassium. 
 

Uncommon (may affect up to 1 in 100 people)  

• raised 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 Kromeya 

 

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 /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. 

 

Alternative Storage: 

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When needed (for example when you are travelling), Kromeya may be stored at room temperature (up 

to 25°C) for a maximum period of 14 days – be sure to protect it from light. 

Once removed from the refrigerator for room temperature storage, your vial must be used within 14 

days or discarded, even if it is later returned to the refrigerator. 

 

You should record the date when the vial 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 Kromeya contains  

 

- The active substance is adalimumab. Each vial contains 40 mg of adalimumab in 0.8 ml of 
solution. 

- The other ingredients are sodium dihydrogen phosphate dihydrate, disodium phosphate 
dihydrate, mannitol, sodium chloride, citric acid monohydrate, sodium citrate, polysorbate 80, 

sodium hydroxide and water for injections.  

 

What Kromeya looks like and contents of the pack 

 

Kromeya 40 mg/0.8 mL solution for injection (injection) for paediatric use is supplied as a sterile 0.8 

mL clear, colourless solution of 40 mg adalimumab. 

 

Kromeya 40 mg/0.8 mL solution for injection for paediatric use is supplied in a glass vial. Each pack 

contains 1 vial (0.8 mL sterile solution), 1 sterile injection syringe, 1 sterile needle, 1 vial adaptor and 

2 alcohol pads. 

 

Kromeya is available as a vial, a pre-filled syringe and a pre-filled pen. 

 

Marketing Authorisation Holder 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1 

61352 Bad Homburg v.d.Höhe 

Germany 

 

Manufacturer 

 

Fresenius Kabi Austria GmbH 

Hafnerstraße 36,  

8055 Graz 

Austria 

 

Merck Serono S.p.A. 

Via delle Magnolie 15 

I-70026 Modugno (Bari) 

Italy. 

 

This leaflet was last revised in  

 

Other sources of information 

 

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Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 

 

7. Instructions for use 

Be sure that you read, understand, and follow these Instructions for Use before injecting Kromeya. 

Your healthcare provider should show you how to prepare and inject Kromeya properly using the 

vial kit before you use it for the first time. Talk to your healthcare provider if you have any 

questions. 

  

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Note : images for illustration purposes only. 

 

Read carefully these entire instructions before using your Kromeya Vial kit.  

Important Information 

• Only use Kromeya Vial Kit if your healthcare professional has trained you how to use it correctly. 

• Kromeya Vial Kit is for single use only. 

• Children are not allowed to inject themselves and injection must be done by a trained adult. 

• Keep all components of the Kromeya Vial Kit and the sharps disposal container out of reach and 

sight of children. 

• Do not shake the syringe or the vial. Shaking can cause damage. 

• Contact your healthcare professional or pharmacist if you have question or need support. 

Storage information 

• Store the Kromeya Vial Kit in its original box to protect it from light. 

• Store the Kromeya Vial Kit in a refrigerator between 2°C to 8°C. 

• If needed, for example when traveling, the Kromeya Vial Kit can be stored at room temperature 

for up to 14 days. 

 

 

Instructions For Use 

 

Kromeya
®

 Vial Kit 

Single use components and medicine vial (adalimumab) 

for subcutaneous injection 

40 mg/0.8 mL 

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1.1 Remove the Kromeya Vial Kit from the refrigerator.  

 

 

 

 

 

 

 

 

1.2 Leave the kit at room temperature for at least 30 minutes to allow the medicine to warm up.  

Injecting cold medicine may be painful. 

 

Warning: Do not warm the kit any other way, such as in a microwave, hot water, or direct 

sunlight. 

1.3 Open the kit and take out all components and put them on a clean, dry, flat surface.  

Check components to make sure that the packaging and the content are not damaged. 

 

  

Vial Vial adapter 

 

 

Step 1 
 

Gather supplies and  

check for damages 

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Alcohol pads 

 

 

Needle 

 

 

Syringe 

 

Warning: Do not use if damaged. 

1.4 You will also need following supplies that are not included in the kit:  

• A clean cotton ball or gauze, and 

• A sharps container (see section 7.2). 

Open your sharps container so it is ready.  

 

 

 

 

 

 

 

 

1.5 Check your records for injection dates and injection sites to figure out the injection site for this 

session.  

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2.1 Wash your hands with soap, water and dry them well. 

 

 

Warning: Gloves do not replace the need for washing hands. 

2.2 Check the label on the vial for Kromeya and expiration date.  

 

Warning: Do not use the vial if: 

• The name on the vial is not Kromeya. 

• The expiration date on the vial has passed.  

2.3 Check the liquid to make sure that : 

The liquid is clear, colorless, and free of particles. 

Step 2 
 

Prepare Vial 

EXP : MM/YYYY M
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Warning: Do not use the vial if the liquid is cloudy, colored or has particles or flakes in it. 

2.4 Gently remove the yellow cap from the vial. 

 

 

2.5 Wipe the entire vial top with an alcohol pad and throw the pad away. 

 

 

 

Warning: Do not touch the top of the vial after cleaning. 

2.6 Peel off the paper from the vial adapter packaging without taking the vial adaptor out of its 

packaging. 

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Warning: Do not touch the vial adapter. 

2.7 With the vial adapter still in its packaging, push the vial adapter onto the vial top until it snaps in 

place. 

 

 

 

2.8 Hold the vial and lift the packaging off. To ensure the adapter remains on top of the vial, hold the 

packaging by the outer rim. 

 

 

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  Plunger Rod 

 

Tip Barrel Syringe 

 

3.1 Peel open the syringe packaging and grab the syringe by the barrel.  

 

 

Warning: Do not touch the syringe tip.  

3.2 Hold the vial adapter, insert the syringe tip into it and screw to connect. 

 

 

3.3 Turn the vial upside down so it is vertical with the syringe still attached. 

Step 3 
 

Prepare Syringe 

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3.4 Keep the vial and syringe vertical and slowly pull the prescribed dose.  

 

 

Warning: If the plunger rod is pulled completely out, throw away the syringe.  

Do not try to reinsert it and use a new kit. 

3.5 Slowly push the plunger rod all the way in to push the medicine back into the vial. This is to 

remove any air gaps or bubbles. 

 

 

 

Again slowly pull the plunger out to the prescribed dose and stop. 

If you still see air gaps or bubbles at the tip of the syringe, repeat this step until air gaps or bubbles 

are gone. Do not shake the syringe. 

Warning: Do not use the syringe if there is a large amount of air in the syringe. 

3.6 Turn over the vial and syringe, firmly hold the vial adapter and unscrew the syringe from the vial 

adapter. 

 

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3.7 Place the syringe on a clean, flat surface. 

Warning: Do not touch the syringe tip. 

Warning: Do not throw the vial away. 

 

 

 

Safety Cover 

Textured finger pad 

 

Yellow  

syringe  

connector 

 

Cap Needle 

 

4.1 Peel open the needle packaging to uncover the yellow syringe connector. 

Step 4 
 

Prepare Needle 

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Warning: Do not take the needle out of its packaging. 

Warning: Do not touch the yellow connector. 

4.2 Insert the syringe tip into the yellow syringe connector and screw to connect. 

 

 

4.3 Pull the needle packaging off. 

Warning: Do not remove the clear needle cap. 

4.4 Pull back the pink needle safety cover toward the syringe. 

 

Warning: Do not detach the pink needle safety cover from the yellow connector. 

4.5 Place the syringe on a clean, flat surface. 

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5.1 Choose an injection site on:  

• Top of the thighs 

  or 

• Lower stomach area (inject at least 5 centimeters away from the belly button). 

 

Choose a different injection site (at least 2.5 centimeters away from the previous injection site) 

each time to reduce redness, irritation or other skin problems.  

Warning: Do not inject into an area that is sore (tender), bruised, red, hard, scarred or where 

there are stretch marks. 

5.2 Clean the injection site with an alcohol pad and throw the pad away. 

 

 

Warning: Do not blow on or touch the injection site after cleaning. 

5.3 Remove the clear needle cap by pulling it straight off and throw it away. 

Step 5 
 

Prepare Injection 

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Warning: Do not try to put the needle cap back on the needle. 

5.4 Hold the syringe like a pencil with the pink needle safety cover pointing up 

 

 

 

 

6.1 With the other hand, gently pinch a fold of cleaned skin and maintain it. 

 

 

Step 6 
 

Give Injection M
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Warning: Do not touch where you aim to inject. 

 

6.2 With a quick, short motion, push the needle into the skin at an angle of 45°.  

 

 

 

Note: With experience, you will find the angle (between 45° an 90°) that is most comfortable for 

you and the child. 

6.3 Gently push the white plunger rod all the way down until the syringe is empty. 

 

 

6.4 Remove the needle from the skin, being careful to pull it out at the same angle that it was inserted.  

Then release the pinched skin. 

 

6.5 Center your thumb or forefinger on the textured finger pad and push the safety cover forward over 

the needle until you hear or feel it locks. 

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6.6 The needle is now covered and is safe. It can now be thrown away in the sharps container.  

Warning: Call your healthcare professional if you did not inject the full dose. 

6.7 If there is blood or liquid on the injection site, gently press a clean cotton ball or gauze on the skin 

for 10 seconds. 

 

 

Warning: Do not rub the injection site. 

 

 

7.1 Now that you have completed your injection, update your record with: 

• the injection site 

• the date 

• any issue you had 

• the lot number (on vial label). 

 

Step 7 
 

Record injection and 

dispose components 

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7.2 Throw away the used syringe with the protected needle and the vial with attached vial adapter into 

a sharps container.  

 

 

 

Warning: Keep your sharps disposal container out of the reach of children.  

Warning: Do not keep any unused medicine. 

Warning: Do not throw away the syringe or the vial in your household trash. 

If you do not have a sharps disposal container, you may use a household container that is: 

• Made of a heavy-duty plastic; 

• Can be closed with a tight-fitting, puncture-resistant lid; that will keep sharps from coming out, 

• Upright and stable during use, 

• Leak-resistant and 

• Properly labeled to warn of hazardous waste inside the container. 

 

7.3 When your sharps disposal container is almost full, you will need to follow your local guidelines 

for the right way to dispose of your sharps disposal container.  

Warning: Do not recycle your used sharps disposal container. 

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