Hefiya

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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 
 
Hefiya 20 mg solution for injection in pre-filled syringe 
 
Hefiya 40 mg solution for injection in pre-filled syringe  
 
Hefiya 40 mg solution for injection in pre-filled pen 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Hefiya 20 mg solution for injection in pre-filled syringe: 
 
Each 0.4 ml single-dose pre-filled syringe contains 20 mg of adalimumab. 
 
Hefiya 40 mg solution for injection in pre-filled syringe: 
 
Each 0.8 ml single-dose pre-filled syringe contains 40 mg of adalimumab. 
 
Hefiya 40 mg solution for injection in pre-filled pen: 
 
Each 0.8 ml single-dose pre-filled pen contains 40 mg of adalimumab. 
 
Adalimumab is a recombinant human monoclonal antibody produced in Chinese Hamster Ovary 
cells. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection. (injection)  
 
Clear to slightly opalescent, colourless to slightly yellowish solution.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rheumatoid arthritis 
 
Hefiya 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. 

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



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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 
 
Hefiya 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). Hefiya 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 
 
Hefiya 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) 
 
Hefiya 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 
 
Hefiya 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 
 
Hefiya 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 
 
Hefiya is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients 
who are candidates for systemic therapy. 
 
Paediatric plaque psoriasis 
 
Hefiya is indicated for the treatment of severe chronic plaque psoriasis in children and adolescents 
from 4 years of age who have had an inadequate response to or are inappropriate candidates for 
topical therapy and phototherapies. 
 
Hidradenitis suppurativa (HS) 
 
Hefiya is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne 



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inversa) in adults and adolescents from 12 years of age with an inadequate response to 
conventional systemic HS therapy (see sections 5.1 and 5.2). 
 
Crohn’s disease 
 
Hefiya 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 
 
Hefiya is indicated for the treatment of moderately to severely active Crohn's disease in paediatric 
patients (from 6 years of age) who have had an inadequate response to conventional therapy including 
primary nutrition therapy and a corticosteroid and / or an immunomodulator, or who are intolerant to 
or have contraindications for such therapies. 
 
Ulcerative colitis 
 
Hefiya 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 
 
Hefiya 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 
 
Hefiya 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 
 
Hefiya treatment should be initiated and supervised by specialist physicians experienced in the 
diagnosis and treatment of conditions for which Hefiya is indicated. Ophthalmologists are advised to 
consult with an appropriate specialist before initiation of treatment with Hefiya (see section 4.4). 
Patients treated with Hefiya should be given the Patient Reminder Card. 
 
After proper training in injection technique, patients may self-inject with Hefiya if their physician 
determines that it is appropriate and with medical follow-up as necessary. 
 
During treatment with Hefiya, other concomitant therapies (e.g., corticosteroids and / or 
immunomodulatory agents) should be optimised. 
 
Posology 
 
Rheumatoid arthritis 
 
The recommended dose of Hefiya 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 Hefiya. 
 
Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics can be continued 



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during treatment with Hefiya. 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 Hefiya 40 mg 
every other week may benefit from an increase in dosage to 40 mg adalimumab every week or 
80 mg every other week. 
 
Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. 
Continued therapy should be reconsidered in a patient not responding within this time period. 
 
Dose interruption 
 
There may be a need for dose interruption, for instance before surgery or if a serious infection occurs. 
 
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 Hefiya 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 Hefiya 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 Hefiya 40 mg every other week may benefit 
from an increase in dosage to 40 mg every week or 80 mg every other week. The benefits and risks of 
continued 40 mg weekly or 80 mg every other week therapy should be carefully reconsidered in a 
patient with an inadequate response after the increase in dosage (see section 5.1). If adequate response 
is achieved with 40 mg every week or 80 mg every other week, the dosage may subsequently be 
reduced to 40 mg every other week. 
 
Hidradenitis suppurativa 
 
The recommended Hefiya dose regimen for adult patients with hidradenitis suppurativa (HS) is 
160 mg initially at Day 1 (given as four 40 mg injections in one day or as two 40 mg injections per 
day for two consecutive days), followed by 80 mg two weeks later at Day 15 (given as two 40 mg 
injections in one day). Two weeks later (Day 29) continue with a dose of 40 mg every week or 80 mg 
every other week (given as two 40 mg injections in one day). Antibiotics may be continued during 
treatment with Hefiya, if necessary. It is recommended that the patient should use a topical antiseptic 
wash on their HS lesions on a daily basis during treatment with Hefiya. 
 
Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no 
improvement within this time period.  
 



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Should treatment be interrupted, Hefiya 40 mg every week or 80 mg every other week may be re-
introduced (see section 5.1).  
 
The benefit and risk of continued long-term treatment should be periodically evaluated 
(see section 5.1). 
 
Crohn’s disease 
 
The recommended Hefiya 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 Hefiya and signs and symptoms of disease recur, 
Hefiya 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 Hefiya 40 mg every other week may 
benefit from an increase in dosage to 40 mg Hefiya every week or 80 mg every other week. 
 
Some patients who have not responded by week 4 may benefit from continued maintenance therapy 
through week 12. Continued therapy should be carefully reconsidered in a patient not responding 
within this time period. 
 
Ulcerative colitis 
 
The recommended Hefiya 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 Hefiya 40 mg every other week may 
benefit from an increase in dosage to 40 mg Hefiya every week or 80 mg every other week. 
 
Available data suggest that the clinical response is usually achieved within 2–8 weeks of 
treatment. Hefiya therapy should not be continued in patients failing to respond within this 
time period. 
 
Uveitis 
 
The recommended dose of Hefiya 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 Hefiya 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 Hefiya. 
 



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It is recommended that the benefit and risk of continued long-term treatment should be evaluated on a 
yearly basis (see section 5.1). 
 
Special populations 
 
Elderly 
 
No dose adjustment is required.  
 
Renal and / or hepatic impairment 
 
Adalimumab has not been studied in these patient populations. No dose recommendations can be 
made.  
 
Paediatric population 
 
Juvenile idiopathic arthritis 
 
Polyarticular juvenile idiopathic arthritis from 2 years of age 
 
The recommended dose of Hefiya for patients with polyarticular juvenile idiopathic arthritis from 
2 years of age is based on body weight (table 1). Hefiya is administered every other week via 
subcutaneous injection.  
 

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

 

Patient weight Dosing regimen 

10 kg to < 30 kg 20 mg every other week 

≥ 30 kg 40 mg every other week 

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

Table 2. Hefiya 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. 
 



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

Table 3. Hefiya 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 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 re-treatment with adalimumab is indicated, the above guidance on dose and treatment duration 
should be followed. 
 
The safety of adalimumab in paediatric patients with plaque psoriasis has been assessed for a 
mean of 13 months. 
 
There is no relevant use of adalimumab in children aged less than 4 years for this indication.  
 
Adolescent hidradenitis suppurativa (from 12 years of age, weighing at least 30 kg) 
 
There are no clinical trials with adalimumab in adolescent patients with HS. The posology of 
adalimumab in these patients has been determined from pharmacokinetic modelling and simulation 
(see section 5.2). 
 
The recommended Hefiya dose is 80 mg at week 0 followed by 40 mg every other week starting at 
week 1 via subcutaneous injection.  
 
In adolescent patients with inadequate response to Hefiya 40 mg every other week, an increase in 
dosage to 40 mg every week or 80 mg every other week may be considered. 
 
Antibiotics may be continued during treatment with Hefiya if necessary. It is recommended that the 
patient should use a topical antiseptic wash on their HS lesions on a daily basis during treatment with 
Hefiya. 
 
Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no 
improvement within this time period. 
 
Should treatment be interrupted, Hefiya may be re-introduced as appropriate. 
 
The benefit and risk of continued long-term treatment should be periodically evaluated (see adult data 
in section 5.1) 
 
There is no relevant use of adalimumab in children aged less than 12 years in this indication. 
 



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

Table 4. Hefiya 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.  
 
Paediatric uveitis 
 
The recommended dose of Hefiya for paediatric patients with uveitis from 2 years of age 
is based on body weight (table 5). Hefiya is administered via subcutaneous injection.  
 
In paediatric uveitis, there is no experience in the treatment with adalimumab without concomitant 
treatment with methotrexate. 
 

Table 5. Hefiya 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 Hefiya 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 Hefiya in children aged less than 2 years in this indication. 
 
It is recommended that the benefit and risk of continued long-term treatment should be 
evaluated on a yearly basis (see section 5.1). 
 
Paediatric ulcerative colitis 
 
The safety and efficacy of adalimumab in children aged 4–17 years have not yet been established. No 
data are available.  
 
There is no relevant use of adalimumab in children aged less than 4 years for this indication. 
 
Psoriatic arthritis and axial spondyloarthritis including ankylosing spondylitis 
 
There is no relevant use of adalimumab in the paediatric population for the indications of 
ankylosing spondylitis and psoriatic arthritis. 
 
Method of administration 
 
Hefiya is administered by subcutaneous injection.  
Full instructions for use are provided in the package leaflet.   
 
Adalimumab is available in other strengths and presentations. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Active tuberculosis or other severe infections such as sepsis, and opportunistic infections 
(see section 4.4). 
 
Moderate to severe heart failure (NYHA class III / IV) (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve traceability of biological medicinal products, the name and the batch number of 
the administered product should be clearly recorded. 
 
Infections 
 
Patients taking TNF-antagonists are more susceptible to serious infections. Impaired lung function 
may increase the risk for developing infections. Patients must therefore be monitored closely for 
infections, including tuberculosis, before, during and after treatment with Hefiya. Because the 
elimination of adalimumab may take up to four months, monitoring should be continued throughout 
this period. 
 
Treatment with Hefiya 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 Hefiya 
should be considered prior to initiating therapy (see Other opportunistic infections). 
 
Patients who develop a new infection while undergoing treatment with Hefiya should be monitored 
closely and undergo a complete diagnostic evaluation. Administration of Hefiya should be 
discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial or 



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antifungal therapy should be initiated until the infection is controlled. Physicians should exercise 
caution when considering the use of Hefiya 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 Hefiya, all patients must be evaluated for both active and 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, Hefiya 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 Hefiya, and in accordance with local recommendations. 
 
Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of 
Hefiya 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 Hefiya. 
 



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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 Hefiya 
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 
Hefiya. 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 Hefiya 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, Hefiya 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 Hefiya in patients with pre-existing or recent-onset central or peripheral nervous system 
demyelinating disorders; discontinuation of Hefiya 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 Hefiya 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 
Hefiya 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. 
 



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



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Hefiya 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 Hefiya therapy. 
 
Patients on Hefiya 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. Hefiya should be used with 
caution in patients with mild heart failure (NYHA class I/II). Hefiya is contraindicated in moderate 
to severe heart failure (see section 4.3). Treatment with Hefiya must be discontinued in patients 
who develop new or worsening symptoms of congestive heart failure. 
 
Autoimmune processes 
 
Treatment with Hefiya 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 Hefiya 
and is positive for antibodies against double-stranded DNA, further treatment with Hefiya 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 Hefiya should be closely monitored for infections, and 
appropriate actions should be taken. There is limited safety experience in patients undergoing 
arthroplasty while receiving adalimumab. 
 



15 

 

Small bowel obstruction 
 
Failure to respond to treatment for Crohn’s disease may indicate the presence of fixed fibrotic 
stricture that may require surgical treatment. Available data suggest that adalimumab does not 
worsen or cause strictures. 
 
Elderly 
 
The frequency of serious infections among adalimumab-treated subjects over 65 years of age 
(3.7 %) was higher than for those under 65 years of age (1.5 %). Some of those had a fatal 
outcome. Particular attention regarding the risk for infection should be paid when treating the 
elderly. 
 
Paediatric population 
 
See Vaccinations above. 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per 0.8 ml dose, that is to say 
essentially ‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and 
psoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitant 
methotrexate. Antibody formation was lower when adalimumab was given together with 
methotrexate in comparison with use as monotherapy. Administration of adalimumab without 
methotrexate resulted in increased formation of antibodies, increased clearance and reduced efficacy 
of adalimumab (see section 5.1). 
 
The combination of adalimumab and anakinra is not recommended (see section 4.4 “Concurrent 
administration of biologic DMARDs or TNF-antagonists”). 
 
The combination of adalimumab and abatacept is not recommended (see section 4.4 “Concurrent 
administration of biologic DMARDs or TNF-antagonists”). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of 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 Hefiya 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, 



16 

 

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, Hefiya can be used during 
breastfeeding. 
 
Fertility 
 
Preclinical data on fertility effects of adalimumab are not available. 
 
4.7 Effects on ability to drive and use machines 
 
Hefiya may have a minor influence on the ability to drive and use machines. Vertigo and visual 
impairment may occur following administration of Hefiya (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Adalimumab was studied in 9,506 patients in pivotal controlled and open label trials for up to 
60 months or more. These trials included rheumatoid arthritis patients with short term and long 
standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-
related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis 
without radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, 
hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients 
receiving adalimumab and 3,801 patients receiving placebo or active comparator during the controlled 
period. 
 
The proportion of patients who discontinued treatment due to adverse events during the double-blind, 
controlled portion of pivotal studies was 5.9 % for patients taking adalimumab and 5.4 % for control-
treated patients. 
 
The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper 
respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain 



17 

 

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 (SOC) and frequency in table 6 
below: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); 
rare (≥ 1/10,000 to < 1/1,000); and not known (cannot be estimated from the available data). 
Within each frequency grouping, undesirable effects are presented in order of decreasing 
seriousness.  
 
The highest frequency seen among the various indications has been included. An asterisk (*) 
appears in the SOC column if further information is found elsewhere in sections 4.3, 4.4 and 4.8. 
 

Table 6  
Undesirable effects 

 

System Organ Class Frequency Adverse Reaction 

Infections and 
infestations* 

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

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



18 

 

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

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

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

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

Rare Leukaemia1) 
 

Not known Hepatosplenic T-cell lymphoma1) 
Merkel cell carcinoma (neuroendocrine 
carcinoma of the skin)1) 
 

Blood and the 
lymphatic system 
disorders* 

Very common Leucopaenia (including neutropaenia and 
agranulocytosis), 
anaemia 
 

Common Leucocytosis, 
thrombocytopaenia 
 

Uncommon Idiopathic thrombocytopaenic purpura 
 

Rare Pancytopaenia 
 

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 
 



19 

 

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, 
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 
 



20 

 

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

Uncommon Pancreatitis, 
dysphagia, 
face oedema 
 

Rare Intestinal perforation1) 
 

Hepato-biliary 
disorders* 

Very common Elevated liver enzymes 
 

Uncommon Cholecystitis and cholelithiasis, 
hepatic steatosis, 
bilirubin increased 
 

Rare Hepatitis, 
reactivation of hepatitis B1), 
autoimmune hepatitis1) 
 

Not known Liver failure1) 
 

Skin and subcutaneous 
tissue disorders 

Very common Rash (including exfoliative rash) 
 

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

Uncommon Night sweats, 
scar 
 

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

Not known Worsening of symptoms of dermatomyositis1) 
 

Musculoskeletal and 
connective tissue 
disorders 

Very common Musculoskeletal pain 
 

Common Muscle spasms (including blood creatine 
phosphokinase increased) 
 

Uncommon Rhabdomyolysis, 
systemic lupus erythematosus 
 

Rare Lupus-like syndrome1) 
 



21 

 

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. 
 
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 



22 

 

0.03 per patient year in placebo and active control-treated patients. 
 
In controlled and open label adult and paediatric studies with adalimumab, serious infections 
(including fatal infections, which occurred rarely) have been reported, which include reports of 
tuberculosis (including miliary and extra-pulmonary locations) and invasive opportunistic infections 
(e.g. disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, 
pneumocystis, candidiasis, aspergillosis and listeriosis). Most of the cases of tuberculosis occurred 
within the first eight months after initiation of therapy and may reflect recrudescence of latent 
disease. 
 
Malignancies and lymphoproliferative disorders 
 
No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years 
during adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile 
idiopathic arthritis and enthesitis-related arthritis). In addition, no malignancies were observed in 
192 paediatric patients with an exposure of 498.1 patient years during adalimumab trials in 
paediatric patients with Crohn’s disease. No malignancies were observed in 77 paediatric patients 
with an exposure of 80.0 patient years during an adalimumab trial in paediatric patients with chronic 
plaque psoriasis. No malignancies were observed in 60 paediatric patients with an exposure of 58.4 
patient years during an adalimumab trial in paediatric patients with uveitis. 
 
During the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in 
duration in patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, 
axial spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, 
hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than 
lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 
6.8 (4.4, 10.5) per 1,000 patient years among 5,291 adalimumab-treated patients versus a rate of 
6.3 (3.4, 11.8) per 1,000 patient years among 3,444 control patients (median duration of treatment 
was 4.0 months for adalimumab and 3.8 months for control-treated patients). The rate (95 % 
confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient years 
among adalimumab-treated patients and 3.2 (1.3, 7.6) per 1,000 patient years among control 
patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95 % confidence 
interval) of 2.7 (1.4, 5.4) per 1,000 patient years among adalimumab-treated patients and 0.6 (0.1, 
4.5) per 1,000 patient years among control patients. The rate (95 % confidence interval) of 
lymphomas was 0.7 (0.2, 2.7) per 1,000 patient years among adalimumab-treated patients and 0.6 
(0.1, 4.5) per 1,000 patient years among control patients. 
 
When combining controlled portions of these trials and ongoing and completed open label extension 
studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 
patient years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma 
skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin 
cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is 
approximately 1.3 per 1,000 patient years. 
 
In post-marketing experience from January 2003 to December 2010, predominantly in patients 
with rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient 
treatment years. The reported rates for non-melanoma skin cancers and lymphomas are 
approximately 0.2 and 0.3 per 1,000 patient treatment years, respectively (see section 4.4). 
 
Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients 
treated with adalimumab (see section 4.4). 
 
Autoantibodies 
 
Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis 
studies I–V. In these trials, 11.9 % of patients treated with adalimumab and 8.1 % of placebo and 
active control-treated patients that had negative baseline anti-nuclear antibody titres reported positive 



23 

 

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 
 
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. 
 



24 

 

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 
 
Hefiya is a biosimilar medicinal product. Detailed information is available on the website of the 
European Medicines Agency http://www.ema.europa.eu. 
 
Mechanism of action 
 
Adalimumab binds specifically to TNF and neutralises the biological function of TNF by blocking its 
interaction with the p55 and p75 cell surface TNF receptors.  
Adalimumab also modulates biological responses that are induced or regulated by TNF, including 
changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, 
and ICAM-1 with an IC50 of 0.1–0.2 nM). 
 
Pharmacodynamic effects 
 
After treatment with adalimumab, a rapid decrease in levels of acute phase reactants of inflammation 
(C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL-6) was 
observed, compared to baseline in patients with rheumatoid arthritis. Serum levels of matrix 
metalloproteinases (MMP-1 and MMP-3) that produce tissue remodelling responsible for cartilage 
destruction were also decreased after adalimumab administration. Patients treated with adalimumab 
usually experienced improvement in haematological signs of chronic inflammation. 
 
A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic 
arthritis, Crohn's disease, ulcerative colitis and hidradenitis suppurativa after treatment with 
adalimumab. In patients with Crohn’s disease, a reduction of the number of cells expressing 
inflammatory markers in the colon including a significant reduction of expression of TNF-α was 
seen. Endoscopic studies in intestinal mucosa have shown evidence of mucosal healing in 
adalimumab-treated patients.  
 
Clinical efficacy and safety 
 
Rheumatoid arthritis 
 
Adalimumab was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. The 
efficacy and safety of adalimumab were assessed in five randomised, double-blind and well-
controlled studies. Some patients were treated for up to 120 months duration. 
 
RA study I evaluated 271 patients with moderately to severely active rheumatoid arthritis who were 



25 

 

≥ 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 percentage 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. 
 



26 

 

Table 7 
ACR responses in placebo-controlled trials 

(percent of patients) 
response RA Study Ia** RA Study IIa** RA Study IIIa** 

placebo / MTXc 
n = 60 

adalimumabb / 
MTXc 
n = 63 

placebo 
n = 110 

adalimumabb 
n = 113 

placebo / MTXc 
n = 200 

adalimumabb / 
MTXc 
n = 207 

ACR 20 
   6 months 
 
   12 months 
 

 
13.3 % 

 
NA 

 

 
65.1 % 

 
NA 

 
19.1 % 

 
NA 

 
46.0 % 

 
NA 

 
29.5 % 

 
24.0 % 

 
63.3 % 

 
58.9 % 

 ACR 50 
   6 months 
 
   12 months 
 

 
6.7 % 

 
NA 

 
52.4 % 

 
NA 

 
8.2 % 

 
NA 

 
22.1 % 

 
NA 

 
9.5 % 

 
9.5 % 

 
39.1 % 

 
41.5 % 

ACR 70 
   6 months 
 
   12 months 

 
3.3 % 

 
NA 

 
23.8 % 

 
NA 

 
1.8 % 

 
NA 

 
12.4 % 

 
NA 

 
2.5 % 

 
4.5 % 

 
20.8 % 

 
23.2 % 

a RA study I at 24 weeks, RA study II at 26 weeks, and RA study III at 24 and 52 weeks 
b 40 mg adalimumab administered every other week 
c MTX = methotrexate 
** p < 0.01, adalimumab versus placebo 
  

In RA studies I–IV, all individual components of the ACR response criteria (number of tender and 
swollen joints, physician and patient assessment of disease activity and pain, disability index 
(HAQ) scores and CRP (mg / dl) values) improved at 24 or 26 weeks compared to placebo. In RA 
study III, these improvements were maintained throughout 52 weeks. 
 
In the open-label extension for RA study III, most patients who were ACR responders maintained 
response when followed for up to 10 years. Of 207 patients who were randomised to adalimumab 
40 mg every other week, 114 patients continued on adalimumab 40 mg every other week for 
5 years. Among those, 86 patients (75.4 %) had ACR 20 responses; 72 patients (63.2 %) had ACR 
50 responses; and 41 patients (36 %) had ACR 70 responses. Of 207 patients, 81 patients continued 
on adalimumab 40 mg every other week for 10 years. Among those, 64 patients (79.0 %) had ACR 
20 responses; 56 patients (69.1 %) had ACR 50 responses; and 43 patients (53.1 %) had ACR 70 
responses. 
 
In RA study IV, the ACR 20 response of patients treated with adalimumab plus standard of care 
was statistically significantly better than patients treated with placebo plus standard of care 
(p < 0.001). 
 
In RA studies I–IV, adalimumab-treated patients achieved statistically significant ACR 20 and 50 
responses compared to placebo as early as one to two weeks after initiation of treatment. 
 
In RA study V with early rheumatoid arthritis patients who were methotrexate naïve, 
combination therapy with adalimumab and methotrexate led to faster and significantly greater 
ACR responses than methotrexate monotherapy and adalimumab monotherapy at week 52 and 
responses were sustained at week 104 (see table 8). 
 



27 

 

Table 8  
ACR responses in RA study V  

(percent of patients) 
response MTX 

n = 257 
adalimumab 

n = 274 
adalimumab / M

TX 
n = 268 

p-valuea p-valueb p-valuec 

ACR 20 
week 52 62.6 % 54.4 % 72.8 % 0.013 < 0.001 0.043 

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

ACR 50 
week 52 45.9 % 41.2 % 61.6 % < 0.001 < 0.001 0.317 

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

ACR 70 
week 52 27.2 % 25.9 % 45.5 % < 0.001 < 0.001 0.656 

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

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

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

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

monotherapy using the Mann-Whitney U test 

 
 
In the open-label extension for RA study V, ACR response rates were maintained when followed 
for up to 10 years. Of 542 patients who were randomised to adalimumab 40 mg every other week, 
170 patients continued on adalimumab 40 mg every other week for 10 years. Among those, 154 
patients (90.6 %) had ACR 20 responses; 127 patients (74.7 %) had ACR 50 responses; and 102 
patients (60.0 %) had ACR 70 responses. 
 
At week 52, 42.9 % of patients who received adalimumab / methotrexate combination therapy 
achieved clinical remission (DAS28 < 2.6) compared to 20.6 % of patients receiving methotrexate 
monotherapy and 23.4% of patients receiving adalimumab monotherapy. 
Adalimumab / methotrexate combination therapy was clinically and statistically superior to 
methotrexate (p < 0.001) and adalimumab monotherapy (p < 0.001) in achieving a low disease 
state in patients with recently diagnosed moderate to severe rheumatoid arthritis. The response for 
the two monotherapy arms was similar (p = 0.447).  
Of 342 subjects originally randomized to adalimumab monotherapy or adalimumab / methotrexate 
combination therapy who entered the open-label extension study, 171 subjects completed 10 years 
of adalimumab treatment. Among those, 109 subjects (63.7 %) were reported to be in remission at 
10 years. 
 



28 

 

Radiographic response 
 
In RA study III, where adalimumab-treated patients had a mean duration of rheumatoid arthritis 
of approximately 11 years, structural joint damage was assessed radiographically and expressed 
as change in modified Total Sharp Score (TSS) and its components, the erosion score and joint 
space narrowing score. Adalimumab / methotrexate patients demonstrated significantly less 
radiographic progression than patients receiving methotrexate alone at 6 and 12 months (see 
table 9). 
 
In the open-label extension of RA Study III, the reduction in rate of progression of structural 
damage is maintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients 
originally treated with 40 mg adalimumab every other week were evaluated radiographically. 
Among those, 48 patients showed no progression of structural damage defined by a change from 
baseline in the mTSS of 0.5 or less. At 10 years, 79 of 207 patients originally treated with 40 mg 
adalimumab every other week were evaluated radiographically. Among those, 40 patients showed 
no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less. 

Table 9 
radiographic mean changes over 12 months in RA study III 

 placebo / MTX
a
 adalimumab / MTX 
40 mg every other 

week 

placebo / MTX- 
adalimumab / MTX 
(95 % confidence 

interval
b
) 

p-value 

total Sharp score 2.7 0.1 2.6 (1.4, 3.8) < 0.001
c
 

erosion score 1.6 0.0 1.6 (0.9, 2.2) < 0.001 

JSN
d score 1.0 0.1 0.9 (0.3, 1.4) 0.002 

a methotrexate 
b 95 % confidence intervals for the differences in change scores between methotrexate and 
adalimumab 
c based on rank analysis 
d  Joint Space Narrowing 
 In RA study V, structural joint damage was assessed radiographically and expressed as change in 

modified total Sharp Score (see table 10). 
 



29 

 

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 / M
TX n=268 (95% 

confidence 
interval) 

 

 
 
p-valuea 

 

 
 
p-valueb 

 

 
 
p-valuec 

total Sharp 
score 

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

erosion score 3.7 (2.7–4.7) 1.7 (1.0–2.4) 0.8 (0.4–1.2) < 0.001 0.0082 < 0.001 
JSN score 2.0 (1.2–2.8) 1.3 (0.5–2.1) 0.5 (0–1.0) < 0.001 0.0037 0.151 

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

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

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

 
 
Following 52 weeks and 104 weeks of treatment, the percentage of patients without progression 
(change from baseline in modified Total Sharp Score ≤ 0.5) was significantly higher with 
adalimumab / methotrexate combination therapy (63.8 % and 61.2 % respectively) compared to 
methotrexate monotherapy (37.4 % and 33.5 % respectively, p < 0.001) and adalimumab monotherapy 
(50.7 %, p < 0.002 and 44.5 %, p < 0.001 respectively). 
 
In the open-label extension of RA study V, the mean change from baseline at Year 10 in the modified 
Total Sharp Score was 10.8, 9.2 and 3.9 in patients originally randomised to methotrexate 
monotherapy, adalimumab monotherapy and adalimumab / methotrexate combination therapy, 
respectively. The corresponding proportions of patients with no radiographic progression were 
31.3 %, 23.7 % and 36.7 % respectively. 
 
Quality of life and physical function 
 
Health-related quality of life and physical function were assessed using the disability index of the 
Health Assessment Questionnaire (HAQ) in the four original adequate and well-controlled trials, 
which was a pre-specified primary endpoint at week 52 in RA study III. All doses / schedules of 
adalimumab in all four studies showed statistically significantly greater improvement in the disability 
index of the HAQ from baseline to Month 6 compared to placebo and in RA study III the same was 
seen at week 52. Results from the Short Form Health Survey (SF 36) for all doses / schedules of 
adalimumab in all four studies support these findings, with statistically significant physical component 
summary (PCS) scores, as well as statistically significant pain and vitality domain scores for the 40 mg 
every other week dose. A statistically significant decrease in fatigue as measured by functional 
assessment of chronic illness therapy (FACIT) scores was seen in all three studies in which it was 
assessed (RA studies I, III, IV). 
 
In RA study III, most subjects who achieved improvement in physical function and continued 
treatment maintained improvement through week 520 (120 months) of open-label treatment. 
Improvement in quality of life was measured up to week 156 (36 months) and improvement 
was maintained through that time. 
 
In RA study V, the improvement in the HAQ disability index and the physical component of the SF 36 
showed greater improvement (p < 0.001) for adalimumab / methotrexate combination therapy versus 
methotrexate monotherapy and adalimumab monotherapy at week 52, which was maintained through 
week 104. Among the 250 subjects who completed the open-label extension study, improvements in 
physical function were maintained through 10 years of treatment. 
 



30 

 

Juvenile idiopathic arthritis (JIA) 
 
Polyarticular juvenile idiopathic arthritis (pJIA) 
 
The safety and efficacy of adalimumab was assessed in two studies (pJIA I and II) in children with 
active polyarticular or polyarticular course juvenile idiopathic arthritis, who had a variety of JIA 
onset types (most frequently rheumatoid-factor negative or positive polyarthritis and extended 
oligoarthritis). 
 
pJIA I 
 
The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind, 
parallel-group study in 171 children (4–17 years old) with polyarticular JIA. In the open-label lead in 
phase (OL LI) patients were stratified into two groups, MTX (methotrexate)-treated or non-MTX-
treated. Patients who were in the non-MTX stratum were either naïve to or had been withdrawn from 
MTX at least two weeks prior to study drug administration. Patients remained on stable doses of 
NSAIDs and or prednisone (≤ 0.2 mg / kg / day or 10 mg / day maximum). In the OL LI phase all 
patients received 24 mg / m2 up to a maximum of 40 mg adalimumab every other week for 16 weeks. 
The distribution of patients by age and minimum, median and maximum dose received during the 
OL LI phase is presented in table 11. 
 

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

age group number of patients at baseline n (%) Minimum, median and maximum 
dose 

4 to 7 years 31 (18.1) 10, 20 and 25 mg 
8 to 12 years 71 (41.5) 20, 25 and 40 mg 
13 to 17 years 69 (40.4) 25, 40 and 40 mg 

 
Patients demonstrating a paediatric ACR 30 response at week 16 were eligible to be randomised 
into the double blind (DB) phase and received either adalimumab 24 mg / m2 up to a maximum of 
40 mg, or placebo every other week for an additional 32 weeks or until disease flare. Disease flare 
criteria were defined as a worsening of ≥ 30 % from baseline in ≥ 3 of 6 paediatric ACR core 
criteria, ≥ 2 active joints, and improvement of > 30 % in no more than 1 of the 6 criteria. After 
32 weeks or at disease flare, patients were eligible to enrol into the open label extension phase 
(table 12). 
 



31 

 

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 paediatric ACR 30 / 50 / 70 /90 
responses were maintained for up to six years in the OLE phase in patients who received 
adalimumab throughout the study. Over all 19 subjects, of which 11 of the baseline age group 4 to 
12 and 8 of the baseline age group 13 to 17 years were treated 6 years or longer. 
 
Overall responses were generally better and, fewer patients developed antibodies when treated with 
the combination of adalimumab and MTX compared to adalimumab alone. Taking these results into 
consideration, Hefiya is recommended for use in combination with MTX and for use as 
monotherapy in patients for whom MTX use is not appropriate (see section 4.2). 
 
pJIA II 
 
The safety and efficacy of adalimumab was assessed in an open-label, multicentre study in 32 children 
(2–< 4 years old or aged 4 and above weighing < 15 kg) with moderately to severely active polyarticular 
JIA. The patients received 24 mg / m2 body surface area (BSA) of adalimumab up to a maximum of 
20 mg every other week as a single dose via SC injection for at least 24 weeks. During the study, most 
subjects used concomitant MTX, with fewer reporting use of corticosteroids or NSAIDs. 
 
At week 12 and week 24, PedACR30 response was 93.5 % and 90.0 %, respectively, using the 
observed data approach. The proportions of subjects with PedACR50 / 70 / 90 at week 12 and week 24 
were 90.3 % / 61.3 % / 38.7 % and 83.3 % / 73.3 % / 36.7 %, respectively. Amongst those who 
responded (paediatric ACR 30) at week 24 (n = 27 out of 30 patients), the paediatric ACR 30 
responses were maintained for up to 60 weeks in the OLE phase in patients who received adalimumab 
throughout this time period. Overall, 20 subjects were treated for 60 weeks or longer. 
 
Enthesitis-related arthritis 
 
The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind study in 
46 paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients were 
randomised to receive either 24 mg / m2 body surface area (BSA) of adalimumab up to a maximum of 
40 mg, or placebo every other week for 12 weeks. The double-blind period is followed by an open-label 
(OL) period during which patients received 24 mg / m2 BSA of adalimumab up to a maximum of 40 mg 
every other week subcutaneously for up to an additional 192 weeks. The primary endpoint was the 
percent change from Baseline to week 12 in the number of active joints with arthritis (swelling not due 



32 

 

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), 
paediatric ACR 50 response, and paediatric ACR 70 response. 
 
Axial spondyloarthritis 
 
Ankylosing spondylitis (AS) 
 
Adalimumab 40 mg every other week was assessed in 393 patients in two randomised, 24 week 
double-blind, placebo-controlled studies in patients with active ankylosing spondylitis (mean baseline 
score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.3 in 
all groups) who have had an inadequate response to conventional therapy. Seventy-nine (20.1 %) 
patients were treated concomitantly with disease modifying anti-rheumatic drugs, and 37 (9.4 %) 
patients with glucocorticoids. The blinded period was followed by an open-label period during which 
patients received adalimumab 40 mg every other week subcutaneously for up to an additional 
28 weeks. Subjects (n = 215, 54.7 %) who failed to achieve ASAS 20 at weeks 12, or 16 or 20 
received early escape open-label adalimumab 40 mg every other week subcutaneously and were 
subsequently treated as non-responders in the double-blind statistical analyses. 
 
In the larger AS study I with 315 patients, results showed statistically significant improvement of 
the signs and symptoms of ankylosing spondylitis in patients treated with adalimumab compared to 
placebo. Significant response was first observed at week 2 and maintained through 24 weeks 
(table 13). 
 



33 

 

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 a 
randomised, 12 week double-blind, placebo-controlled study in patients with active nr-axSpA (mean 
baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] 
was 6.4 for patients treated with adalimumab and 6.5 for those on placebo) who have had an 
inadequate response to or intolerance to ≥ 1 NSAIDs, or a contraindication for NSAIDs. 
 
Thirty-three (18 %) patients were treated concomitantly with disease modifying anti-rheumatic drugs, 
and 146 (79 %) patients with NSAIDs at baseline. The double-blind period was followed by an open-
label period during which patients receive adalimumab 40 mg every other week subcutaneously for up 



34 

 

to an additional 144 weeks. Week 12 results showed statistically significant improvement of the signs 
and symptoms of active nr-axSpA in patients treated with adalimumab compared to placebo 
(table 14). 

Table 14 
efficacy response in placebo-controlled study nr-axSpA I 

double-blind 

response at week 12 

placebo 
N=94 

adalimumab 
N=91 

ASASa 40 15 % 36 %*** 
ASAS 20 31 % 52 %** 
ASAS 5/6 6 % 31 %*** 
ASAS partial remission 5 % 16 %* 
BASDAIb 50 15 % 35 %** 
ASDASc,d,e -0.3 -1.0*** 
ASDAS inactive disease 4 % 24 %*** 
hs-CRPd,f,g -0.3 -4.7*** 
SPARCCh MRI sacroiliac jointsd,i -0.6 -3.2** 
SPARCC MRI spined,j -0.2 -1.8** 

a 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. These patients also had objective evidence of inflammation in the sacroiliac joints or 



35 

 

spine on MRI or elevated hs-CRP. Patients who achieved sustained remission for at least 12 weeks 
(N=305) (ASDAS < 1.3 at weeks 16, 20, 24, and 28) during the open-label period were then 
randomized to receive either continued treatment with adalimumab 40 mg eow (N=152) or placebo 
(N=153) for an additional 40 weeks in a double-blind, placebo-controlled period (total study duration 
68 weeks). Subjects who flared during the double-blind period were allowed adalimumab 40 mg eow 
rescue therapy for at least 12 weeks. 
 
The primary efficacy endpoint was the proportion of patients with no flare by Week 68 of the study. 
Flare was defined as ASDAS ≥ 2.1 at two consecutive visits four weeks apart. A greater proportion 
of patients on adalimumab had no disease flare during the double-blind period, when compared with 
those on placebo (70.4% vs. 47.1%, p<0.001) (Figure 1). 

Figure 1: Kaplan-Meier Curves summarizing time to flare in study nr-axSpA II 

   
   

   
   

   
   

 P
R

O
B

A
B

IL
IT

Y
 O

F 
N

O
 F

L
A

R
E

 

 
                                                                             TIME (WEEKS) 
                                   Treatment        Placebo        Adalimumab       ∆ Censored 
 
Note: P = Placebo (Number at Risk (flared)); A = Adalimumab (Number at Risk (flared)). 
 
Among the 68 patients who flared in the group allocated to treatment withdrawal, 65 completed 
12 weeks of rescue therapy with adalimumab, out of which 37 (56.9%) had regained remission 
(ASDAS < 1.3) after 12 weeks of restarting the open-label treatment.  
 
By week 68, patients receiving continuous adalimumab treatment showed statistically significant 
greater improvement of the signs and symptoms of active nr-axSpA as compared to patients allocated 
to treatment withdrawal during the double-blind period of the study (table 15). 
 



36 

 

Table 15 
efficacy response in placebo-controlled period for study nr-axSpA II 

double-blind 

response at week 68 

placebo 

N=153 

adalimumab 

N=152 

ASASa,b 20 47.1 % 70.4 %*** 

ASASa,b 40 45.8 % 65.8 %*** 

ASASa partial remission 26.8 % 42.1 %** 

ASDASc inactive disease 33.3 % 57.2 %*** 

partial flared 64.1 % 40.8 %*** 

a assessment of SpondyloArthritis International Society 
b baseline is defined as open label baseline when patients have active disease. 
c Ankylosing Spondylitis Disease Activity Score 
d partial flare is defined as ASDAS ≥ 1.3 but < 2.1 at 2 consecutive visits. 
***, ** statistically significant at p < 0.001 and < 0.01, respectively, for all comparisons between 
adalimumab and placebo. 
 
Psoriatic arthritis 
 
Adalimumab, 40 mg every other week, was studied in patients with moderately to severely active 
psoriatic arthritis in two placebo-controlled studies, PsA studies I and II. PsA study I with 24 week 
duration, treated 313 adult patients who had an inadequate response to non-steroidal anti-
inflammatory drug therapy and of these, approximately 50 % were taking methotrexate. PsA study 
II with 12-week duration, treated 100 patients who had an inadequate response to DMARD therapy. 
Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 
40 mg adalimumab was administered every other week (eow). 
 
There is insufficient evidence of the efficacy of adalimumab in patients with ankylosing 
spondylitis-like psoriatic arthropathy due to the small number of patients studied. 
 

Table 16 
ACR response in placebo-controlled psoriatic arthritis studies 

 (percent of patients) 
 PsA study I PsA study II 
 

response placebo N=162 
adalimumab 
N=151 

placebo 
N=49 

adalimumab 
N=51 

ACR 20 
week 12 
week 24 

ACR 50 
week 12 
week 24 

ACR 70 
week 12 
week 24 

 
14 % 
15 % 

 
4 % 
6 % 

 
1 % 
1 % 

 
58 %*** 
57 %*** 

 
36 %*** 
39 %*** 

 
20 %*** 
23 %*** 

 
16 % 
N/A 

 
2 % 
N/A 

 
0 % 
N/A 

 
39 %* 
N/A 

 
25 %*** 

N/A 
 

14 % * 
N/A 

*** p < 0.001 for all comparisons between adalimumab and placebo  
* p < 0.05 for all comparisons between adalimumab and placebo 
N/A not applicable 
 



37 

 

ACR responses in PsA study I were similar with and without concomitant methotrexate therapy. 
ACR responses were maintained in the open-label extension study for up to 136 weeks. 
 
Radiographic changes were assessed in the psoriatic arthritis studies. Radiographs of hands, wrists, 
and feet were obtained at baseline and week 24 during the double-blind period when patients were on 
adalimumab or placebo and at week 48 when all patients were on open-label adalimumab. A modified 
Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e. not identical to the TSS 
used for rheumatoid arthritis), was used. 
 
Adalimumab treatment reduced the rate of progression of peripheral joint damage compared with 
placebo treatment as measured by change from baseline in mTSS (mean ± SD) 0.8 ± 2.5 in the 
placebo group (at week 24) compared with 0.0 ± 1.9; (p < 0.001) in the adalimumab group (at week 
48). 
 
In subjects treated with adalimumab with no radiographic progression from baseline to week 48 
(n=102), 84 % continued to show no radiographic progression through 144 weeks of treatment. 
Adalimumab-treated patients demonstrated statistically significant improvement in physical function 
as assessed by HAQ and Short Form Health Survey (SF 36) compared to placebo at week 24. 
Improved physical function continued during the open label extension up to week 136. 
 
Psoriasis 
 
The safety and efficacy of adalimumab were studied in adult patients with chronic plaque psoriasis 
(≥ 10 % BSA involvement and Psoriasis Area and Severity Index (PASI) ≥ 12 or ≥ 10) who were 
candidates for systemic therapy or phototherapy in randomised, double-blind studies. 73 % of patients 
enrolled in Psoriasis Studies I and II had received prior systemic therapy or phototherapy. The safety 
and efficacy of adalimumab were also studied in adult patients with moderate to severe chronic 
plaque psoriasis with concomitant hand and / or foot psoriasis who were candidates for systemic 
therapy in a randomised double-blind study (Psoriasis Study III). 
 
Psoriasis Study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A, 
patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other 
week starting one week after the initial dose. After 16 weeks of therapy, patients who achieved at 
least a PASI 75 response (PASI score improvement of at least 75 % relative to baseline), entered 
period B and received open-label 40 mg adalimumab every other week. Patients who maintained 
≥PASI 75 response at week 33 and were originally randomised to active therapy in period A, were 
re-randomised in period C to receive 40 mg adalimumab every other week or placebo for an 
additional 19 weeks. Across all treatment groups, the mean baseline PASI score was 18.9 and the 
baseline Physician’s Global Assessment (PGA) score ranged from “moderate” (53 % of subjects 
included) to “severe” (41 %) to “very severe” (6 %). 
 
Psoriasis Study II (CHAMPION) compared the efficacy and safety of adalimumab versus 
methotrexate and placebo in 271 patients. Patients received placebo, an initial dose of MTX 7.5 mg 
and thereafter dose increases up to week 12, with a maximum dose of 25 mg or an initial dose of 
80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) for 
16 weeks. There are no data available comparing adalimumab and MTX beyond 16 weeks of therapy. 
Patients receiving MTX who achieved a ≥PASI 50 response at week 8 and / or 12 did not receive 
further dose increases. Across all treatment groups, the mean baseline PASI score was 19.7 and the 
baseline PGA score ranged from “mild” (< 1 %) to “moderate” (48 %) to “severe” (46 %) to “very 
severe” (6 %). 
 
Patients participating in all Phase 2 and Phase 3 psoriasis studies were eligible to enrol into an open- 
label extension trial, where adalimumab was given for at least an additional 108 weeks. 
 
In Psoriasis Studies I and II, a primary endpoint was the proportion of patients who achieved a 
PASI 75 response from baseline at Week 16 (see tables 17 and 18). 
 



38 

 

Table 17 
Ps study I (REVEAL) – efficacy results at 16 weeks 

 placebo N = 398 
n (%) 

adalimumab 40 mg eow 
N = 814 n (%) 

≥PASI 75a 26 (6.5) 578 (70.9)b 
PASI 100 3 (0.8) 163 (20.0)b 
PGA: clear / minimal 17 (4.3) 506 (62.2)b 

a percent of patients achieving PASI75 response was calculated as centre-
adjusted rate 
b p<0.001, adalimumab vs. placebo 

 
 

Table 18 
Ps study II (CHAMPION) efficacy results at 16 weeks 

 placebo 
N = 53 n (%) 

MTX N = 110 
n (%) 

adalimumab 40 mg eow 
N=108 n (%) 

≥PASI 75 10 (18.9) 39 (35.5) 86 (79.6) a, b 
PASI 100 1 (1.9) 8 (7.3) 18 (16.7) c, d 
PGA: 

clear/minimal 
6 (11.3) 33 (30.0) 79 (73.1) a, b 

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

 
 
In Psoriasis Study I, 28 % of patients who were PASI 75 responders and were re-randomised to 
placebo at week 33 compared to 5 % continuing on adalimumab, p < 0.001, experienced “loss of 
adequate response” (PASI score after week 33 and on or before week 52 that resulted in a < PASI 50 
response relative to baseline with a minimum of a 6-point increase in PASI score relative to week 
33). Of the patients who lost adequate response after re-randomisation to placebo who then enrolled 
into the open-label extension trial, 38 % (25 / 66) and 55 % (36 / 66) regained PASI 75 response 
after 12 and 24 weeks of re-treatment, respectively. 
 
A total of 233 PASI 75 responders at week 16 and week 33 received continuous adalimumab therapy 
for 52 weeks in Psoriasis Study I, and continued adalimumab in the open-label extension trial. PASI 75 
and PGA of clear or minimal response rates in these patients were 74.7 % and 59.0 %, respectively, 
after an additional 108 weeks of open-label therapy (total of 160 weeks). In an analysis in which all 
patients who dropped out of the study for adverse events or lack of efficacy, or who dose-escalated, 
were considered non-responders, PASI 75 and PGA of clear or minimal response rates in these patients 
were 69.6 % and 55.7 %, respectively, after an additional 108 weeks of open-label therapy (total of 
160 weeks). 
 
A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open- 
label extension study. During the withdrawal period, symptoms of psoriasis returned over time with 
a median time to relapse (decline to PGA “moderate” or worse) of approximately 5 months. None of 
these patients experienced rebound during the withdrawal period. A total of 76.5 % (218 / 285) of 
patients who entered the retreatment period had a response of PGA “clear” or “minimal” after 16 
weeks of retreatment, irrespective of whether they relapsed during withdrawal (69.1 % [123 / 178] 
and 88.8 % [95 / 107] for patients who relapsed and who did not relapse during the withdrawal 
period, respectively). A similar safety profile was observed during retreatment as before withdrawal. 
Significant improvements at week 16 from baseline compared to placebo (Studies I and II) and MTX 
(Study II) were demonstrated in the DLQI (Dermatology Life Quality Index). In Study I, 
improvements in the physical and mental component summary scores of the SF-36 were also 



39 

 

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. 
 
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). 
 



40 

 

Table 20 
paediatric plaque psoriasis efficacy results at 16 weeks 

  MTXa 
N = 37 

adalimumab 0.8 mg / kg eow 
N=38 

PASI 75b 12 (32.4 %) 22 (57.9 %) 
PGA: clear/minimalc 15 (40.5 %) 23 (60.5 %) 

a MTX = methotrexate 
b p = 0.027, adalimumab 0.8 mg / kg versus MTX 
c p = 0.083, adalimumab 0.8 mg / kg versus MTX 

 
 
Patients who achieved PASI 75 and PGA clear or minimal were withdrawn from treatment for up to 
36 weeks and monitored for loss of disease control (i.e. a worsening of PGA by at least 2 grades). 
Patients were then re-treated with adalimumab 0.8 mg / kg eow for an additional 16 weeks and 
response rates observed during retreatment were similar to the previous double-blind period: PASI 75 
response of 78.9 % (15 of 19 subjects) and PGA clear or minimal of 52.6 % (10 of 19 subjects). 
 
In the open label period of the study, PASI 75 and PGA clear or minimal responses were 
maintained for up to an additional 52 weeks with no new safety findings. 
 
Hidradenitis suppurativa 
 
The safety and efficacy of adalimumab were assessed in randomised, double-blind, placebo-controlled 
studies and an open-label extension study in adult patients with moderate to severe hidradenitis 
suppurativa (HS) who were intolerant, had a contraindication or an inadequate response to at least a 
3-month trial of systemic antibiotic therapy. The patients in HS-I and HS-II had Hurley Stage II or III 
disease with at least 3 abscesses or inflammatory nodules. 
 
Study HS-I (PIONEER I) evaluated 307 patients with 2 treatment periods. In period A, patients 
received placebo or adalimumab at an initial dose of 160 mg at week 0, 80 mg at week 2, and 40 mg 
every week starting at week 4 to week 11. Concomitant antibiotic use was not allowed during the 
study. After 12 weeks of therapy, patients who had received adalimumab in period A were re-
randomised in period B to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 
40 mg every other week, or placebo from week 12 to week 35). Patients who had been randomised to 
placebo in period A were assigned to receive adalimumab 40 mg every week in period B. 
 
Study HS-II (PIONEER II) evaluated 326 patients with 2 treatment periods. In period A, patients 
received placebo or adalimumab at an initial dose of 160 mg at week 0 and 80 mg at week 2 and 
40 mg every week starting at week 4 to week 11. 19.3 % of patients had continued baseline oral 
antibiotic therapy during the study. After 12 weeks of therapy, patients who had received 
adalimumab in period A were re-randomised in period B to 1 of 3 treatment groups (adalimumab 
40 mg every week, adalimumab 40 mg every other week, or placebo from week 12 to week 35). 
Patients who had been randomised to placebo in period A were assigned to receive placebo in 
period B. 
 
Patients participating in Studies HS-I and HS-II were eligible to enrol into an open-label extension 
study in which adalimumab 40 mg was administered every week. Mean exposure in all adalimumab 
population was 762 days. Throughout all 3 studies patients used topical antiseptic wash daily. 
 
Clinical Response 
 
Reduction of inflammatory lesions and prevention of worsening of abscesses and draining fistulas 
was assessed using Hidradenitis Suppurativa Clinical Response (HiSCR; at least a 50 % reduction in 
total abscess and inflammatory nodule count with no increase in abscess count and no increase in 
draining fistula count relative to Baseline). Reduction in HS-related skin pain was assessed using a 
Numeric Rating Scale in patients who entered the study with an initial baseline score of 3 or greater 
on a 11 point scale. 



41 

 

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

Table 21 
efficacy results at 12 weeks, HS studies I and II 

 HS study I HS study II 
 

placebo 
adalimumab 

40 mg 
weekly 

 
placebo 

adalimumab 
40 mg 
weekly 

hidradenitis suppurativa 
clinical response (HiSCR)a 

N = 154 
40 (26.0 %) 

N = 153 
64 (41.8 %)* 

N = 163 
45 (27.6 %) 

N = 163 
96 (58.9 %)*** 

≥30% reduction in skin 
painb 

N = 109 
27 (24.8 %) 

N = 122 
34 (27.9 %) 

N = 111 
23 (20.7 %) 

N = 105 
48 (45.7 %)*** 

* p < 0.05,  
*** p < 0.001, adalimumab versus placebo 
a among all randomised patients. 
b among patients with baseline HS-related skin pain assessment ≥ 3, based on Numeric Rating Scale 0–10; 

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

Treatment with adalimumab 40 mg every week significantly reduced the risk of worsening of 
abscesses and draining fistulas. Approximately twice the proportion of patients in the placebo group 
in the first 12 weeks of Studies HS-I and HS-II, compared with those in the adalimumab group 
experienced worsening of abscesses (23.0 % vs 11.4 %, respectively) and draining fistulas (30.0 % 
vs 13.9 %, respectively). 
 
Greater improvements at week 12 from baseline compared to placebo were demonstrated in 
skin-specific health-related quality of life, as measured by the Dermatology Life Quality Index 
(DLQI; Studies HS-I and HS-II), patient global satisfaction with medication treatment as 
measured by the Treatment Satisfaction Questionnaire – medication (TSQM; Studies HS-I and 
HS-II), and physical health as measured by the physical component summary score of the SF-36 
(Study HS-I). 
 
In patients with at least a partial response to adalimumab 40 mg weekly at week 12, the HiSCR 
rate at week 36 was higher in patients who continued weekly adalimumab than in patients in 
whom dosing frequency was reduced to every other week, or in whom treatment was withdrawn 
(see table 22). 
 



42 

 

Table 22 
proportion of patientsa achieving HiSCRb at weeks 24 and 36 after 

treatment reassignment from weekly adalimumab at week 12 

 placebo 
(treatment 

withdrawal) 
N = 73 

adalimumab 
40 mg every 
other week 

N = 70 

adalimumab 
40 mg weekly 

N = 70 

week 24 24 (32.9 %) 36 (51.4 %) 40 (57.1 %) 
week 36 22 (30.1 %) 28 (40.0 %) 39 (55.7 %) 

a patients with at least a partial response to adalimumab 40 mg weekly after
  12 weeks of treatment. 
b patients meeting protocol-specified criteria for loss of response or no 

improvement were required to discontinue from the studies and were counted as 
non-responders. 

 
 
Among patients who were at least partial responders at week 12, and who received continuous weekly 
adalimumab therapy, the HiSCR rate at week 48 was 64.3 % and at week 96 was 65.1 %. Longer term 
treatment with adalimumab 40 mg weekly for 96 weeks identified no new safety findings.  
 
Among patients whose adalimumab treatment was withdrawn at week 12 in Studies HS-I and 
HS-II, the HiSCR rate 12 weeks after re-introduction of adalimumab 40 mg weekly returned 
to levels similar to that observed before withdrawal (56.0 %). 
 
Adolescent hidradenitis suppurativa 
 
There are no clinical trials with adalimumab in adolescent patients with HS. Efficacy of adalimumab 
for the treatment of adolescent patients with HS is predicted based on the demonstrated efficacy and 
exposure-response relationship in adult HS patients and the likelihood that the disease course, 
pathophysiology, and drug effects are substantially similar to that of adults at the same exposure 
levels. Safety of the recommended adalimumab dose in the adolescent HS population is based on 
cross-indication safety profile of adalimumab in both adults and paediatric patients at similar or more 
frequent doses (see section 5.2). 
 
Crohn’s disease 
 
The safety and efficacy of adalimumab were assessed in over 1500 patients with moderately to 
severely active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in 
randomised, double-blind, placebo-controlled studies. Concomitant stable doses of 
aminosalicylates, corticosteroids, and / or immunomodulatory agents were permitted and 80 % of 
patients continued to receive at least one of these medications. 
 
Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies, CD Study I 
(CLASSIC I) and CD Study II (GAIN). In CD Study I, 299 TNF-antagonist naïve 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 



43 

 

of 56 weeks. Patients in clinical response (decrease in CDAI ≥ 70) at week 4 were stratified and 
analysed separately from those not in clinical response at week 4. Corticosteroid taper was 
permitted after week 8. 
 
CD study I and CD study II induction of remission and response rates are presented in table 23. 
 

Table 23 
induction of clinical remission and response  

(percent of patients) 
 CD study I: infliximab-naïve 

patients 
CD study II: infliximab-
experienced patients 

 placebo 
N = 74 

adalimumab
80 / 40 mg 

N = 75 

adalimumab 
160 / 80 mg 

N = 76 

placebo 
N=166 

adalimumab 
160 / 80 mg 

N = 159 

week 4      
clinical remission 12 % 24 % 36 %* 7 % 21 %* 
clinical response (CR- 
100) 

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

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

 
 
Similar remission rates were observed for the 160 / 80 mg and 80 / 40 mg induction regimens by 
week 8 and adverse events were more frequently noted in the 160 / 80 mg group. 
 
In CD study III, at week 4, 58 % (499 / 854) of patients were in clinical response and were assessed 
in the primary analysis. Of those in clinical response at week 4, 48 % had been previously exposed 
to other TNF-antagonists. Maintenance of remission and response rates are presented in table 24. 
Clinical remission results remained relatively constant irrespective of previous TNF-antagonist 
exposure. Disease-related hospitalisations and surgeries were statistically significantly reduced with 
adalimumab compared with placebo at week 56. 
 



44 

 

Table 24 
maintenance of clinical remission and response 

(percent of patients) 
 placebo 40 mg adalimumab 

every other week 
40 mg adalimumab 

every week 

week 26 N = 170 N = 172 N = 157 
clinical remission 17 % 40 %* 47 %* 
clinical response (CR-100) 27 % 52 %* 52 %* 

patients in steroid-free remission 
for > = 90 daysa 

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

week 56 N = 170 N = 172 N = 157 
clinical remission 12 % 36 %* 41 %* 
clinical response (CR-100) 17 % 41 %* 48 %* 

patients in steroid-free remission 
for > = 90 daysa 

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

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

 
 
Among patients who were not in response at week 4, 43 % of adalimumab maintenance patients 
responded by week 12 compared to 30 % of placebo maintenance patients. These results suggest that 
some patients who have not responded by Week 4 benefit from continued maintenance therapy 
through Week 12. Therapy continued beyond 12 weeks did not result in significantly more 
responses (see section 4.2). 
 
117 / 276 patients from CD study I and 272 / 777 patients from CD studies II and III were 
followed through at least 3 years of open-label adalimumab therapy. 88 and 189 patients, 
respectively, continued to be in clinical remission. Clinical response (CR-100) was maintained 
in 102 and 233 patients, respectively. 
 
Quality of life 
 
In CD study I and CD study II, statistically significant improvement in the disease-specific 
inflammatory bowel disease questionnaire (IBDQ) total score was achieved at week 4 in patients 
randomised to adalimumab 80 / 40 mg and 160 / 80 mg compared to placebo and was seen at 
weeks 26 and 56 in CD study III as well among the adalimumab treatment groups compared to the 
placebo group. 
 
Paediatric Crohn’s disease 
 
Adalimumab was assessed in a multicentre, randomised, double-blind clinical trial designed to 
evaluate the efficacy and safety of induction and maintenance treatment with doses dependent on 
body weight (< 40 kg or ≥ 40 kg) in 192 paediatric subjects between the ages of 6 and 
17 (inclusive) years, with moderate to severe Crohn’s disease (CD) defined as Paediatric Crohn’s 
Disease Activity Index (PCDAI) score > 30. Subjects had to have failed conventional therapy 
(including a corticosteroid and/or an immunomodulator) for CD. Subjects may also have previously 
lost response or been intolerant to infliximab. 
 
All subjects received open-label induction therapy at a dose based on their Baseline body weight: 
160 mg at week 0 and 80 mg at week 2 for subjects ≥ 40 kg, and 80 mg and 40 mg, respectively, for 
subjects < 40 kg. 
 



45 

 

At week 4, subjects were randomised 1:1 based on their body weight at the time to either the Low 
Dose or Standard Dose maintenance regimens as shown in table 25. 
 

Table 25 
maintenance regimen 

patient 
weight 

low dose standard 
dose 

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

 
Efficacy results 
 
The primary endpoint of the study was clinical remission at week 26, defined as PCDAI score ≤ 10. 
 
Clinical remission and clinical response (defined as reduction in PCDAI score of at least 15 points 
from Baseline) rates are presented in table 26. Rates of discontinuation of corticosteroids or 
immunomodulators are presented in table 27. 
 

Table 26 
paediatric CD study 

PCDAI clinical remission and response 
 standard dose 

40 / 20 mg 
eow 

N = 93 

low dose 
20 / 10 mg 

eow 
N = 95 

p value* 

week 26    
clinical remission 38.7 % 28.4 % 0.075 
clinical response 59.1 % 48.4 % 0.073 

week 52    
clinical remission 33.3 % 23.2 % 0.100 
clinical response 41.9 % 28.4 % 0.038 

* p-value for standard dose versus low dose comparison. 

 
 



46 

 

Table 27 
paediatric CD study 

discontinuation of corticosteroids or immunomodulators and fistula remission 
 standard dose 

40 / 20 mg eow 
low dose 

20 / 10 mg eow 
p value1 

discontinued corticosteroids N = 33 N = 38  

week 26 84.8 % 65.8 % 0.066 
week 52 69.7 % 60.5 % 0.420 
discontinuation of Immunomodulators2 N = 60 N = 57  

week 52 30.0 % 29.8 % 0.983 
fistula remission3 N = 15 N = 21  

week 26 46.7 % 38.1 % 0.608 
week 52 40.0 % 23.8 % 0.303 
1 p value for standard dose versus low dose comparison. 
2 immunosuppressant therapy could only be discontinued at or after week 26 

at the investigator's discretion if the subject met the clinical response 
criterion 

3 defined as a closure of all fistulas that were draining at Baseline for at least 2 consecutive 
post-Baseline visits 

 
 
Statistically significant increases (improvement) from Baseline to week 26 and 52 in Body Mass 
Index and height velocity were observed for both treatment groups. 
 
Statistically and clinically significant improvements from Baseline were also observed in both 
treatment groups for quality of life parameters (including IMPACT III). 
 
One hundred patients (n = 100) from the Paediatric CD Study continued in an open-label long-term 
extension study. After 5 years of adalimumab therapy, 74.0 % (37 / 50) of the 50 patients remaining 
in the study continued to be in clinical remission, and 92.0 % (46 / 50) of patients continued to be in 
clinical response per PCDAI. 
 
Ulcerative colitis 
 
The safety and efficacy of multiple doses of adalimumab were assessed in adult patients with 
moderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopy subscore of 2 to 
3) in randomised, double-blind, placebo-controlled studies. 
 
In study UC-I, 390 TNF-antagonist naïve patients were randomised to receive either placebo at 
weeks 0 and 2, 160 mg adalimumab at week 0 followed by 80 mg at week 2, or 80 mg adalimumab at 
week 0 followed by 40 mg at week 2. After week 2, patients in both adalimumab arms received 40 mg 
eow. Clinical remission (defined as Mayo score ≤ 2 with no subscore > 1) was assessed at week 8. 
 
In study UC-II, 248 patients received 160 mg of adalimumab at week 0, 80 mg at week 2 and 40 mg 
eow thereafter, and 246 patients received placebo. Clinical results were assessed for induction of 
remission at week 8 and for maintenance of remission at week 52. 
 
Patients induced with 160 / 80 mg adalimumab achieved clinical remission versus placebo at week 
8 in statistically significantly greater percentages in study UC-I (18 % vs. 9 % respectively, 
p = 0.031) and study UC-II (17 % vs. 9 % respectively, p = 0.019). In study UC-II, among those 
treated with adalimumab who were in remission at week 8, 21 / 41 (51 %) were in remission at 
week 52. 



47 

 

 
Results from the overall UC-II study population are shown in table 28. 
 

Table 28 
response, remission and mucosal healing in study UC-II  

(percent of patients)  
 placebo adalimumab 40 mg 

eow 
week 52 N = 246 N = 248 
clinical response 18 % 30 %* 
clinical remission 9 % 17 %* 
mucosal healing 15 % 25 %* 
steroid-free remission for ≥ 90 daysa 6 % 13 %* 
 (N = 140) (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. 
 
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 



48 

 

the initial dose. Concomitant stable doses of one non-biologic immunosuppressant were permitted. 
 
Study UV I evaluated 217 patients with active uveitis despite treatment with corticosteroids (oral 
prednisone at a dose of 10 to 60 mg / day). All patients received a 2-week standardised dose of 
prednisone 60 mg / day at study entry followed by a mandatory taper schedule, with complete 
corticosteroid discontinuation by week 15. 
 
Study UV II evaluated 226 patients with inactive uveitis requiring chronic corticosteroid treatment 
(oral prednisone 10 to 35 mg / day) at baseline to control their disease. Patients subsequently 
underwent a mandatory taper schedule, with complete corticosteroid discontinuation by week 19. 
 
The primary efficacy endpoint in both studies was ‘time to treatment failure’. Treatment failure was 
defined by a multi-component outcome based on inflammatory chorioretinal and/or inflammatory 
retinal vascular lesions, anterior chamber (AC) cell grade, vitreous haze (VH) grade and best 
corrected visual acuity (BCVA). 
 
Clinical Response 
 
Results from both studies demonstrated statistically significant reduction of the risk of treatment 
failure in patients treated with adalimumab versus patients receiving placebo (see table 29). Both 
studies demonstrated an early and sustained effect of adalimumab on the treatment failure rate versus 
placebo (see Figure 2). 
 

Table 29  
time to treatment failure in studies UV I and UV II 

analysis N failure median time to HRa CI 95 % p Value b 
treatment  N (%) failure (months)  for HRa  

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. 

 



49 

 

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

  

 
 

 
Note: P# = Placebo (Number of Events/Number at Risk); A# = Adalimumab (Number of 
Events/Number at Risk). 
 
In Study UV I statistically significant differences in favour of adalimumab versus placebo were 
observed for each component of treatment failure. In Study UV II, statistically significant differences 
were observed for visual acuity only, but the other components were numerically in favour of 
adalimumab. 
 
Of the 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. 



50 

 

 
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 UV I and for 
colour vision, peripheral vision and near vision in study UV II.  
 
Paediatric Uveitis 
 
The safety and efficacy of adalimumab was assessed in a randomized, double-masked, controlled 
study of 90 paediatric patients from 2 to < 18 years of age with active JIA-associated non-infectious 
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]). 

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

 



51 

 

 
Immunogenicity 
 
Anti-adalimumab antibodies may develop during adalimumab treatment. 
Formation of anti-adalimumab antibodies is associated with increased clearance and reduced 
efficacy of adalimumab. There is no apparent correlation between the presence of anti-adalimumab 
antibodies and the occurrence of adverse events. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of the studies with 
the reference medicinal product containing adalimumab in one or more subsets of the paediatric 
population in ulcerative colitis (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption and distribution 
 
After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab 
was slow, with peak serum concentrations being reached about 5 days after administration. The 
average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg 
subcutaneous dose was 64 %. After single intravenous doses ranging from 0.25 to 10 mg / kg, 
concentrations were dose proportional. After doses of 0.5 mg / kg (~40 mg), clearances ranged from 
11 to 15 ml / hour, the distribution volume (Vss) ranged from 5 to 6 litres and the mean terminal 
phase half-life was approximately two weeks. Adalimumab concentrations in the synovial fluid from 
several rheumatoid arthritis patients ranged from 31–96 % of those in serum. 
 
Following subcutaneous administration of 40 mg of adalimumab every other week in adult 
rheumatoid arthritis (RA) patients the mean steady-state trough concentrations were 
approximately 5 µg / ml (without concomitant methotrexate) and 8 to 9 µg / ml (with concomitant 
methotrexate), respectively. The serum adalimumab trough levels at steady-state increased roughly 
proportionally with dose following 20, 40 and 80 mg subcutaneous dosing every other week and 
every week. 
 
Following the administration of 24 mg / m2 (up to a maximum of 40 mg) subcutaneously every other 
week to patients with polyarticular juvenile idiopathic arthritis (JIA) who were 4 to 17 years the mean 
trough steady-state (values measured from week 20 to 48) serum adalimumab concentration was 
5.6 ± 5.6 µg / ml (102 % CV) for adalimumab without concomitant methotrexate and 
10.9 ± 5.2 µg / ml (47.7 % CV) with concomitant methotrexate. 
 
In patients with polyarticular JIA who were 2 to < 4 years old or aged 4 and above 
weighing < 15 kg dosed with adalimumab 24 mg / m2, the mean trough steady-state serum 
adalimumab concentrations was 6.0 ± 6.1 µg / ml (101 % CV) for adalimumab without 
concomitant methotrexate and 7.9 ± 5.6 µg / ml (71.2 % CV) with concomitant methotrexate. 
 
Following the administration of 24 mg / m2 (up to a maximum of 40 mg) subcutaneously every other 
week to patients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state 
(values measured at week 24) serum adalimumab concentrations were 8.8 ± 6.6 μg / ml for 
adalimumab without concomitant methotrexate and 11.8 ± 4.3 μg / ml with concomitant 
methotrexate. 
 
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). 



52 

 

 
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 hidradenitis suppurativa, a dose of 160 mg adalimumab on week 0 followed by 
80 mg on week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 μg / ml 
at week 2 and week 4. The mean steady-state trough concentration at week 12 through week 36 were 
approximately 8 to 10 μg / ml during adalimumab 40 mg every week treatment. 
 
Adalimumab exposure in adolescent HS patients was predicted using population pharmacokinetic 
modelling and simulation based on cross-indication pharmacokinetics in other paediatric patients 
(paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn’s disease, and enthesitis-related 
arthritis). The recommended adolescent HS dosing schedule is 40 mg every other week. Since 
exposure to adalimumab can be affected by body size, adolescents with higher body weight and 
inadequate response may benefit from receiving the recommended adult dose of 40 mg every week.  
 
In patients with Crohn’s disease, the loading dose of 80 mg adalimumab on week 0 followed by 
40 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 
5.5 µg / ml during the induction period. A loading dose of 160 mg adalimumab on week 0 followed 
by 80 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 
12 µg / ml during the induction period. Mean steady-state trough levels of approximately 7 µg / ml 
were observed in Crohn’s disease patients who received a maintenance dose of 40 mg adalimumab 
every other week. 
 
In paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was 
160 / 80 mg or 80 / 40 mg at weeks 0 and 2, respectively, dependent on a body weight cut-off of 
40 kg. At week 4, patients were randomised 1:1 to either the Standard Dose (40 / 20 mg eow) or 
Low Dose (20 / 10 mg eow) maintenance treatment groups based on their body weight. The mean 
(± SD) serum adalimumab trough concentrations achieved at week 4 were 15.7±6.6 µg/ml for 
patients ≥ 40 kg (160 / 80 mg) and 10.6 ± 6.1 µg / ml for patients < 40 kg (80 / 40 mg). 
 
For patients who stayed on their randomised therapy, the mean (± SD) adalimumab trough 
concentrations at week 52 were 9.5 ± 5.6 µg / ml for the Standard Dose group and 3.5 ± 2.2 µg / ml 
for the Low Dose group. The mean trough concentrations were maintained in patients who continued 
to receive adalimumab treatment eow for 52 weeks. For patients who dose-escalated from eow to 
weekly regimen, the mean (± SD) serum concentrations of adalimumab at week 52 were 
15.3 ± 11.4 μg / ml (40 / 20 mg, weekly) and 6.7 ± 3.5 μg / ml (20 / 10 mg, weekly). 
 
In patients with ulcerative colitis, a loading dose of 160 mg adalimumab on week 0 followed by 80 mg 
adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 12 µg / ml 
during the induction period. Mean steady-state trough levels of approximately 8 µg / ml were 
observed in ulcerative colitis patients who received a maintenance dose of 40 mg adalimumab every 
other week. 
 
In adult patients with uveitis, a loading dose of 80 mg adalimumab on week 0 followed by 40 mg 
adalimumab every other week starting at week 1, resulted in mean steady-state concentrations of 
approximately 8 to 10 µg/ml. 
 
Adalimumab exposure in paediatric uveitis patients was predicted using population pharmacokinetic 
modelling and simulation based on cross-indication pharmacokinetics in other paediatric patients 
(paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn’s disease, and enthesitis-related 
arthritis). No clinical exposure data are available on the use of a loading dose in children < 6 years. 
The predicted exposures indicate that in the absence of methotrexate, a loading dose may lead to an 
initial increase in systemic exposure. 
 
Population pharmacokinetic and pharmacokinetic / pharmacodynamic modelling and simulation 



53 

 

predicted comparable adalimumab exposure and efficacy in patients treated with 80 mg every other 
week when compared with 40 mg every week (including adult patients with RA, HS, UC, CD or Ps, 
patients with adolescent HS, and paediatric patients ≥ 40 kg with CD). 
 
Exposure-response relationship in paediatric population 
 
On the basis of clinical trial data in patients with JIA (pJIA and ERA), an exposure-response 
relationship was established between plasma concentrations and PedACR 50 response. The apparent 
adalimumab plasma concentration that produces half the maximum probability of PedACR 50 
response (EC50) was 3 μg/ml (95% CI: 1-6 μg/ml). 
 
Exposure-response relationships between adalimumab concentration and efficacy in paediatric patients 
with severe chronic plaque psoriasis were established for PASI 75 and PGA clear or minimal, 
respectively. PASI 75 and PGA clear or minimal increased with increasing adalimumab 
concentrations, both with a similar apparent EC50 of approximately 4.5 μg/mL (95% CI 0.4-47.6 and 
1.9-10.5, respectively). 
 
Elimination 
 
Population pharmacokinetic analyses with data from over 1,300 RA patients revealed a trend toward 
higher apparent clearance of adalimumab with increasing body weight. After adjustment for weight 
differences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum 
levels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be 
lower in patients with measurable AAA. 
 
Hepatic or renal impairment 
 
Adalimumab has not been studied in patients with hepatic or renal impairment. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of single dose toxicity, 
repeated dose toxicity, and genotoxicity. 
 
An embryo-foetal developmental toxicity / perinatal developmental study has been performed in 
cynomolgus monkeys at 0, 30 and 100 mg / kg (9–17 monkeys / group) and has revealed no 
evidence of harm to the foetuses due to adalimumab. Neither carcinogenicity studies, nor a standard 
assessment of fertility and postnatal toxicity, were performed with adalimumab due to the lack of 
appropriate models for an antibody with limited cross-reactivity to rodent TNF and to the 
development of neutralising antibodies in rodents. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Adipic acid 
Citric acid monohydrate 
Sodium chloride 
Mannitol 
Polysorbate 80 
Hydrochloric acid (for pH adjustment) 
Sodium hydroxide (for pH adjustment) 
Water for injections 
 
 



54 

 

6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other 
medicinal products. 
 
6.3 Shelf life 
 
30 months 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C–8°C). Do not freeze. Keep the pre-filled syringe / pre-filled pen in 
the outer carton in order to protect from light. Do not shake. 
 
A single Hefiya pre-filled syringe / pre-filled pen may be stored at temperatures up to a maximum of 
25°C for a period of up to 14 days. The pre-filled syringe / pre-filled pen must be protected from 
light, and discarded if not used within the 14-day period. 
 
6.5 Nature and contents of container 
 
Hefiya 20 mg solution for injection in a single-use pre-filled syringe 
 
Hefiya is supplied in a single-use clear type I glass syringe with a rubber stopper and a stainless steel 
needle with an automatic needle guard with finger flange, rubber needle cap and plastic plunger, 
containing 0.4 ml solution.  
 
Pack of 2 pre-filled syringes in a blister 
 
Hefiya 40 mg solution for injection in a single-use pre-filled syringe 
Hefiya is supplied in a single-use clear type I glass syringe with a rubber stopper and a stainless steel 
needle with an automatic needle guard with finger flange, rubber needle cap and plastic plunger, 
containing 0.8 ml solution.  
 
Packs of 1 and 2 pre-filled syringes in a blister 
Multipack containing 6 (3 packs of 2) pre-filled syringes in a blister 
 
Hefiya 40 mg solution for injection in single-use pre-filled SensoReady pen  
Hefiya is supplied in a single-use pre-filled syringe assembled into a triangular-shaped pen with 
transparent window and label (SensoReady). The syringe inside the pen is made of type I glass with a 
stainless steel needle, an inner rubber needle cap, and a rubber stopper, containing 0.8 ml solution.  
 
Packs of 1 and 2 pre-filled pens 
Multipack containing 6 (3 packs of 2) pre-filled pens 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Full instructions for use are given in the package leaflet, section 7, "Instructions for Use".  
 



55 

 

7. MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestr. 10 
6250 Kundl 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
Hefiya 20 mg solution for injection in pre-filled syringe with needle guard 
EU/1/18/1287/007 
 
Hefiya 40 mg solution for injection in pre-filled syringe with needle guard 
EU/1/18/1287/001 
EU/1/18/1287/002 
EU/1/18/1287/003 
 
Hefiya 40 mg solution for injection in pre-filled pen 
EU/1/18/1287/004 
EU/1/18/1287/005 
EU/1/18/1287/006 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 July 2018 
 
 
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 



56 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 



57 

 

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)  
 
Catalent Biologics 
1300 S. Patterson Drive 
Bloomington 
Indiana 
47403 
UNITED STATES 
 
Sandoz GmbH 
Biochemiestr. 10 
6336 Langkampfen 
AUSTRIA 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Sandoz GmbH 
Biochemiestr. 10 
6336 Langkampfen 
AUSTRIA 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 

• At the request of the European Medicines Agency; 
 

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



58 

 

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:  

• that Hefiya treatment may increase the potential risks of  

o infections, including tuberculosis 

o cancer 

o nervous system problems 

o vaccinations 



59 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



60 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



61 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF UNIT PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hefiya 20 mg solution for injection in pre-filled syringe  
adalimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
One 0.4 ml pre-filled syringe contains 20 mg adalimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: adipic acid, citric acid monohydrate, sodium chloride, mannitol, polysorbate 80, 
hydrochloric acid, sodium hydroxide, water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
solution for injection 
 
2 pre-filled syringes  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Do not shake 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 



62 

 

Store in a refrigerator. 
Do not freeze. 
 
Keep the pre-filled syringes in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestr. 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1287/007 2 pre-filled syringes 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Hefiya 20 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



63 

 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER TEXT  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hefiya 20 mg  
injection 
adalimumab 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SANDOZ a Novartis Division 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
SC 
20 mg / 0.4 ml 
 



64 

 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Hefiya 20 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 
 
 
6. OTHER 
 
 



65 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF UNIT PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hefiya 40 mg solution for injection in pre-filled syringe  
adalimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
One 0.8 ml pre-filled syringe contains 40 mg adalimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: adipic acid, citric acid monohydrate, sodium chloride, mannitol, polysorbate 80, 
hydrochloric acid, sodium hydroxide, water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
solution for injection 
 
1 pre-filled syringe  
 
2 pre-filled syringes  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Do not shake 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



66 

 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
 
Keep the pre-filled syringe in the outer carton in order to protect from light. 
Keep the pre-filled syringes in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestr. 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1287/001 1 pre-filled syringe 
EU/1/18/1287/002 2 pre-filled syringes 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Hefiya 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



67 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hefiya 40 mg solution for injection in pre-filled syringe  
adalimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
One 0.8 ml pre-filled syringe contains 40 mg adalimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: adipic acid, citric acid monohydrate, sodium chloride, mannitol, polysorbate 80, 
hydrochloric acid, sodium hydroxide, water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
solution for injection 
 
Multipack: 6 (3 packs of 2) pre-filled syringes  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Do not shake 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 



68 

 

Store in a refrigerator. 
Do not freeze. 
 
Keep the pre-filled syringes in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestr. 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1287/003 6 pre-filled syringes (3 packs of 2) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Hefiya 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



69 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INNER CARTON OF MULTIPACK (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hefiya 40 mg solution for injection in pre-filled syringe  
adalimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
One 0.8 ml pre-filled syringe contains 40 mg adalimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: adipic acid, citric acid monohydrate, sodium chloride, mannitol, polysorbate 80, 
hydrochloric acid, sodium hydroxide, water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
solution for injection 
 
2 pre-filled syringes 
 
Component of a multipack, cannot be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Do not shake 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



70 

 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
 
Keep the pre-filled syringes in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestr. 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1287/003 6 pre-filled syringes (3 packs of 2) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Hefiya 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



71 

 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER TEXT  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hefiya 40 mg / 0.8 ml injection 
adalimumab 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SANDOZ a Novartis Division 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
SC 



72 

 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Hefiya 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 
 
 
6. OTHER 
 
 



73 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF UNIT PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hefiya 40 mg solution for injection in pre-filled pen 
adalimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
One 0.8 ml pre-filled pen contains 40 mg adalimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: adipic acid, citric acid monohydrate, sodium chloride, mannitol, polysorbate 80, 
hydrochloric acid, sodium hydroxide, water for injections.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
solution for injection 
 
1 pre-filled pen (SensoReady) 
 
2 pre-filled pens (SensoReady) 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use.  
Subcutaneous use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Do not shake 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



74 

 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
 
Keep the pre-filled pen in the outer carton in order to protect from light. 
Keep the pre-filled pens in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestr. 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1287/004 1 pre-filled pen 
EU/1/18/1287/005 2 pre-filled pens 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Hefiya 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 



75 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hefiya 40 mg solution for injection in pre-filled pen 
adalimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
One 0.8 ml pre-filled pen contains 40 mg adalimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: adipic acid, citric acid monohydrate, sodium chloride, mannitol, polysorbate 80, 
hydrochloric acid, sodium hydroxide, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
solution for injection 
 
Multipack: 6 (3 packs of 2) pre-filled pens (SensoReady) 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Do not shake 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 



76 

 

Store in a refrigerator. 
Do not freeze. 
 
Keep the pre-filled pens in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestr. 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1287/006 6 pre-filled pens (3 packs of 2) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Hefiya 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



77 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INNER CARTON OF MULTIPACK (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hefiya 40 mg solution for injection in pre-filled pen 
adalimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
One 0.8 ml pre-filled pen contains 40 mg adalimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: adipic acid, citric acid monohydrate, sodium chloride, mannitol, polysorbate 80, 
hydrochloric acid, sodium hydroxide, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
solution for injection 
 
2 pre-filled pens (SensoReady) 
 
Component of a multipack, cannot be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Do not shake 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



78 

 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze. 
 
Keep the pre-filled pens in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestr. 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1287/006 6 pre-filled pens (3 packs of 2) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Hefiya 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 



79 

 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PEN LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Hefiya 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 
 
 
6. OTHER 
 
 



80 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



81 

 

Package leaflet: Information for the patient 
 

Hefiya 20 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 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 begins using Hefiya and during 
treatment with Hefiya. Keep this Patient Reminder Card with you during your treatment and 
for 4 months after your (or your child’s) last injection of Hefiya. 

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

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

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Hefiya is and what it is used for 
2. What you need to know before your child uses Hefiya 
3. How to use Hefiya 
4. Possible side effects 
5. How to store Hefiya 
6. Contents of the pack and other information 
7. Instructions for use  
 
1. What Hefiya is and what it is used for 
 
Hefiya contains the active substance adalimumab, a medicine that acts on your body’s immune 
(defence) system.  
 
Hefiya 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 non-infectious uveitis.  
 
The active ingredient in Hefiya, 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, Hefiya blocks its 
action and reduces the inflammation in these diseases. 
 
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.  
 
Hefiya is used to treat polyarticular juvenile idiopathic arthritis in children and adolescents aged 2 to 



82 

 

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 Hefiya to treat their polyarticular juvenile idiopathic 
arthritis or enthesitis-related arthritis. 
 
Paediatric plaque psoriasis  
 
Plaque psoriasis is an inflammatory skin condition that causes red, flaky, crusty patches of skin 
covered with silvery scales. Plaque psoriasis can also affect the nails, causing them to crumble, 
become thickened and lift away from the nail bed which can be painful. Psoriasis is believed to be 
caused by a problem with the body’s immune system that leads to an increased production of skin 
cells. 
 
Hefiya is also 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. 
 
Hefiya is used to treat moderate to severe Crohn’s disease in children and adolescents 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 Hefiya to reduce the signs and symptoms of his / her disease. 
 
Paediatric non-infectious uveitis  
 
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). Hefiya works by reducing this inflammation. 
 
Hefiya is used to treat children from 2 years of age with chronic non-infectious uveitis with 
inflammation affecting the front of the eye. 
 
Your child may first be given other medicines. If these medicines do not work well enough, your child 
will be given Hefiya to reduce the signs and symptoms of his / her disease. 
 
 
2. What you need to know before your child uses Hefiya 
 
Do not use Hefiya 
 
• 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 shows 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 doctor or pharmacist before using Hefiya. 



83 

 

 
Allergic reaction 
 
• If your child has allergic reactions with symptoms such as chest tightness, wheezing, dizziness, 

swelling or rash, do not inject more Hefiya 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 Hefiya. If you are unsure, contact your doctor. 

• Your child might get infections more easily while he / she is receiving Hefiya treatment. This 
risk may increase if your child’s 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 shows symptoms such as fever, wounds, feeling tired or dental problems. Your doctor may 
recommend temporarily stopping Hefiya. 

 
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 Hefiya. 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 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. 

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

taking Hefiya. Your doctor may recommend temporarily stopping Hefiya. 
 
Demyelinating disease 
 



84 

 

• If your child has or develops 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 Hefiya. Tell your doctor immediately if he / she experiences 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 disease-causing bacteria or viruses and 

should not be given during treatment with Hefiya 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 Hefiya.  

If your child receives Hefiya while she is pregnant, her baby may be at higher risk for getting an 
infection for up to about five months after the last dose she received during pregnancy. It is 
important that you tell her baby's doctors and other health care professionals about your child’s 
Hefiya use during herpregnancy so they can decide when her 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 

he / she has mild heart failure and is being treated with Hefiya, the heart failure status must be 
closely monitored by your doctor. If your child develops 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 stop bleeding. If your child develops a fever that does not go away, or he / she bruises or 
bleeds very easily or looks very pale, call your doctor right away. Your doctor may decide to 
stop treatment. 

 
Cancer 
 
• There have been very rare cases of certain kinds of cancer in children and adults taking 

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 Hefiya, 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 Hefiya.  

• 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. 

 
Autoimmune diseases 
 
• On rare occasions, treatment with Hefiya could result in lupus-like syndrome. Contact your 

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



85 

 

Children and adolescents 
 
• Do not give Hefiya to children with polyarticular juvenile idiopathic arthritis below the age of 

2 years. 

• Do not give Hefiya to children with paediatric plaque psoriasis or paediatric ulcerative colitis below 
the age of 4 years. 

• Do not give Hefiya to children with paediatric Crohn’s disease below the age of 6 years. 

• Do not use the 40 mg pre-filled syringe if doses other than 40 mg are recommended. 
 
Other medicines and Hefiya 
 
Tell your doctor or pharmacist if your child is taking, has recently taken or might take any 
other medicines. 
 
Hefiya 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 Hefiya 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 
 
• Your child should consider the use of adequate contraception to prevent pregnancy and continue 

its use for at least 5 months after the last Hefiya treatment. 

• If your child is pregnant, thinks she may be pregnant or is planning to have a baby, ask her 
doctor for advice before taking this medicine. 

• Hefiya 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. 

• Hefiya can be used during breast-feeding. 

• If your child  receives Hefiya during her pregnancy, the 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 
Hefiya use during her pregnancy before the baby receives any vaccine (for more information on 
vaccines see the “Warnings and precautions” section). 

 
Driving and using machines 
 
Hefiya 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 Hefiya. 
 
Hefiya contains sodium 
 
This medicine contains less than 1 mmol of sodium (23 mg) per 0.4 ml dose, that is to say essentially 
‘sodium-free’. 
 
 



86 

 

3. How to use Hefiya 
 
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or 
pharmacist if you are not sure. 
 
Hefiya is available as a 40 mg pen as well as 20 mg and 40 mg pre-filled syringes for patients to 
administer a full 20 mg or 40 mg dose. 
Polyarticular juvenile idiopathic arthritis 
Age and 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, adolescents and adults 
from 2 years of age weighing 
10 kg to less than 30 kg 

20 mg every other week Not applicable 

 
 
Enthesitis-related arthritis 
Age and 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, adolescents and adults 
from 6 years of age weighing 
15 kg to less than 30 kg 

20 mg every other week Not applicable 

 
 
Paediatric plaque psoriasis 
Age and 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 

First 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 

First 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 and body weight How much and how often to 

take? 
Notes 

Children and 
adolescent from 6 to 
17 years of age 

First dose of 80 mg (as two 
40 mg injections in one day), 
followed by 40 mg every other 
week starting two weeks later.  

If this dose does not work well 
enough, your child’s doctor 
may increase the dosage to 
40 mg every week or 80 mg 



87 

 

weighing 40 kg or 
more 

 
If a faster response is required 
your doctor may prescribe a 
first 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. 

every other week. 

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

First dose of 40 mg, followed 
by 20 mg every other week 
starting two weeks later.  
 
If a faster response is required, 
your doctor may prescribe a 
first 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 non-infectious uveitis 
Age and body weight How much and how often to 

take? 
Notes 

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

40 mg every other week with 
methotrexate 

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

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

20 mg every other week with 
methotrexate 

Your doctor may also prescribe 
a first dose of 40 mg which 
may be administered one week 
prior to the start of the usual 
dose. 

 
 
Method and route of administration 
 
Hefiya is administered by injection under the skin (by subcutaneous injection). 
 
Detailed instructions on how to inject Hefiya are provided in section 7, “Instructions for use”. 
 
If you use more Hefiya than you should 
 
If you accidentally inject Hefiya more frequently than you should, call your doctor or pharmacist 
and explain that your child has received more medication than required. Always take the outer 
carton of medicine with you, even if it is empty. 
 



88 

 

If you forget to use Hefiya 
 
If you forget to give your child an injection, you should inject the next dose of Hefiya as soon as you 
remember. Then take your child’s next dose as you would have on the originally scheduled day, had 
you not forgotten a dose. 
 
If you stop using Hefiya 
 
The decision to stop using Hefiya should be discussed with your child’s doctor. The 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 Hefiya 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; 



89 

 

• 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; 
• bacterial infections; 
• diverticulitis (inflammation and infection of the large intestine); 



90 

 

• 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 (localised swelling of the skin); 
• lichenoid skin reaction (itchy reddish-purple skin rash). 

 



91 

 

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 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 Hefiya 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label / blister / carton after EXP. 
The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C–8°C). Do not freeze. Do not shake. 
 



92 

 

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), Hefiya 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 your pre-
filled syringe is first removed from the 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 Hefiya contains 
 
• The active substance is adalimumab. Each pre-filled syringe contains 20 mg of adalimumab in 

0.4 ml of solution. 

• The other ingredients are adipic acid, citric acid monohydrate, sodium chloride, mannitol, 
polysorbate 80, hydrochloric acid, sodium hydroxide and water for injections. 

 
What Hefiya looks like and contents of the pack 
 
Hefiya 20 mg solution for injection (injection) in pre-filled syringe for paediatric use is supplied as a 
0.4 ml clear to slightly opalescent, colourless to slightly yellowish solution. 
 
Hefiya is supplied in a single-use clear type I glass syringe with a stainless steel needle with a needle 
guard with finger flange, rubber needle cap and plastic plunger rod, containing 0.4 ml of solution.  
 
Carton contains 2 pre-filled syringes of Hefiya. 
 
Not all pack sizes may be marketed.  
Hefiya is available as a pre-filled syringe and a pre-filled pen (SensoReady). 
 
Marketing Authorisation Holder  
 
Sandoz GmbH 
Biochemiestr. 10 
6250 Kundl 
Austria 
 
Manufacturer 
 
Sandoz GmbH Schaftenau  
Biochemiestr. 10 
6336 Langkampfen  
Austria 
 
 
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. 



93 

 

 
7. Instructions for use  
 
To help avoid possible infections and to ensure that you use the medicine correctly, it is important that 
you follow these instructions.  
 
Be sure that you read, understand, and follow these Instructions for Use before injecting Hefiya. Your 
healthcare provider should show you how to prepare and inject Hefiya properly using the pre-filled 
syringe before you use it for the first time. Talk to your healthcare provider if you have any questions. 
 
Your Hefiya single-use pre-filled syringe with needle guard and add-on finger flange 
 

 

Figure A: Hefiya pre-filled syringe with needle guard and add-on finger flange 

 
It is important that you: 
• do not open the outer box until you are ready to use the syringe. 
• do not use the syringe if the seals of the blister are broken, as it may not be safe for you to use.  
• never leave the syringe unattended where others might tamper with it.  
• do not shake the syringe. 
• if you drop your syringe, do not use it if it looks damaged, or if you dropped it with the needle 

cap removed. 
• do not remove the needle cap until just before you give the injection. 
• be careful not to touch the needle guard wings before use. Touching them may cause the needle 

guard to be activated too early. Do not remove the finger flange before the injection. 
• inject Hefiya 15–30 minutes after taking it out of the refrigerator for a more comfortable 

injection. 
• throw away the used syringe right away after use. Do not re-use a syringe. See “4. Disposing 

of used syringes” at the end of these Instructions for Use. 
 

How should you store Hefiya? 
• Store your outer carton of syringes in a refrigerator, between 2°C to 8°C. 
• When needed (for example when you are travelling), Hefiya 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 your pre-filled syringe is first removed from the refrigerator, and the date after which it 
should be discarded.  

• Keep the syringes in the original carton until ready to use to protect from light.  
• Do not store the syringes in extreme heat or cold.  



94 

 

• Do not freeze the syringes. 
 
Keep Hefiya and all medicines out of the reach of children.  
 
What do you need for your injection? 
 
Place the following items on a clean, flat surface. 
Included in your carton is:  

• Hefiya pre-filled syringe/s (see Figure A). Each syringe contains 20 mg / 0.4 ml of Hefiya.  
Not included in your carton are (see Figure B): 

• Alcohol wipe  
• Cotton ball or gauze  
• Sharps disposal container 
 

 
Figure B: items not included in the carton 

 
See “4. Disposing of used syringes” at the end of these Instructions for Use. 
 
Before your injection 
 

 

 

 

Figure C: needle guard is not activated – the 
syringe is ready for use 

 

Figure D: needle guard is activated – do not 
use 

o In this configuration the needle guard is 
NOT ACTIVATED.  

o The syringe is ready for use (see Figure C). 

o In this configuration the needle guard is 
ACTIVATED. 

o DO NOT USE the syringe (see 
Figure D). 

 
Preparing the syringe 
• For a more comfortable injection, take the blister containing the syringe out of the refrigerator 

and leave it unopened on your work surface for about 15 to 30 minutes so that it reaches room 
temperature. 

• Take the syringe out of the blister. 
• Look through the viewing window. The solution should be colourless to slightly yellowish as 

well as clear to slightly opalescent. Do not use if any particulates and / or discolorations are 
observed. If you are concerned with the appearance of the solution, then contact your pharmacist 
for assistance.  



95 

 

• Do not use the syringe if it is broken or the needle guard is activated. Return the syringe and the 
package it came in to the pharmacy. 

• Look at the expiration date (EXP) on your syringe. Do not use the syringe if the expiration date 
has passed.  

 
Contact your pharmacist if the syringe fails any of the above mentioned checks.  

 
1. Choosing your injection site:  
 

• The recommended injection site is the front of your thighs. 
You may also use the lower abdomen, but not the area 5 cm 
around your navel (belly button) (see Figure E).  

• Choose a different site each time you give yourself an 
injection.  

• Do not inject into areas where the skin is tender, bruised, red, 
scaly, or hard. Avoid areas with scars or stretch marks. If you 
have psoriasis, you should NOT inject directly into areas with 
psoriasis plaques. 

 

Figure E: choose your injection site 

 
2. Cleaning your injection site: 
 

• Wash your hands well with soap and water.  

• Using a circular motion, clean the injection site with an 
alcohol wipe. Leave it to dry before injecting (see Figure F). 

• Do not touch the cleaned area before injecting. 

 

Figure F: clean your injection site 
 
3. Giving your injection: 
 

• Carefully pull the needle cap straight off to remove it from 
the syringe (see Figure G).   

• Discard the needle cap.  

• You may see a drop of liquid at the end of the needle. This is 
normal.  

 

Figure G: pull the needle cap off 



96 

 

• Gently pinch the skin at the injection site (see Figure H). 

• Insert the needle into your skin as shown.  

• Push the needle all the way in to ensure that the medication 
can be fully administered.  

Figure H: insert the needle 
• Hold the syringe as shown (see Figure I). 

• Slowly press down on the plunger as far as it will go, so that 
the plunger head is completely between the needle guard 
wings. 

• Keep the plunger pressed fully down while you hold the 
syringe in place for 5 seconds.  

 

Figure I: hold the syringe 

• Keep the plunger fully pressed down while you carefully 
lift the needle straight out from the injection site and let go 
of your skin (see Figure J).  

 

Figure J: lift the needle straight out 

• Slowly release the plunger and allow the needle safety guard 
to automatically cover the exposed needle (see Figure K). 

• There may be a small amount of blood at the injection site. 
You can press a cotton ball or gauze onto the injection site 
and hold it for 10 seconds. Do not rub the injection site. You 
may cover the injection site with a small adhesive bandage, 
if needed.  

 

Figure K: slowly release the plunger 



97 

 

 
4. Disposing of used syringes: 
 

• Dispose of the used syringe in a sharps container (closable, 
puncture-resistant container). For the safety and health of 
you and others, needles and used syringes must never be 
re-used. 

• Do not throw away any medicines via wastewater or 
household waste. Ask your doctor or pharmacist how to 
throw away medicines you no longer use. These measures 
will help protect the environment. Any unused product or 
waste material should be disposed of in accordance with 
local requirements. 

  

 
 
If you have any questions, please talk to a doctor, pharmacist or nurse who is familiar with 
Hefiya. 



98 

 

  
Package leaflet: Information for the patient 

 
Hefiya 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 Hefiya and during treatment with 
Hefiya. Keep this Patient Reminder Card with you during your treatment and for 4 months 
after your (or your child’s) last injection of Hefiya. 

- 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 Hefiya is and what it is used for 
2. What you need to know before you use Hefiya 
3. How to use Hefiya 
4. Possible side effects 
5. How to store Hefiya 
6. Contents of the pack and other information 
7. Instructions for use  
 
1. What Hefiya is and what it is used for 
 
Hefiya contains the active substance adalimumab, a medicine that acts on your body’s immune 
(defence) system.  
 
Hefiya 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, 
• hidradenitis suppurativa, 
• Crohn’s disease, 
• ulcerative colitis and 
• non-infectious uveitis.  
 
The active ingredient in Hefiya, 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, Hefiya blocks its 



99 

 

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



100 

 

Psoriatic arthritis 
 
Psoriatic arthritis is an inflammatory disease of the joints associated with psoriasis. 
 
Hefiya is used to treat psoriatic arthritis in adults. Hefiya can slow down the damage to the cartilage 
and bone of the joints caused by the disease and improve physical function. 
 
Hidradenitis suppurativa in adults and adolescents 
 
Hidradenitis suppurativa (sometimes called acne inversa) is a long-term and often painful 
inflammatory skin disease. Symptoms may include tender nodules (lumps) and abscesses (boils) that 
may leak pus. 
It most commonly affects specific areas of the skin, such as under the breasts, the armpits, inner 
thighs, groin and buttocks. Scarring may also occur in affected areas. 
 
Hefiya is used to treat hidradenitis suppurativa in adults and adolescents from 12 years of age. Hefiya 
can reduce the number of nodules and abscesses you have, and the pain that is often associated with 
the disease. You may first be given other medicines. If these medicines do not work well enough, you 
will be given Hefiya. 
 
Crohn’s disease in adults and children 
 
Crohn’s disease is an inflammatory disease of the gut. 
 
Hefiya 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 Hefiya to reduce the signs and symptoms of your Crohn’s disease. 
 
Ulcerative colitis 
 
Ulcerative colitis is an inflammatory disease of the bowel. 
 
Hefiya 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 Hefiya 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). Hefiya works by reducing this inflammation. 
 
Hefiya 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 Hefiya 
 
Do not use Hefiya 
 
• 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 



101 

 

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 Hefiya. 
 
Allergic reaction 
 
• If you have allergic reactions with symptoms such as chest tightness, wheezing, dizziness, 

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

 
Infection 
 
• If you have an infection, including long-term or localised infection (for example leg ulcer), 

consult your doctor before starting Hefiya. If you are unsure, contact your doctor. 

• You might get infections more easily while you are receiving Hefiya 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 Hefiya. 

 
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 Hefiya. 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. 

 



102 

 

Age over 65 years 
 
• If you are over 65 years you may be more susceptible to infections while taking Hefiya. You 

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

Your doctor may recommend temporarily stopping Hefiya. 
 
Demyelinating disease 
 
• If you have or develop demyelinating disease (a disease that affects the insulating layer around 

the nerves, such as multiple sclerosis), your doctor will decide if you should receive or continue 
to receive Hefiya. 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 Hefiya 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 Hefiya. If you receive 
Hefiya 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 Hefiya 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 Hefiya, 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 Hefiya 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 Hefiya.  



103 

 

• 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. 

 
Autoimmune diseases 
 
• On rare occasions, treatment with Hefiya could result in lupus-like syndrome. Contact your 

doctor, if symptoms such as persistent unexplained rash, fever, joint pain or tiredness occur. 
 
Children and adolescents 
 
• Do not give Hefiya to children with polyarticular juvenile idiopathic arthritis below the age of 

2 years. 

• Do not give Hefiya to children with paediatric plaque psoriasis or paediatric ulcerative colitis 
below the age of 4 years. 

• Do not give Hefiya to children with paediatric Crohn’s disease below the age of 6 years. 

• Do not use the 40 mg pre-filled syringe if doses other than 40 mg are recommended. 
 
Other medicines and Hefiya 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Hefiya 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 Hefiya 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 
 
• You should consider the use of adequate contraception to prevent pregnancy and continue its 

use for at least 5 months after the last Hefiya treatment. 

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

• Hefiya 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. 

• Hefiya can be used during breast-feeding. 

• If you receive Hefiya during your pregnancy, your baby may have a higher risk for getting an 
infection.  



104 

 

• It is important that you tell your baby’s doctors and other health care professionals about your 
Hefiya use during your pregnancy before the baby receives any vaccine (for more information 
on vaccines see the “Warnings and precautions” section). 

 
Driving and using machines 
 
Hefiya 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 Hefiya. 
 
Hefiya contains sodium 
 
This medicine contains less than 1 mmol of sodium (23 mg) per 0.4 ml dose, that is to say essentially 
‘sodium-free’. 
 
 
3. How to use Hefiya 
 
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or 
pharmacist if you are not sure. 
 
Hefiya is available as a 40 mg pen as well as 20 mg and 40 mg pre-filled syringes for patients to 
administer a full 20 mg or 40 mg dose. 
 
Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis 
without radiographic evidence of ankylosing spondylitis 
Age and body weight How much and how often to 

take? 
Notes 

Adults 40 mg every other week as a 
single dose 

In rheumatoid arthritis, 
methotrexate is continued 
while using Hefiya. If your 
doctor determines that 
methotrexate is inappropriate, 
Hefiya can be given alone. 
 
If you have rheumatoid 
arthritis and you do not 
receive methotrexate with 
your Hefiya therapy, your 
doctor may decide to give 
40 mg Hefiya every week or 
80 mg every other week. 

 
 
Polyarticular juvenile idiopathic arthritis 
Age and 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, adolescents and adults 
from 2 years of age weighing 
10 kg to less than 30 kg 

20 mg every other week Not applicable 

 
 
Enthesitis-related arthritis 
Age and body weight How much and how often to Notes 



105 

 

take? 
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 

 
 
Psoriasis 
Age and body weight How much and how often to 

take? 
Notes 

Adults First dose of 80 mg (as two 
40 mg injections in one day), 
followed by 40 mg given 
every other week starting one 
week after the first dose.  
 

You should continue to inject 
Hefiya for as long as your 
doctor has told you. If this 
dose does not work well 
enough, your doctor may 
increase the dosage to 40 mg 
every week or 80 mg every 
other week. 

 
 
Paediatric plaque psoriasis 
Age and 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 

First 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 

First dose of 20 mg, 
followed by 20 mg one week 
later. 
 
Thereafter, the usual dose is 
20 mg every other week. 

Not applicable 

 
 
Hidradenitis suppurativa 
Age and body weight How much and how often to 

take? 
Notes 

Adults  First dose of 160 mg (as four 
40 mg injections in one day 
or two 40 mg injections per 
day for two consecutive 
days), followed by an 80 mg 
dose (as two 
40 mg injections on the 
same day) two weeks later.  
 
After two further weeks, 
continue with a dosage of 
40 mg every week or 80 mg 
every other week, as 
prescribed by your doctor. 

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



106 

 

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

First dose of 80 mg (as two 
40 mg injections in one day), 
followed by 40 mg every other 
week starting one week later. 

If this dose does not work well 
enough, your doctor may 
increase the dosage to 40 mg 
every week or 80 mg every 
other week. 
 
It is recommended that you use 
an antiseptic wash daily on the 
affected areas. 

 
 
Crohn’s disease 
Age and body weight How much and how often to 

take? 
Notes 

Adults First dose of 80 mg (as two 
40 mg injections in one day), 
followed by 40 mg every other 
week starting two weeks later.  
 
If a faster response is required 
your doctor may prescribe a 
first 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 dosage to 40 mg 
every week or 80 mg every 
other week. 

 
 
Paediatric Crohn’s disease 
Age and body weight How much and how often to 

take? 
Notes 

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

First dose of 80 mg (as two 
40 mg injections in one day), 
followed by 40 mg every other 
week starting two weeks later.  
 
If a faster response is required 
your doctor may prescribe a 
first 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 child’s doctor 
may increase the dosage to 
40 mg every week or 80 mg 
every other week. 

Children and 
adolescents from 6 
to 17 years of age 

First dose of 40 mg, followed 
by 20 mg every other week 
starting two weeks later.  
 

If this dose does not work well 
enough, your child’s doctor may 
increase the dose frequency to 
20 mg every week. 



107 

 

weighing less than 
40 kg 

If a faster response is required, 
your doctor may prescribe a 
first 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. 

 
 
Ulcerative colitis 
Age and body weight How much and how often to 

take? 
Notes 

Adults First dose is 160 mg (as four 
40 mg injections in one day 
or as two 40 mg injections per 
day for two consecutive 
days), followed by 80 mg (as 
two 40 mg injections in one 
day) two weeks later. 
 
Thereafter, the usual dose is 
40 mg every other week. 

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

 
 
Non-infectious uveitis 
Age and body weight How much and how often to 

take? 
Notes 

Adults First dose of 80 mg (as two 
40 mg injections), followed by 
40 mg every other week 
starting one week after the 
first dose. 

In non-infectious uveitis, 
corticosteroids or other 
medicines that influence the 
immune system may be 
continued while using Hefiya. 
Hefiya can also be given alone. 
 
You should continue to inject 
Hefiya for as long as your 
doctor has told you. 

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

40 mg every other week with 
methotrexate 

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

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

20 mg every other week with 
methotrexate 

Your doctor may also prescribe 
a first dose of 40 mg which 
may be administered one week 
prior to the start of the usual 
dose. 

 
 
Method and route of administration 
 
Hefiya is administered by injection under the skin (by subcutaneous injection). 
 



108 

 

Detailed instructions on how to inject Hefiya are provided in section 7, “Instructions for use”. 
 
If you use more Hefiya than you should 
 
If you accidentally inject Hefiya 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 medicine 
with you, even if it is empty. 
 
If you forget to use Hefiya 
 
If you forget to give yourself an injection, you should inject the next dose of Hefiya 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 Hefiya 
 
The decision to stop using Hefiya 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 Hefiya 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. 
 



109 

 

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



110 

 

 
• 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); 
• 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); 



111 

 

• 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 (localised swelling of the skin); 
• lichenoid skin reaction (itchy reddish-purple skin rash). 

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

weakness). 
 
Some side effects observed with adalimumab may not have symptoms and may only be discovered 
through blood tests. These include: 
 
Very common (may affect more than 1 in 10 people) 
 
• low blood measurements for white blood cells; 
• low blood measurements for red blood cells; 
• increased lipids in the blood; 
• raised liver enzymes. 
 
Common (may affect up to 1 in 10 people) 
 
• high blood measurements for white blood cells; 
• low blood measurements for platelets; 
• increased uric acid in the blood; 
• abnormal blood measurements for sodium; 
• low blood measurements for calcium; 
• low blood measurements for phosphate; 
• high blood sugar; 
• high blood measurements for lactate dehydrogenase; 
• autoantibodies present in the blood; 
• 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. 
 
 



112 

 

5. How to store Hefiya 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label / blister / carton after EXP. 
The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C–8°C). Do not freeze. Do not shake. 
 
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), Hefiya 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 your pre-
filled syringe is first removed from the 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 Hefiya 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 adipic acid, citric acid monohydrate, sodium chloride, mannitol, 
polysorbate 80, hydrochloric acid, sodium hydroxide and water for injections. 

 
What Hefiya looks like and contents of the pack 
 
Hefiya 40 mg solution for injection (injection) in pre-filled syringe is supplied as a 0.8 ml clear to 
slightly opalescent, colourless to slightly yellowish solution. 
 
Hefiya is supplied in a single-use clear type I glass syringe with a stainless steel needle with a needle 
guard with finger flange, rubber needle cap and plastic plunger rod, containing 0.8 ml of solution.  
 
Cartons contain 1 and 2 pre-filled syringes of Hefiya. 
Multipack cartons contain 6 (3 packs of 2) pre-filled syringes of Hefiya. 
 
Not all pack sizes may be marketed.  
Hefiya is available as a pre-filled syringe and a pre-filled pen (SensoReady). 
 
Marketing Authorisation Holder  
 
Sandoz GmbH 
Biochemiestr. 10 
6250 Kundl 
Austria 
 
Manufacturer 
 
Sandoz GmbH Schaftenau  
Biochemiestr. 10 
6336 Langkampfen  



113 

 

Austria 
 
 
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  
 
To help avoid possible infections and to ensure that you use the medicine correctly, it is important that 
you follow these instructions.  
 
Be sure that you read, understand, and follow these Instructions for Use before injecting Hefiya. Your 
healthcare provider should show you how to prepare and inject Hefiya properly using the pre-filled 
syringe before you use it for the first time. Talk to your healthcare provider if you have any questions. 
 
Your Hefiya single-use pre-filled syringe with needle guard and add-on finger flange 
 

 

Figure A: Hefiya pre-filled syringe with needle guard and add-on finger flange 

 
It is important that you: 
• do not open the outer box until you are ready to use the syringe. 
• do not use the syringe if the seals of the blister are broken, as it may not be safe for you to use.  
• never leave the syringe unattended where others might tamper with it.  
• do not shake the syringe. 
• if you drop your syringe, do not use it if it looks damaged, or if you dropped it with the needle 

cap removed. 
• do not remove the needle cap until just before you give the injection. 
• be careful not to touch the needle guard wings before use. Touching them may cause the needle 

guard to be activated too early. Do not remove the finger flange before the injection. 
• inject Hefiya 15–30 minutes after taking it out of the refrigerator for a more comfortable 

injection. 
• throw away the used syringe right away after use. Do not re-use a syringe. See “4. Disposing 

of used syringes” at the end of these Instructions for Use. 
 

How should you store Hefiya? 
• Store your outer carton of syringes in a refrigerator, between 2°C to 8°C. 



114 

 

• When needed (for example when you are travelling), Hefiya 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 your pre-filled syringe is first removed from the refrigerator, and the date after which it 
should be discarded.  

• Keep the syringes in the original carton until ready to use to protect from light.  
• Do not store the syringes in extreme heat or cold.  
• Do not freeze the syringes. 
 
Keep Hefiya and all medicines out of the reach of children.  
 
What do you need for your injection? 
 
Place the following items on a clean, flat surface. 
Included in your carton is:  

• Hefiya pre-filled syringe/s (see Figure A). Each syringe contains 40 mg/0.8 ml of Hefiya.  
Not included in your carton are (see Figure B): 

• Alcohol wipe  
• Cotton ball or gauze  
• Sharps disposal container 
 

 
Figure B: items not included in the carton 

 
See “4. Disposing of used syringes” at the end of these Instructions for Use. 
 
Before your injection 
 

 

 

 

Figure C: needle guard is not activated – the 
syringe is ready for use 

 

Figure D: needle guard is activated – do not 
use 

o In this configuration the needle guard is 
NOT ACTIVATED.  

o The syringe is ready for use (see Figure C). 

o In this configuration the needle guard is 
ACTIVATED. 

o DO NOT USE the syringe (see 
Figure D). 

 
Preparing the syringe 



115 

 

• For a more comfortable injection, take the blister containing the syringe out of the refrigerator 
and leave it unopened on your work surface for about 15 to 30 minutes so that it reaches room 
temperature. 

• Take the syringe out of the blister. 
• Look through the viewing window. The solution should be colourless to slightly yellowish as 

well as clear to slightly opalescent. Do not use if any particulates and / or discolorations are 
observed. If you are concerned with the appearance of the solution, then contact your pharmacist 
for assistance.  

• Do not use the syringe if it is broken or the needle guard is activated. Return the syringe and the 
package it came in to the pharmacy. 

• Look at the expiration date (EXP) on your syringe. Do not use the syringe if the expiration date 
has passed.  

 
Contact your pharmacist if the syringe fails any of the above mentioned checks.  

 
1. Choosing your injection site:  
 

• The recommended injection site is the front of your thighs. 
You may also use the lower abdomen, but not the area 5 cm 
around your navel (belly button) (see Figure E).  

• Choose a different site each time you give yourself an 
injection.  

• Do not inject into areas where the skin is tender, bruised, red, 
scaly, or hard. Avoid areas with scars or stretch marks. If you 
have psoriasis, you should NOT inject directly into areas with 
psoriasis plaques. 

 

Figure E: choose your injection site 

 
2. Cleaning your injection site: 
 

• Wash your hands well with soap and water.  

• Using a circular motion, clean the injection site with an 
alcohol wipe. Leave it to dry before injecting (see Figure F). 

• Do not touch the cleaned area before injecting. 

 

Figure F: clean your injection site 
 
3. Giving your injection: 
 



116 

 

• Carefully pull the needle cap straight off to remove it from 
the syringe (see Figure G).   

• Discard the needle cap.  

• You may see a drop of liquid at the end of the needle. This is 
normal.  

 

Figure G: pull the needle cap off 

• Gently pinch the skin at the injection site (see Figure H). 

• Insert the needle into your skin as shown.  

• Push the needle all the way in to ensure that the medication 
can be fully administered  

Figure H: insert the needle 
• Hold the syringe as shown (see Figure I). 

• Slowly press down on the plunger as far as it will go, so that 
the plunger head is completely between the needle guard 
wings. 

• Keep the plunger pressed fully down while you hold the 
syringe in place for 5 seconds.  

 

Figure I: hold the syringe 

• Keep the plunger fully pressed down while you carefully 
lift the needle straight out from the injection site and let go 
of your skin (see Figure J).  

 

Figure J: lift the needle straight out 



117 

 

• Slowly release the plunger and allow the needle safety guard 
to automatically cover the exposed needle (see Figure K). 

• There may be a small amount of blood at the injection site. 
You can press a cotton ball or gauze onto the injection site 
and hold it for 10 seconds. Do not rub the injection site. You 
may cover the injection site with a small adhesive bandage, 
if needed.  

 

Figure K: slowly release the plunger 

 
4. Disposing of used syringes: 
 

• Dispose of the used syringe in a sharps container (closable, 
puncture-resistant container). For the safety and health of 
you and others, needles and used syringes must never be 
re-used. 

• Do not throw away any medicines via wastewater or 
household waste. Ask your doctor or pharmacist how to 
throw away medicines you no longer use. These measures 
will help protect the environment. Any unused product or 
waste material should be disposed of in accordance with 
local requirements. 

  

 
 
If you have any questions, please talk to a doctor, pharmacist or nurse who is familiar with 
Hefiya. 
 



118 

 

 

Package leaflet: Information for the patient 
 

Hefiya 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 Hefiya and during treatment with 
Hefiya. Keep this Patient Reminder Card with you during your treatment and for 4 months 
after your (or your child’s) last injection of Hefiya. 

- 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 Hefiya is and what it is used for 
2. What you need to know before you use Hefiya 
3. How to use Hefiya 
4. Possible side effects 
5. How to store Hefiya 
6. Contents of the pack and other information 
7. Instructions for use  
 
1. What Hefiya is and what it is used for 
 
Hefiya contains the active substance adalimumab, a medicine that acts on your body’s immune 
(defence) system.  
 
Hefiya 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, 
• hidradenitis suppurativa, 
• Crohn’s disease, 
• ulcerative colitis and 
• non-infectious uveitis. 
 
The active ingredient in Hefiya, adalimumab, is a monoclonal antibody. Monoclonal antibodies are 
proteins that attach to a specific target in the body.  
 



119 

 

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



120 

 

Psoriatic arthritis 
 
Psoriatic arthritis is an inflammatory disease of the joints associated with psoriasis. 
 
Hefiya is used to treat psoriatic arthritis in adults. Hefiya can slow down the damage to the cartilage 
and bone of the joints caused by the disease and improve physical function. 
 
Hidradenitis suppurativa in adults and adolescents 
 
Hidradenitis suppurativa (sometimes called acne inversa) is a long-term and often painful 
inflammatory skin disease. Symptoms may include tender nodules (lumps) and abscesses (boils) that 
may leak pus. 
It most commonly affects specific areas of the skin, such as under the breasts, the armpits, inner 
thighs, groin and buttocks. Scarring may also occur in affected areas. 
 
Hefiya is used to treat hidradenitis suppurativa in adults and adolescents from 12 years of age. Hefiya 
can reduce the number of nodules and abscesses you have, and the pain that is often associated with 
the disease. You may first be given other medicines. If these medicines do not work well enough, you 
will be given Hefiya. 
 
Crohn’s disease in adults and children 
 
Crohn’s disease is an inflammatory disease of the gut. 
 
Hefiya 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 Hefiya to reduce the signs and symptoms of your Crohn’s disease. 
 
Ulcerative colitis 
 
Ulcerative colitis is an inflammatory disease of the bowel. 
 
Hefiya 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 Hefiya 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). Hefiya works by reducing this inflammation. 
 
Hefiya 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 Hefiya 
 
Do not use Hefiya 
 
• 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 



121 

 

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 Hefiya. 
 
Allergic reaction 
 
• If you have allergic reactions with symptoms such as chest tightness, wheezing, dizziness, 

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

 
Infection 
 
• If you have an infection, including long-term or localised infection (for example leg ulcer), 

consult your doctor before starting Hefiya. If you are unsure, contact your doctor. 

• You might get infections more easily while you are receiving Hefiya 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 Hefiya. 

 
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 Hefiya. 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. 

 



122 

 

Age over 65 years 
 
• If you are over 65 years you may be more susceptible to infections while taking Hefiya. You 

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

Your doctor may recommend temporarily stopping Hefiya. 
 
Demyelinating disease 

 
• If you have or develop demyelinating disease (a disease that affects the insulating layer around 

the nerves, such as multiple sclerosis), your doctor will decide if you should receive or continue 
to receive Hefiya. 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 Hefiya 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 Hefiya. If you receive 
Hefiya 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 Hefiya 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 Hefiya, 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 Hefiya 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 Hefiya.  

• 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. 



123 

 

• 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. 

 
Autoimmune diseases 
 
• On rare occasions, treatment with Hefiya could result in lupus-like syndrome. Contact your 

doctor, if symptoms such as persistent unexplained rash, fever, joint pain or tiredness occur. 
 
Children and adolescents 
 
• Do not give Hefiya to children with polyarticular juvenile idiopathic arthritis below the age of 

2 years. 

• Do not give Hefiya to children with paediatric plaque psoriasis or paediatric ulcerative colitis 
below the age of 4 years. 

• Do not give Hefiya to children with paediatric Crohn’s disease below the age of 6 years. 

• Do not use the 40 mg pre-filled pen if doses other than 40 mg are recommended. 
 
Other medicines and Hefiya 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Hefiya 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 Hefiya 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 
 
• You should consider the use of adequate contraception to prevent pregnancy and continue its 

use for at least 5 months after the last Hefiya treatment. 

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

• Hefiya 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. 

• Hefiya can be used during breast-feeding. 

• If you receive Hefiya 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 
Hefiya use during your pregnancy before the baby receives any vaccine (for more information 
on vaccines see the “Warnings and precautions” section). 

 
Driving and using machines 



124 

 

 
Hefiya 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 Hefiya. 
 
Hefiya contains sodium 
 
This medicine contains less than 1 mmol of sodium (23 mg) per 0.4 ml dose, that is to say essentially 
‘sodium-free’. 
 
 
3. How to use Hefiya 
 
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  
 
Hefiya is available as a 40 mg pen as well as 20 mg and 40 mg pre-filled syringes for patients to 
administer a full 20 mg or 40 mg dose. 
 
Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis 
without radiographic evidence of ankylosing spondylitis 
Age and body weight How much and how often to 

take? 
Notes 

Adults 40 mg every other week as a 
single dose 

In rheumatoid arthritis, 
methotrexate is continued 
while using Hefiya. If your 
doctor determines that 
methotrexate is inappropriate, 
Hefiya can be given alone. 
 
If you have rheumatoid 
arthritis and you do not 
receive methotrexate with 
your Hefiya therapy, your 
doctor may decide to give 
40 mg Hefiya every week or 
80 mg every other week. 

 
 
Polyarticular juvenile idiopathic arthritis 
Age and 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, adolescents and adults 
from 2 years of age weighing 
10 kg to less than 30 kg 

20 mg every other week Not applicable 

 
 
Enthesitis-related arthritis 
Age and 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 



125 

 

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

20 mg every other week Not applicable 

 
 
Psoriasis 
Age and body weight How much and how often to 

take? 
Notes 

Adults First dose of 80 mg (as two 
40 mg injections in one day), 
followed by 40 mg given 
every other week starting one 
week after the first dose.  
 

You should continue to inject 
Hefiya for as long as your 
doctor has told you. If this 
dose does not work well 
enough, your doctor may 
increase the dosage to 40 mg 
every week or 80 mg every 
other week. 

 
 
Plaque psoriasis 
Age and 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 

First 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 

First dose of 20 mg, 
followed by 20 mg one week 
later. 
 
Thereafter, the usual dose is 
20 mg every other week. 

Not applicable 

 
 
Hidradenitis suppurativa 
Age and body weight How much and how often to 

take? 
Notes 

Adults First dose of 160 mg (as four 
40 mg injections in one day 
or two 40 mg injections per 
day for two consecutive 
days), followed by an 80 mg 
dose (as two 
40 mg injections on the 
same day) two weeks later.  
 
After two further weeks, 
continue with a dosage of 
40 mg every week or 80 mg 
every other week, as 
prescribed by your doctor. 

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

Adolescents from 
12 to 17 years of 
age weighing 30 kg 

First dose of 80 mg (as two 
40 mg injections in one day), 
followed by 40 mg every other 
week starting one week later. 

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



126 

 

or more other week. 
 
It is recommended that you use 
an antiseptic wash daily on the 
affected areas. 

 
 
Crohn’s disease 
Age and body weight How much and how often to 

take? 
Notes 

Adults First dose of 80 mg (as two 
40 mg injections in one day), 
followed by 40 mg every other 
week starting two weeks later.  
 
If a faster response is required 
your doctor may prescribe a 
first 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 dosage to 40 mg 
every week or 80 mg every 
other week. 

 
 
Paediatric Crohn’s disease 
Age and body weight How much and how often to 

take? 
Notes 

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

First dose of 80 mg (as two 
40 mg injections in one day), 
followed by 40 mg every other 
week starting two weeks later.  
 
If a faster response is required 
your doctor may prescribe a 
first 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 child’s doctor 
may increase the dosage 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 

First dose of 40 mg, followed 
by 20 mg every other week 
starting two weeks later.  
 
If a faster response is required, 
your doctor may prescribe a 
first dose of 80 mg (as two 
40 mg injections in one day), 

If this dose does not work well 
enough, your child’s doctor may 
increase the dose frequency to 
20 mg every week. 



127 

 

followed by 40 mg two weeks 
later. 
 
Thereafter the usual dose is 
20 mg every other week. 

 
 
Ulcerative colitis 
Age and body weight How much and how often to 

take? 
Notes 

Adults First dose is 160 mg (as four 
40 mg injections in one day 
or as two 40 mg injections per 
day for two consecutive 
days), followed by 80 mg (as 
two 40 mg injections in one 
day) two weeks later. 
 
Thereafter, the usual dose is 
40 mg every other week. 

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

 
 
Non-infectious uveitis 
Age and body weight How much and how often to 

take? 
Notes 

Adults First dose of 80 mg (as two 
40 mg injections), followed by 
40 mg every other week 
starting one week after the 
first dose. 

In non-infectious uveitis, 
corticosteroids or other 
medicines that influence the 
immune system may be 
continued while using Hefiya. 
Hefiya can also be given alone. 
 
You should continue to inject 
Hefiya for as long as your 
doctor has told you. 

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

40 mg every other week with 
methotrexate 

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

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

20 mg every other week with 
methotrexate 

Your doctor may also prescribe 
a first dose of 40 mg which 
may be administered one week 
prior to the start of the usual 
dose. 

 
 
Method and route of administration 
 
Hefiya is administered by injection under the skin (by subcutaneous injection). 
 
Detailed instructions on how to inject Hefiya are provided in section 7, “Instructions for use”. 
 
If you use more Hefiya than you should 
 



128 

 

If you accidentally inject Hefiya 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 medicine 
with you, even if it is empty. 
 
If you forget to use Hefiya 
 
If you forget to give yourself an injection, you should inject the next dose of Hefiya 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 Hefiya 
 
The decision to stop using Hefiya 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 Hefiya 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); 



129 

 

• 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; 



130 

 

• 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 (localised swelling of the skin); 



131 

 

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

weakness). 
 
Some side effects observed with adalimumab may not have symptoms and may only be discovered 
through blood tests. These include: 
 
Very common (may affect more than 1 in 10 people) 
 
• low blood measurements for white blood cells; 
• low blood measurements for red blood cells; 
• increased lipids in the blood; 
• raised liver enzymes. 
 
Common (may affect up to 1 in 10 people) 
 
• high blood measurements for white blood cells; 
• low blood measurements for platelets; 
• increased uric acid in the blood; 
• abnormal blood measurements for sodium; 
• low blood measurements for calcium; 
• low blood measurements for phosphate; 
• high blood sugar; 
• high blood measurements for lactate dehydrogenase; 
• autoantibodies present in the blood; 
• 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 Hefiya 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label / blister / carton after EXP. 
The expiry date refers to the last day of that month. 
 



132 

 

Store in a refrigerator (2°C–8°C). Do not freeze. Do not shake. 
 
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), Hefiya 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 your pre-
filled pen is first removed from the 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 Hefiya contains 
 
• The active substance is adalimumab. Each pre-filled pen contains 40 mg of adalimumab in 

0.8 ml of solution. 

The other ingredients are adipic acid, citric acid monohydrate, sodium chloride, mannitol, polysorbate 
80, hydrochloric acid, sodium hydroxide and water for injections. 
 
What Hefiya looks like and contents of the pack 
 
Hefiya 40 mg solution for injection (injection) in pre-filled pen is supplied as a 0.8 ml clear to slightly 
opalescent, colourless to slightly yellowish solution. 
 
Hefiya is supplied in a single-use pre-filled syringe assembled into a triangular-shaped pen 
(SensoReady) with transparent window and label. The syringe inside the pen is made of type I glass 
with a stainless steel needle and an inner rubber needle cap, containing 0.8 ml of solution. 
 
Cartons contain 1 and 2 pre-filled pens of Hefiya. 
Multipack cartons contain 6 (3 packs of 2) pre-filled pens of Hefiya. 
 
Not all pack sizes may be marketed.  
Hefiya is available as a pre-filled syringe and a pre-filled pen (SensoReady). 
 
 
Marketing Authorisation Holder  
 
Sandoz GmbH 
Biochemiestr. 10 
6250 Kundl 
Austria 
 
Manufacturer 
 
Sandoz GmbH Schaftenau  
Biochemiestr. 10 
6336 Langkampfen  
Austria 
 
 
This leaflet was last revised in 



133 

 

 
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  
 
To help avoid possible infections and to ensure that you use the medicine correctly, it is important that 
you follow these instructions.  
 
Be sure that you read, understand, and follow these Instructions for use before injecting Hefiya. Your 
healthcare provider should show you how to prepare and inject Hefiya properly using the pre-filled pen 
before you use it for the first time. Talk to your healthcare provider if you have any questions. 

Your Hefiya single-use pre-filled SensoReady pen  

 

 
Figure A: Hefiya SensoReady pen parts 

 
In Figure A, the pen is shown with the cap removed. Do not remove the cap until you are ready to 
inject. 
It is important that you: 
• do not open the outer box until you are ready to use the pen. 
• do not use the pen if either the seal on the outer carton or the safety seal on the pen is broken.  
• never leave the pen unattended where others might tamper with it. 
• do not shake the pen. 
• if you drop your pen, do not use it if it looks damaged, or if you dropped it with the cap 

removed. 
• inject Hefiya 15–30 minutes after taking it out of the refrigerator for a more comfortable 

injection. 
• throw away the used pen right away after use. Do not re-use the pen. See “8. Disposing of 

used pens” at the end of this Instructions for Use. 
 
How should you store your pen? 
• Store your pen within the carton in a refrigerator, between 2°C to 8°C. 
• When needed (for example when you are travelling), Hefiya 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 your pre-filled pen is first removed from the refrigerator, and the date after which it should 
be discarded.  

• Keep your pen in the original carton until ready to use to protect from light.  
• Do not store your pen in extreme heat or cold.  
• Do not freeze your pen. 



134 

 

 
Keep Hefiya and all medicines out of the reach of children. 
 
What do you need for your injection? 
 
Place the following items on a clean, flat surface. 
Included in your carton is:  

• Hefiya pre-filled SensoReady pen/s (see Figure A). Each pen contains 40 mg/0.8 ml of Hefiya. 
Not included in your carton are (see Figure B): 

• Alcohol wipe  
• Cotton ball or gauze  
• Sharps disposal container 
 

 
Figure B: items not included in the carton 

 
See “8. Disposing of used pens” at the end of these Instructions for Use.  

Before your injection  
Preparing the pen 
 
• For a more comfortable injection, take your pen out of the refrigerator 15 to 30 minutes before 

injecting Hefiya to allow it to reach room temperature.   
• Look through the viewing window. The solution should be colourless to slightly yellowish as 

well as clear to slightly opalescent. Do not use if any particulates and / or discolorations are 
observed. If you are concerned with the appearance of the solution, then contact your pharmacist 
for assistance.  

 
 

Figure C: Safety Checks before injection  
 
• Look at the expiration date (EXP) on your pen. Do not use your pen if the expiration date has 

passed.  
• Do not use if the safety seal has been broken. 
 
Contact your pharmacist if the pen fails any of the above mentioned checks. 
 
1. Choosing your injection site:  



135 

 

 
• The recommended injection site is the front of your thighs. 

You may also use the lower abdomen, but not the area 5 cm 
around your navel (belly button) (see Figure D).  

• Choose a different site each time you give yourself an 
injection.  

• Do not inject into areas where the skin is tender, bruised, red, 
scaly, or hard. Avoid areas with scars or stretch marks. If you 
have psoriasis, you should NOT inject directly into areas with 
psoriasis plaques. 

 

Figure D: choose your injection site 

 
2. Cleaning your injection site: 
 

• Wash your hands well with soap and water.  

• Using a circular motion, clean the injection site with an 
alcohol wipe. Leave it to dry before injecting (see Figure E). 

• Do not touch the cleaned area again before injecting.  

 

Figure E: clean your injection site 

 
3. Removing the cap of the pen: 
 

• Only remove the cap when you are ready to use the pen.  

• Twist off the cap in the direction of the arrows (see 
Figure F).  

• Once removed, throw away the cap. Do not try to re-attach 
the cap.  

• Use your pen within 5 minutes of removing the cap.  

• You may see a few drops of liquid come out of the needle. 
This is normal. 

 

Figure F: remove the cap 

 
4. Holding the pen: 
 

• Hold your pen at 90 degrees to the cleaned injection site (see 
Figure G). 

 

 

      Correct         Incorrect 
 

 

Figure G: hold your pen  



136 

 

Your injection 

You must read this before injecting 
During the injection you will hear 2 loud clicks:  

o The 1st click indicates that the injection has started.  
o Several seconds later a 2nd click will indicate that the injection is almost finished.  

You must keep holding your pen firmly against your skin until you see a green indicator fill the 
window and stop moving. 

 
5. Starting your injection:  
 

• Press your pen firmly against the skin to start the injection 
(see Figure H).  

• The 1st click indicates the injection has started.  

• Keep holding your pen firmly against your skin. 

• The green indicator shows the progress of the injection.  

 

Figure H: start your injection 
 
6. Completing your injection: 

 
• Listen for the 2nd click. This indicates the injection is almost 

complete.  

• Check the green indicator fills the window and has stopped 
moving (see Figure I).  

• The pen can now be removed.  

 

Figure I: complete your injection 
 
After your injection 
 
7. Check the green indicator fills the window (see Figure J): 
 

• This means the medicine has been delivered. Contact your 
doctor if the green indicator is not visible.  

• There may be a small amount of blood at the injection site. 
You can press a cotton ball or gauze over the injection site 
and hold it for 10 seconds. Do not rub the injection site. You 
may cover the injection site with a small adhesive bandage, if 
needed.  

 

Figure J: check the green indicator 
 



137 

 

8. Disposing of used pens: 
 

• Dispose of the used pens in a sharps container (closable, 
puncture-resistant container). For the safety and health of 
you and others, the pens must never be re-used. 

• Do not throw away any medicines via wastewater or 
household waste. Ask your doctor or pharmacist how to 
throw away medicines you no longer use. These measures 
will help protect the environment. Any unused product or 
waste material should be disposed of in accordance with 
local requirements. 

 
 
If you have any questions, please talk to a doctor, pharmacist or nurse who is familiar with 
Hefiya. 
 


	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