Flixabi

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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 
 
Flixabi 100 mg powder for concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial contains 100 mg of infliximab*. After reconstitution, each ml contains 10 mg of infliximab. 
 
* Infliximab is a chimeric human-murine IgG1 monoclonal antibody produced in Chinese Hamster Ovary 
(CHO) cells by recombinant DNA technology. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion (powder for concentrate). 
 
White powder. 
 
 
4. CLINICAL PARTICULARS  
 
4.1 Therapeutic indications 
 
Rheumatoid arthritis 
Flixabi, in combination with methotrexate, is indicated for the reduction of signs and symptoms as well as 
the improvement in physical function in: 
 adult patients with active disease when the response to disease-modifying antirheumatic drugs 

(DMARDs), including methotrexate, has been inadequate. 
 adult patients with severe, active and progressive disease not previously treated with methotrexate or 

other DMARDs. 
In these patient populations, a reduction in the rate of the progression of joint damage, as measured by X-ray, 
has been demonstrated (see section 5.1). 
 
Adult Crohn’s disease 
Flixabi 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. 

 treatment of fistulising, active Crohn’s disease, in adult patients who have not responded despite a full 
and adequate course of therapy with conventional treatment (including antibiotics, drainage and 
immunosuppressive therapy). 

 
Paediatric Crohn’s disease 
Flixabi is indicated for treatment of severe, active Crohn’s disease in children and adolescents aged 6 to 
17 years, who have not responded to conventional therapy including a corticosteroid, an immunomodulator 
and primary nutrition therapy; or who are intolerant to or have contraindications for such therapies. 
Infliximab has been studied only in combination with conventional immunosuppressive therapy. 



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Ulcerative colitis 
Flixabi 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. 
 
Paediatric ulcerative colitis 
Flixabi is indicated for treatment of severely active ulcerative colitis in children and adolescents aged 6 to 
17 years, who have had an inadequate response to conventional therapy including corticosteroids and 6-MP 
or AZA, or who are intolerant to or have medical contraindications for such therapies. 
 
Ankylosing spondylitis 
Flixabi is indicated for treatment of severe, active ankylosing spondylitis, in adult patients who have 
responded inadequately to conventional therapy. 
 
Psoriatic arthritis 
Flixabi is indicated for treatment of active and progressive psoriatic arthritis in adult patients when the 
response to previous DMARD therapy has been inadequate. 
Flixabi should be administered 
 in combination with methotrexate 
 or alone in patients who show intolerance to methotrexate or for whom methotrexate is contraindicated. 
Infliximab has been shown to improve physical function in patients with psoriatic arthritis, and 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). 
 
Psoriasis 
Flixabi is indicated for treatment of moderate to severe plaque psoriasis in adult patients who failed to 
respond to, or who have a contraindication to, or are intolerant to other systemic therapy including 
ciclosporin, methotrexate or psoralen ultra-violet A (PUVA) (see section 5.1). 
 
4.2 Posology and method of administration 
 
Flixabi treatment is to be initiated and supervised by qualified physicians experienced in the diagnosis and 
treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis or 
psoriasis. Flixabi should be administered intravenously. Flixabi infusions should be administered by 
qualified healthcare professionals trained to detect any infusion-related issues. Patients treated with Flixabi 
should be given the package leaflet and the patient reminder card. 
 
During Flixabi treatment, other concomitant therapies, e.g. corticosteroids and immunosuppressants should 
be optimised. 
 
Posology 
 
Adults (≥ 18 years) 
Rheumatoid arthritis 
3 mg/kg given as an intravenous infusion followed by additional 3 mg/kg infusion doses at 2 and 6 weeks 
after the first infusion, then every 8 weeks thereafter. 
 
Flixabi must be given concomitantly with methotrexate. 
 
Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. If a 
patient has an inadequate response or loses response after this period, consideration may be given to increase 
the dose step-wise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kg every 8 weeks. Alternatively, 
administration of 3 mg/kg as often as every 4 weeks may be considered. If adequate response is achieved, 
patients should be continued on the selected dose or dose frequency. Continued therapy should be carefully 



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reconsidered in patients who show no evidence of therapeutic benefit within the first 12 weeks of treatment 
or after dose adjustment. 
 
Moderately to severely active Crohn’s disease 
5 mg/kg given as an intravenous infusion followed by an additional 5 mg/kg infusion 2 weeks after the first 
infusion. If a patient does not respond after 2 doses, no additional treatment with Flixabi should be given. 
Available data do not support further Flixabi treatment, in patients not responding within 6 weeks of the 
initial infusion. 
 
In responding patients, the alternative strategies for continued treatment are: 
 Maintenance: Additional infusion of 5 mg/kg at 6 weeks after the initial dose, followed by infusions 

every 8 weeks or 
 Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur (see ‘Re-

administration’ below and section 4.4). 
 
Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but who 
lost response indicate that some patients may regain response with dose escalation (see section 5.1). 
Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit 
after dose adjustment. 
 
Fistulising, active Crohn’s disease 
5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusions at 2 and 6 weeks after the 
first infusion. If a patient does not respond after 3 doses, no additional treatment with Flixabi should be given. 
 
In responding patients, the alternative strategies for continued treatment are: 
 Maintenance: Additional infusions of 5 mg/kg every 8 weeks or 
 Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur followed by 

infusions of 5 mg/kg every 8 weeks (see ‘Re-administration’ below and section 4.4). 
 
Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but who 
lost response indicate that some patients may regain response with dose escalation (see section 5.1). 
Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit 
after dose adjustment. 
 
In Crohn’s disease, experience with re-administration if signs and symptoms of disease recur is limited and 
comparative data on the benefit/risk of the alternative strategies for continued treatment are lacking. 
 
Ulcerative colitis 
5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks 
after the first infusion, then every 8 weeks thereafter. 
 
Available data suggest that the clinical response is usually achieved within 14 weeks of treatment, i.e. three 
doses. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic 
benefit within this time period. 
 
Ankylosing spondylitis 
5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks 
after the first infusion, then every 6 to 8 weeks. If a patient does not respond by 6 weeks (i.e. after 2 doses), 
no additional treatment with Flixabi should be given. 
 
Psoriatic arthritis 
5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks 
after the first infusion, then every 8 weeks thereafter. 
 
Psoriasis 



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5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks 
after the first infusion, then every 8 weeks thereafter. If a patient shows no response after 14 weeks (i.e. after 
4 doses), no additional treatment with Flixabi should be given. 
 
Re-administration for Crohn’s disease and rheumatoid arthritis 
If the signs and symptoms of disease recur, Flixabi can be re-administered within 16 weeks following the last 
infusion. In clinical studies, delayed hypersensitivity reactions have been uncommon and have occurred after 
infliximab-free intervals of less than 1 year (see sections 4.4 and 4.8). The safety and efficacy of re-
administration after an infliximab-free interval of more than 16 weeks has not been established. This applies 
to both Crohn’s disease patients and rheumatoid arthritis patients. 
 
Re-administration for ulcerative colitis 
The safety and efficacy of re-administration, other than every 8 weeks, has not been established (see sections 
4.4 and 4.8). 
 
Re-administration for ankylosing spondylitis 
The safety and efficacy of re-administration, other than every 6 to 8 weeks, has not been established (see 
sections 4.4 and 4.8). 
 
Re-administration for psoriatic arthritis 
The safety and efficacy of re-administration, other than every 8 weeks, has not been established (see sections 
4.4 and 4.8). 
 
Re-administration for psoriasis 
Limited experience from re-treatment with one single infliximab dose in psoriasis after an interval of 
20 weeks suggests reduced efficacy and a higher incidence of mild to moderate infusion reactions when 
compared to the initial induction regimen (see section 5.1). 
 
Limited experience from re-treatment following disease flare by a re-induction regimen suggests a higher 
incidence of infusion reactions, including serious ones, when compared to 8-weekly maintenance treatment 
(see section 4.8). 
 
Re-administration across indications 
In case maintenance therapy is interrupted, and there is a need to restart treatment, use of a re-induction 
regimen is not recommended (see section 4.8). In this situation, Flixabi should be re-initiated as a single dose 
followed by the maintenance dose recommendations described above. 
 
Special populations 
Elderly  
Specific studies of infliximab in elderly patients have not been conducted. No major age-related differences 
in clearance or volume of distribution were observed in clinical studies. No dose adjustment is required (see 
section 5.2). For more information about the safety of infliximab in elderly patients (see sections 4.4 and 4.8). 
 
Renal and/or hepatic impairment 
Infliximab has not been studied in these patient populations. No dose recommendations can be made (see 
section 5.2). 
 
Paediatric population 
 
Crohn’s disease (6 to 17 years) 
5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks 
after the first infusion, then every 8 weeks thereafter. Available data do not support further infliximab 
treatment in children and adolescents not responding within the first 10 weeks of treatment (see section 5.1). 
 



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Some patients may require a shorter dosing interval to maintain clinical benefit, while for others a longer 
dosing interval may be sufficient. Patients who have had their dose interval shortened to less than 8 weeks 
may be at greater risk for adverse reactions. Continued therapy with a shortened interval should be carefully 
considered in those patients who show no evidence of additional therapeutic benefit after a change in dosing 
interval. 
 
The safety and efficacy of infliximab have not been studied in children with Crohn’s disease below the age 
of 6 years. Currently available pharmacokinetic data are described in section 5.2 but no recommendation on 
a posology can be made in children younger than 6 years. 
 
Ulcerative colitis (6 to 17 years) 
5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks 
after the first infusion, then every 8 weeks thereafter. Available data do not support further infliximab 
treatment in paediatric patients not responding within the first 8 weeks of treatment (see section 5.1). 
 
The safety and efficacy of infliximab have not been studied in children with ulcerative colitis below the age 
of 6 years. Currently available pharmacokinetic data are described in section 5.2 but no recommendation on 
a posology can be made in children younger than 6 years. 
 
Psoriasis 
The safety and efficacy of infliximab in children and adolescents younger than 18 years for the indication of 
psoriasis have not been established. Currently available data are described in section 5.2 but no 
recommendation on a posology can be made. 
 
Juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis 
The safety and efficacy of infliximab in children and adolescents younger than 18 years for the indications of 
juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis have not been established. 
Currently available data are described in section 5.2 but no recommendation on a posology can be made. 
 
Juvenile rheumatoid arthritis 
The safety and efficacy of infliximab in children and adolescents younger than 18 years for the indication of 
juvenile rheumatoid arthritis have not been established. Currently available data are described in sections 4.8 
and 5.2 but no recommendation on a posology can be made. 
 
Method of administration 
Flixabi should be administered intravenously over a 2-hour period. All patients administered Flixabi are to 
be observed for at least 1-2 hours post-infusion for acute infusion-related reactions. Emergency equipment, 
such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available. Patients may be 
pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol and infusion rate may be slowed 
in order to decrease the risk of infusion-related reactions especially if infusion-related reactions have 
occurred previously (see section 4.4). 
 
Shortened infusions across adult indications 
In carefully selected adult patients who have tolerated at least 3 initial 2-hour infusions of Flixabi (induction 
phase) and are receiving maintenance therapy, consideration may be given to administering subsequent 
infusions over a period of not less than 1 hour. If an infusion reaction occurs in association with a shortened 
infusion, a slower infusion rate may be considered for future infusions if treatment is to be continued. 
Shortened infusions at doses > 6 mg/kg have not been studied (see section 4.8). 
 
For preparation and administration instructions, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance, to other murine proteins, or to any of the excipients listed in section 
6.1. 



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Patients with tuberculosis or other severe infections such as sepsis, abscesses, and opportunistic infections 
(see section 4.4). 
 
Patients with moderate or severe heart failure (NYHA class III/IV) (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
In order to improve the traceability of biological medicinal products, the name and the batch number of the 
administered product should be clearly recorded. 
 
Infusion reactions and hypersensitivity 
Infliximab has been associated with acute infusion-related reactions, including anaphylactic shock, and 
delayed hypersensitivity reactions (see section 4.8). 
 
Acute infusion reactions including anaphylactic reactions may develop during (within seconds) or within a 
few hours following infusion. If acute infusion reactions occur, the infusion must be interrupted immediately. 
Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be 
available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol to 
prevent mild and transient effects. 
Antibodies to infliximab may develop and have been associated with an increased frequency of infusion 
reactions. A low proportion of the infusion reactions was serious allergic reactions. An association between 
development of antibodies to infliximab and reduced duration of response has also been observed. 
Concomitant administration of immunomodulators has been associated with lower incidence of antibodies to 
infliximab and a reduction in the frequency of infusion reactions. The effect of concomitant 
immunomodulator therapy was more profound in episodically-treated patients than in patients given 
maintenance therapy. Patients who discontinue immunosuppressants prior to or during infliximab treatment 
are at greater risk of developing these antibodies. Antibodies to infliximab cannot always be detected in 
serum samples. If serious reactions occur, symptomatic treatment must be given and further Flixabi infusions 
must not be administered (see section 4.8). 
 
In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest an increased 
risk for delayed hypersensitivity with increasing infliximab-free interval. Patients should be advised to seek 
immediate medical advice if they experience any delayed adverse reaction (see section 4.8). If patients are 
re-treated after a prolonged period, they must be closely monitored for signs and symptoms of delayed 
hypersensitivity. 
 
Infections 
Patients must be monitored closely for infections including tuberculosis before, during and after treatment 
with Flixabi. Because the elimination of infliximab may take up to six months, monitoring should be 
continued throughout this period. Further treatment with Flixabi must not be given if a patient develops a 
serious infection or sepsis. 
 
Caution should be exercised when considering the use of Flixabi in patients with chronic infection or a 
history of recurrent infections, including concomitant immunosuppressive therapy. Patients should be 
advised of and avoid exposure to potential risk factors for infection as appropriate. 
 
Tumour necrosis factor alpha (TNFα) mediates inflammation and modulates cellular immune responses. 
Experimental data show that TNFα is essential for the clearing of intracellular infections. Clinical experience 
shows that host defence against infection is compromised in some patients treated with infliximab. 
 
It should be noted that suppression of TNFα may mask symptoms of infection such as fever. Early 
recognition of atypical clinical presentations of serious infections and of typical clinical presentation of rare 
and unusual infections is critical in order to minimise delays in diagnosis and treatment. 



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Patients taking TNF-blockers are more susceptible to serious infections. 
Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral, and other 
opportunistic infections have been observed in patients treated with infliximab. Some of these infections 
have been fatal; the most frequently reported opportunistic infections with a mortality rate of > 5% include 
pneumocystosis, candidiasis, listeriosis and aspergillosis. 
Patients who develop a new infection while undergoing treatment with Flixabi, should be monitored closely 
and undergo a complete diagnostic evaluation. Administration of Flixabi should be discontinued if a patient 
develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be 
initiated until the infection is controlled. 
 
Tuberculosis 
There have been reports of active tuberculosis in patients receiving infliximab. It should be noted that in the 
majority of these reports tuberculosis was extrapulmonary, presenting as either local or disseminated disease. 
 
Before starting treatment with Flixabi, all patients must be evaluated for both active and inactive (‘latent’) 
tuberculosis. This evaluation should include a detailed medical history with personal history of tuberculosis 
or possible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. 
Appropriate screening tests, e.g. tuberculin skin test, chest X-ray, and/or Interferon Gamma Release Assay), 
should be performed in all patients (local recommendations may apply). It is recommended that the conduct 
of these tests should be recorded in the patient’s 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, Flixabi therapy must not be initiated (see section 4.3). 
 
If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be 
consulted. In all situations described below, the benefit/risk balance of Flixabi therapy should be very 
carefully considered. 
 
If inactive (‘latent’) tuberculosis is diagnosed, treatment for latent tuberculosis must be started with 
antituberculosis therapy before the initiation of Flixabi, and in accordance with local recommendations. 
 
In patients who have several or significant risk factors for tuberculosis and have a negative test for latent 
tuberculosis, antituberculosis therapy should be considered before the initiation of Flixabi. 
 
Use of anti-tuberculosis therapy should also be considered before the initiation of Flixabi in patients with a 
past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. 
Some cases of active tuberculosis have been reported in patients treated with Flixabi during and after 
treatment for latent tuberculosis. 
All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g. 
persistent cough, wasting/weight loss, low-grade fever) appear during or after Flixabi treatment. 
 
Invasive fungal infections 
In patients treated with Flixabi, an invasive fungal infection such as aspergillosis, candidiasis, 
pneumocystosis, histoplasmosis, coccidioidomycosis or blastomycosis should be suspected if they develop a 
serious systemic illness, and a physician with expertise in the diagnosis and treatment of invasive fungal 
infections should be consulted at an early stage when investigating these patients. 
Invasive fungal infections may present as disseminated rather than localised disease, and antigen and 
antibody testing may be negative in some patients with active infection. Appropriate empiric antifungal 
therapy should be considered while a diagnostic workup is being performed taking into account both the risk 
for severe fungal infection and the risks of antifungal therapy. 
 
For patients who have resided in or travelled to regions where invasive fungal infections such as 
histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of Flixabi 
treatment should be carefully considered before initiation of Flixabi therapy. 



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Fistulising Crohn’s disease 
Patients with fistulising Crohn’s disease with acute suppurative fistulas must not initiate Flixabi therapy until 
a source for possible infection, specifically abscess, has been excluded (see section 4.3). 
 
Hepatitis B (HBV) reactivation 
Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including infliximab, who are 
chronic carriers of this virus. Some cases have had fatal outcome. 
 
Patients should be tested for HBV infection before initiating treatment with Flixabi. For patients who test 
positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is 
recommended. Carriers of HBV who require treatment with Flixabi should be closely monitored for signs 
and symptoms of active HBV infection throughout therapy and for several months following termination of 
therapy. Adequate data of treating patients who are carriers of HBV with antiviral therapy in conjunction 
with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBV 
reactivation, Flixabi should be stopped and effective antiviral therapy with appropriate supportive treatment 
should be initiated. 
 
Hepatobiliary events 
Cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have been 
observed in the post-marketing experience of infliximab. Isolated cases of liver failure resulting in liver 
transplantation or death have occurred. Patients with symptoms or signs of liver dysfunction should be 
evaluated for evidence of liver injury. If jaundice and/or ALT elevations ≥ 5 times the upper limit of normal 
develop(s), Flixabi should be discontinued, and a thorough investigation of the abnormality should be 
undertaken. 
 
Concurrent administration of TNF-alpha inhibitor and anakinra 
Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another 
TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of 
the nature of the adverse reactions seen with combination of etanercept and anakinra therapy, similar 
toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the 
combination of Flixabi and anakinra is not recommended. 
 
Concurrent administration of TNF-alpha inhibitor and abatacept 
In clinical studies concurrent administration of TNF-antagonists and abatacept has been associated with an 
increased risk of infections including serious infections compared to TNF-antagonists alone, without 
increased clinical benefit. The combination of Flixabi and abatacept is not recommended. 
 
Concurrent administration with other biological therapeutics 
There is insufficient information regarding the concomitant use of infliximab with other biological 
therapeutics used to treat the same conditions as infliximab. The concomitant use of Flixabi with these 
biologics is not recommended because of the possibility of an increased risk of infection, and other potential 
pharmacological interactions. 
 
Switching between biological DMARDS 
Care should be taken and patients should continue to be monitored when switching from one biologic to 
another, since overlapping biological activity may further increase the risk for adverse reactions, including 
infection. 
 
Vaccinations 
It is recommended that patients, if possible, be brought up to date with all vaccinations in agreement with 
current vaccination guidelines prior to initiating Flixabi therapy. Patients on infliximab may receive 
concurrent vaccinations, except for live vaccines (see sections 4.5 and 4.6). 
 



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In a subset of 90 adult patients with rheumatoid arthritis from the ASPIRE study a similar proportion of 
patients in each treatment group (methotrexate plus: placebo [n = 17], 3 mg/kg [n = 27] or 6 mg/kg 
infliximab [n = 46]) mounted an effective two-fold increase in titers to a polyvalent pneumococcal vaccine, 
indicating that infliximab did not interfere with T-cell independent humoral immune responses. However, 
studies from the published literature in various indications (e.g. rheumatoid arthritis, psoriasis, Crohn’s 
disease) suggest that non-live vaccinations received during treatment with anti-TNF therapies, including 
infliximab, may elicit a lower immune response than in patients not receiving anti-TNF therapy. 
 
Live vaccines/therapeutic infectious agents 
In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with live 
vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines can result in 
clinical infections, including disseminated infections. The concurrent administration of live vaccines with 
Flixabi is not recommended. 
 
In infants exposed in utero to infliximab, fatal outcome due to disseminated Bacillus Calmette-Guérin (BCG) 
infection has been reported following administration of BCG vaccine after birth. At least a six month waiting 
period following birth is recommended before the administration of live vaccines to infants exposed in utero 
to infliximab (see section 4.6). 
 
Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for 
the treatment of cancer) could result in clinical infections, including disseminated infections. It is 
recommended that therapeutic infectious agents not be given concurrently with Flixabi. 
 
Autoimmune processes 
The relative deficiency of TNFα caused by anti-TNF therapy may result in the initiation of an autoimmune 
process. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with 
Flixabi and is positive for antibodies against double-stranded DNA, further treatment with Flixabi must not 
be given (see section 4.8). 
 
Neurological events 
Use of TNF-blocking agents, including infliximab, has been associated with cases of new onset or 
exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating 
disorders, including multiple sclerosis, and peripheral demyelinating disorders, including Guillain-Barré 
syndrome. In patients with pre-existing or recent onset of demyelinating disorders, the benefits and risks of 
anti-TNF treatment should be carefully considered before initiation of Flixabi therapy. Discontinuation of 
Flixabi should be considered if these disorders develop. 
 
Malignancies and lymphoproliferative disorders 
In the controlled portions of clinical studies of TNF-blocking agents, more cases of malignancies including 
lymphoma have been observed among patients receiving a TNF blocker compared with control patients. 
During clinical studies of infliximab across all approved indications the incidence of lymphoma in 
infliximab-treated patients was higher than expected in the general population, but the occurrence of 
lymphoma 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 risk estimation. 
 
In an exploratory clinical study evaluating the use of infliximab in patients with moderate to severe chronic 
obstructive pulmonary disease (COPD), more malignancies were reported in infliximab-treated patients 
compared with control patients. All patients had a history of heavy smoking. Caution should be exercised in 
considering treatment of patients with increased risk for malignancy due to heavy smoking. 
 
With the current knowledge, a risk for the development of lymphomas or other malignancies in patients 
treated with a TNF-blocking agent cannot be excluded (see section 4.8). Caution should be exercised when 
considering TNF-blocking therapy for patients with a history of malignancy or when considering continuing 
treatment in patients who develop a malignancy. 



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Caution should also be exercised in patients with psoriasis and a medical history of extensive 
immunosuppressant therapy or prolonged PUVA treatment. 
 
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years 
of age) treated with TNF-blocking agents (initiation of therapy ≤ 18 years of age), including infliximab 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 patients treated with TNF-blockers cannot be excluded. 
 
Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated 
with TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a very aggressive 
disease course and is usually fatal. Almost all patients had received treatment with AZA or 6-MP 
concomitantly with or immediately prior to a TNF-blocker. The vast majority of infliximab cases have 
occurred in patients with Crohn’s disease or ulcerative colitis and most were reported in adolescent or young 
adult males. The potential risk with the combination of AZA or 6-MP and Flixabi should be carefully 
considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with Flixabi 
cannot be excluded (see section 4.8). 
 
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, 
including infliximab (see section 4.8). Periodic skin examination is recommended, particularly for patients 
with risk factors for skin cancer. 
 
A population-based retrospective cohort study using data from Swedish national health registries found an 
increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab compared 
to biologics-naïve patients or the general population, including those over 60 years of age. Periodic screening 
should continue in women treated with infliximab, including those over 60 years of age. 
 
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. Current data do not indicate that infliximab treatment influences the risk for developing 
dysplasia or colon cancer. 
 
Since the possibility of increased risk of cancer development in patients with newly diagnosed dysplasia 
treated with infliximab is not established, the risk and benefits of continued therapy to the individual patients 
should be carefully considered by the clinician. 
 
Heart failure 
Flixabi should be used with caution in patients with mild heart failure (NYHA class I/II). Patients should be 
closely monitored and Flixabi must not be continued in patients who develop new or worsening symptoms of 
heart failure (see sections 4.3 and 4.8). 
 
Haematologic reactions 
There have been reports of pancytopenia, leucopenia, neutropenia, and thrombocytopenia in patients 
receiving TNF-blockers, including infliximab. 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). Discontinuation of Flixabi therapy should be considered in patients with confirmed 
significant haematologic abnormalities. 
 
Others 
There is limited safety experience of infliximab treatment in patients who have undergone surgical 
procedures, including arthroplasty. The long half-life of infliximab should be taken into consideration if a 



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surgical procedure is planned. A patient who requires surgery while on Flixabi should be closely monitored 
for infections, and appropriate actions should be taken. 
 
Failure to respond to treatment for Crohn’s disease may indicate the presence of a fixed fibrotic stricture that 
may require surgical treatment. There is no evidence to suggest that infliximab worsens or causes fibrotic 
strictures. 
 
Special populations 
 
Elderly 
The incidence of serious infections in infliximab-treated patients 65 years and older was greater than in those 
under 65 years of age. Some of those had a fatal outcome. Particular attention regarding the risk for infection 
should be paid when treating the elderly (see section 4.8). 
 
Paediatric population 
 
Infections 
In clinical studies, infections have been reported in a higher proportion of paediatric patients compared to 
adult patients (see section 4.8). 
 
Vaccinations 
It is recommended that paediatric patients, if possible, be brought up to date with all vaccinations in 
agreement with current vaccination guidelines prior to initiating Flixabi therapy. Paediatric patients on 
infliximab may receive concurrent vaccinations, except for live vaccines (see sections 4.5 and 4.6). 
 
Malignancies and lymphoproliferative disorders 
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years 
of age) treated with TNF-blocking agents (initiation of therapy ≤ 18 years of age), including infliximab 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-blockers cannot be 
excluded. 
 
Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with TNF-
blocking agents including infliximab. This rare type of T-cell lymphoma has a very aggressive disease 
course and is usually fatal. Almost all patients had received treatment with AZA or 
6-MP concomitantly with or immediately prior to a TNF-blocker. The vast majority of infliximab cases have 
occurred in patients with Crohn’s disease or ulcerative colitis and most were reported in adolescent or young 
adult males. The potential risk with the combination of AZA or 6-MP and Flixabi should be carefully 
considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with Flixabi 
cannot be excluded (see section 4.8). 
 
Sodium content 
Flixabi contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’. Flixabi is however, 
diluted in sodium chloride 9 mg/ml (0.9%) solution for infusion. This should be taken into consideration for 
patients on a controlled sodium diet (see section 6.6). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. 
 
In rheumatoid arthritis, psoriatic arthritis and Crohn's disease patients, there are indications that concomitant 
use of methotrexate and other immunomodulators reduces the formation of antibodies against infliximab and 
increases the plasma concentrations of infliximab. However, the results are uncertain due to limitations in the 
methods used for serum analyses of infliximab and antibodies against infliximab. 



13 
 

 
Corticosteroids do not appear to affect the pharmacokinetics of infliximab to a clinically relevant extent. 
 
The combination of Flixabi with other biological therapeutics used to treat the same conditions as Flixabi, 
including anakinra and abatacept, is not recommended (see section 4.4). 
 
It is recommended that live vaccines not be given concurrently with Flixabi. It is also recommended that live 
vaccines not be given to infants after in utero exposure to infliximab for at least 6 months following birth 
(see section 4.4). 
 
It is recommended that therapeutic infectious agents not be given concurrently with Flixabi (see section 4.4). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
Women of childbearing potential should consider the use of adequate contraception to prevent pregnancy 
and continue its use for at least 6 months after the last Flixabi treatment. 
 
Pregnancy 
The moderate number of prospectively collected pregnancies exposed to infliximab resulting in live birth 
with known outcomes, including approximately 1100 exposed during the first trimester, does not indicate an 
increase in the rate of malformation in the newborn. 
 
Based on an observational study from Northern Europe, an increased risk (OR, 95% CI; p-value) for C-
section (1.50, 1.14-1.96; p=0.0032), preterm birth (1.48, 1.05-2.09; p=0.024), small for gestational age (2.79, 
1.54-5.04; p=0.0007), and low birth weight (2.03, 1.41-2.94; p=0.0002) was observed in women exposed 
during pregnancy to infliximab (with or without immunomodulators/corticosteroids, 270 pregnancies) as 
compared to women exposed to immunomodulators and/or corticosteroids only (6,460 pregnancies). The 
potential contribution of exposure to inflixumab and/or the severity of the underlying disease in these 
outcomes remains unclear. 
 
Due to its inhibition of TNFα, infliximab administered during pregnancy could affect normal immune 
responses in the newborn. In a developmental toxicity study conducted in mice using an analogous antibody 
that selectively inhibits the functional activity of mouse TNFα, there was no indication of maternal toxicity, 
embryotoxicity or teratogenicity (see section 5.3). 
 
The available clinical experience is limited. Infliximab should only be used during pregnancy if clearly 
needed. 
 
Infliximab crosses the placenta and has been detected in the serum of infants up to 6 months following birth. 
After in utero exposure to infliximab, infants may be at increased risk of infection, including serious 
disseminated infection that can become fatal. Administration of live vaccines (e.g. BCG vaccine) to infants 
exposed to infliximab in utero is not recommended for at least 6 months after birth (see sections 4.4 and 4.5). 
Cases of agranulocytosis have also been reported (see section 4.8). 
 
Breast-feeding 
It is unknown whether infliximab is excreted in human milk or absorbed systemically after ingestion. 
Because human immunoglobulins are excreted in milk, women must not breast-feed for at least 6 months 
after Flixabi treatment. 
 
Fertility 
There are insufficient preclinical data to draw conclusions on the effects of infliximab on fertility and general 
reproductive function (see section 5.3). 
 



14 
 

4.7 Effects on ability to drive and use machines 
 
Flixabi may have a minor influence on the ability to drive and use machines. Dizziness may occur following 
administration of Flixabi (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Upper respiratory tract infection was the most common adverse drug reaction (ADR) reported in clinical 
trials, occurring in 25.3% of infliximab-treated patients compared with 16.5% of control patients. The most 
serious ADRs associated with the use of TNF blockers that have been reported for infliximab include HBV 
reactivation, CHF (congestive heart failure), serious infections (including sepsis, opportunistic infections and 
TB), serum sickness (delayed hypersensitivity reactions), haematologic reactions, systemic lupus 
erythematosus/lupus-like syndrome, demyelinating disorders, hepatobiliary events, lymphoma, HSTCL, 
leukaemia, Merkel cell carcinoma, melanoma, paediatric malignancy, sarcoidosis/sarcoid-like reaction, 
intestinal or perianal abscess (in Crohn’s disease), and serious infusion reactions (see section 4.4). 
 
Tabulated list of adverse reactions 
Table 1 lists ADRs based on experience from clinical studies as well as adverse reactions, some with fatal 
outcome, reported from post-marketing experience. Within the organ system classes, adverse reactions are 
listed under headings of frequency using the following categories: 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); very rare (< 1/10,000), not 
known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 
 

Table 1 
Undesirable effects in clinical studies and from post-marketing experience 

Infections and infestations 
 Very Common: Viral infection (e.g. influenza, herpes 

virus infection). 
 Common: Bacterial infections (e.g. sepsis, 

cellulitis, abscess). 
 Uncommon: Tuberculosis, fungal infections (e.g. 

candidiasis, onychomycosis). 
 Rare: Meningitis, opportunistic infections (such as 

invasive fungal infections [pneumocystosis, 

histoplasmosis, aspergillosis, coccidioidomycosis, 

cryptococcosis, blastomycosis], bacterial 

infections [atypical mycobacterial, listeriosis, 

salmonellosis], and viral infections 

[cytomegalovirus]), parasitic infections, hepatitis 

B reactivation. 
 Not known: Vaccine breakthrough infection (after in utero exposure to 

infliximab)*.  
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
 Rare: Lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s 

disease, leukaemia, melanoma, cervical cancer. 
 Not known: Hepatosplenic T-cell lymphoma (primarily in 

adolescents and young adult males with Crohn’s 
disease or ulcerative colitis), Merkel cell 
carcinoma. 

Blood and lymphatic system disorders 



15 
 

 Common: Neutropenia, leucopenia, anaemia, lymphadenopathy. 
 Uncommon: Thrombocytopenia, lymphopenia, lymphocytosis. 
 Rare: Agranulocytosis (including infants exposed in utero to 

infliximab), thrombotic thrombocytopenic purpura, 
pancytopenia, haemolytic anaemia, idiopathic 

thrombocytopenic purpura. 

Immune system disorders 

 Common: Allergic respiratory symptom. 
 Uncommon: Anaphylactic reaction, lupus-like syndrome, serum 

sickness or serum sickness-like reaction. 

 Rare: Anaphylactic shock, vasculitis, sarcoid-like 
reaction. 

Psychiatric disorders 
 Common: Depression, insomnia. 
 Uncommon: Amnesia, agitation, confusion, somnolence, 

nervousness. 
 Rare: Apathy. 
Nervous system disorders 

 Very common: Headache. 
 Common: Vertigo, dizziness, hypoaesthesia, paraesthesia. 
 Uncommon: Seizure, neuropathy. 
 Rare: Transverse myelitis, central nervous system 

demyelinating disorders (multiple sclerosis-like 

disease and optic neuritis), peripheral 

demyelinating disorders (such as Guillain-Barré 

syndrome, chronic inflammatory demyelinating 

polyneuropathy and multifocal motor neuropathy). 

 Not known: Cerebrovascular accidents in close temporal 
association with infusion. 

Eye disorders 

 Common: Conjunctivitis. 
 Uncommon: Keratitis, periorbital oedema, hordeolum. 
 Rare: Endophthalmitis. 
 Not known: Transient visual loss occurring during or within 2 

hours of infusion. 

Cardiac disorders 

 Common: Tachycardia, palpitation. 
 Uncommon: Cardiac failure (new onset or worsening), 

arrhythmia, syncope, bradycardia. 

 Rare: Cyanosis, pericardial effusion. 
 Not known: Myocardial ischaemia/myocardial infarction. 
Vascular disorders 

 Common: Hypotension, hypertension, ecchymosis, hot flush, 
flushing. 

 Uncommon: Peripheral ischaemia, thrombophlebitis, haematoma. 
 Rare: Circulatory failure, petechia, vasospasm. 
Respiratory, thoracic and mediastinal disorders 

 Very common: Upper respiratory tract infection, sinusitis. 
 Common: Lower respiratory tract infection (e.g. bronchitis, 



16 
 

pneumonia), dyspnoea, epistaxis. 

 Uncommon: Pulmonary oedema, bronchospasm, pleurisy, pleural 
effusion. 

 Rare: Interstitial lung disease (including rapidly 
progressive disease, lung fibrosis and 

pneumonitis). 

Gastrointestinal disorders 

 Very common: Abdominal pain, nausea. 
 Common: Gastrointestinal haemorrhage, diarrhoea, dyspepsia, 

gastroesophageal reflux, constipation. 

 Uncommon: Intestinal perforation, intestinal stenosis, 
diverticulitis, pancreatitis, cheilitis. 

Hepatobiliary disorders 
 Common: Hepatic function abnormal, transaminases increased. 
 Uncommon: Hepatitis, hepatocellular damage, cholecystitis. 
 Rare: Autoimmune hepatitis, jaundice. 
 Not known: Liver failure. 
Skin and subcutaneous tissue disorders 

 Common: New onset or worsening psoriasis including pustular 
psoriasis (primarily palm & soles), urticaria, 

rash, pruritus, hyperhidrosis, dry skin, fungal 

dermatitis, eczema, alopecia. 

 Uncommon: Bullous eruption, seborrhoea, rosacea, skin 
papilloma, hyperkeratosis, abnormal skin 

pigmentation. 

 Rare: Toxic epidermal necrolysis, Stevens-Johnson 
Syndrome, erythema multiforme, furunculosis, linear 
IgA bullous dermatosis (LABD), acute generalised 
exanthematous pustulosis (AGEP), lichenoid reactions. 

 Not known: Worsening of symptoms of dermatomyositis. 
Musculoskeletal and connective tissue disorders 

 Common: Arthralgia, myalgia, back pain. 
Renal and urinary disorders 

 Common: Urinary tract infection. 
 Uncommon: Pyelonephritis. 
Reproductive system and breast disorders 

 Uncommon: Vaginitis. 
General disorders and administration site conditions 

 Very common: Infusion-related reaction, pain. 
 Common: Chest pain, fatigue, fever, injection site 

reaction, chills, oedema. 

 Uncommon: Impaired healing. 
 Rare: Granulomatous lesion. 
Investigations 

 Uncommon: Autoantibody positive. 
 Rare: Complement factor abnormal. 
* including bovine tuberculosis (disseminated BCG infection), see section 4.4 
 
Description of selected adverse reactions 
 



17 
 

Infusion-related reactions 
An infusion-related reaction was defined in clinical studies as any adverse event occurring during an infusion 
or within 1 hour after an infusion. In Phase III clinical studies, 18% of infliximab-treated patients compared 
with 5% of placebo-treated patients experienced an infusion-related reaction. Overall, a higher proportion of 
patients receiving infliximab monotherapy experienced an infusion-related reaction compared to patients 
receiving infliximab with concomitant immunomodulators. Approximately 3% of patients discontinued 
treatment due to infusion-related reactions and all patients recovered with or without medical therapy. Of 
infliximab-treated patients who had an infusion reaction during the induction period, through week 6, 27% 
experienced an infusion reaction during the maintenance period, week 7 through week 54. Of patients who 
did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the 
maintenance period. 
 
In a clinical study of patients with rheumatoid arthritis (ASPIRE), infusions were to be administered over 
2 hours for the first 3 infusions. The duration of subsequent infusions could be shortened to not less than 
40 minutes in patients who did not experience serious infusion reactions. In this trial, sixty six percent of the 
patients (686 out of 1,040) received at least one shortened infusion of 90 minutes or less and 44% of the 
patients (454 out of 1,040) received at least one shortened infusion of 60 minutes or less. Of the infliximab-
treated patients who received at least one shortened infusion, infusion-related reactions occurred in 15% of 
patients and serious infusion reactions occurred in 0.4% of patients. 
 
In a clinical study of patients with Crohn’s disease (SONIC), infusion-related reactions occurred in 
16.6% (27/163) of patients receiving infliximab monotherapy, 5% (9/179) of patients receiving infliximab in 
combination with AZA, and 5.6% (9/161) of patients receiving AZA monotherapy. One serious infusion 
reaction (< 1%) occurred in a patient on infliximab monotherapy. 
 
In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngeal oedema 
and severe bronchospasm, and seizure have been associated with infliximab administration (see section 4.4). 
Cases of transient visual loss occurring during or within 2 hours of infliximab infusion have been reported. 
Events (some fatal) of myocardial ischaemia/infarction and arrhythmia have been reported, some in close 
temporal association with infusion of infliximab; cerebrovascular accidents have also been reported in close 
temporal association with infusion of infliximab. 
 
Infusion reactions following re-administration of infliximab 
A clinical study in patients with moderate to severe psoriasis was designed to assess the efficacy and safety 
of long-term maintenance therapy versus re-treatment with an induction regimen of infliximab (maximum of 
four infusions at 0, 2, 6 and 14 weeks) following disease flare. Patients did not receive any concomitant 
immunosuppressant therapy. In the re-treatment arm, 4% (8/219) of patients experienced a serious infusion 
reaction versus < 1% (1/222) on maintenance therapy. The majority of serious infusion reactions occurred 
during the second infusion at week 2. The interval between the last maintenance dose and the first re-
induction dose ranged from 35-231 days. Symptoms included, but were not limited to, dyspnoea, urticaria, 
facial oedema, and hypotension. In all cases, infliximab treatment was discontinued and/or other treatment 
instituted with complete resolution of signs and symptoms. 
 
Delayed hypersensitivity 
In clinical studies delayed hypersensitivity reactions have been uncommon and have occurred after 
infliximab-free intervals of less than 1 year. In the psoriasis studies, delayed hypersensitivity reactions 
occurred early in the treatment course. Signs and symptoms included myalgia and/or arthralgia with fever 
and/or rash, with some patients experiencing pruritus, facial, hand or lip oedema, dysphagia, urticaria, sore 
throat and headache. 
 
There are insufficient data on the incidence of delayed hypersensitivity reactions after infliximab-free 
intervals of more than 1 year but limited data from clinical studies suggest an increased risk for delayed 
hypersensitivity with increasing infliximab-free interval (see section 4.4). 
In a 1-year clinical study with repeated infusions in patients with Crohn's disease (ACCENT I study), the 
incidence of serum sickness-like reactions was 2.4%. 



18 
 

 
Immunogenicity 
Patients who developed antibodies to infliximab were more likely (approximately 2-3 fold) to develop 
infusion-related reactions. Use of concomitant immunosuppressant agents appeared to reduce the frequency 
of infusion-related reactions. 
In clinical studies using single and multiple infliximab doses ranging from 1 to 20 mg/kg, antibodies to 
infliximab were detected in 14% of patients with any immunosuppressant therapy, and in 24% of patients 
without immunosuppressant therapy. In rheumatoid arthritis patients who received the recommended 
repeated treatment dose regimens with methotrexate, 8% of patients developed antibodies to infliximab. In 
psoriatic arthritis patients who received 5 mg/kg with and without methotrexate, antibodies occurred overall 
in 15% of patients (antibodies occurred in 4% of patients receiving methotrexate and in 26% of patients not 
receiving methotrexate at baseline). In Crohn's disease patients who received maintenance treatment, 
antibodies to infliximab occurred overall in 3.3% of patients receiving immunosuppressants and in 13.3% of 
patients not receiving immunosuppressants. The antibody incidence was 2-3 fold higher for patients treated 
episodically. Due to methodological limitations, a negative assay did not exclude the presence of antibodies 
to infliximab. Some patients who developed high titres of antibodies to infliximab had evidence of reduced 
efficacy. In psoriasis patients treated with infliximab as a maintenance regimen in the absence of 
concomitant immunomodulators, approximately 28% developed antibodies to infliximab (see section 4.4: 
“Infusion reactions and hypersensitivity”). 
 
Infections 
Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral, and other 
opportunistic infections have been observed in patients receiving infliximab. Some of these infections have 
been fatal; the most frequently reported opportunistic infections with a mortality rate of > 5% include 
pneumocystosis, candidiasis, listeriosis and aspergillosis (see section 4.4). 
 
In clinical studies 36% of infliximab-treated patients were treated for infections compared with 25% of 
placebo-treated patients. 
 
In rheumatoid arthritis clinical studies, the incidence of serious infections including pneumonia was higher in 
infliximab plus methotrexate-treated patients compared with methotrexate alone especially at doses of 
6 mg/kg or greater (see section 4.4). 
 
In post-marketing spontaneous reporting, infections are the most common serious adverse reaction. Some of 
the cases have resulted in a fatal outcome. Nearly 50% of reported deaths have been associated with 
infection. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis and tuberculosis with extra-
pulmonary location have been reported (see section 4.4). 
 
Malignancies and lymphoproliferative disorders 
In clinical studies with infliximab in which 5,780 patients were treated, representing 5,494 patient years, 
5 cases of lymphomas and 26 non-lymphoma malignancies were detected as compared with no lymphomas 
and 1 non-lymphoma malignancy in 1,600 placebo-treated patients representing 941 patient years. 
 
In long-term safety follow-up of clinical studies with infliximab of up to 5 years, representing 6,234 patients-
years (3,210 patients), 5 cases of lymphoma and 38 cases of non-lymphoma malignancies were reported. 
 
Cases of malignancies, including lymphoma, have also been reported in the post-marketing setting (see 
section 4.4). 
 
In an exploratory clinical study involving patients with moderate to severe COPD who were either current 
smokers or ex-smokers, 157 adult patients were treated with infliximab at doses similar to those used in 
rheumatoid arthritis and Crohn’s disease. Nine of these patients developed malignancies, including 
1 lymphoma. The median duration of follow-up was 0.8 years (incidence 5.7% [95% CI 2.65%-10.6%]. 
There was one reported malignancy amongst 77 control patients (median duration of follow-up 0.8 years; 



19 
 

incidence 1.3% [95% CI 0.03%-7.0%]). The majority of the malignancies developed in the lung or head and 
neck. 
 
A population-based retrospective cohort study found an increased incidence of cervical cancer in women 
with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general 
population, including those over 60 years of age (see section 4.4). 
 
In addition, post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated 
with infliximab with the vast majority of cases occurring in Crohn’s disease and ulcerative colitis, and most 
of whom were adolescent or young adult males (see section 4.4). 
 
Heart failure 
In a Phase II study aimed at evaluating infliximab in CHF, higher incidence of mortality due to worsening of 
heart failure were seen in patients treated with infliximab, especially those treated with the higher dose of 10 
mg/kg (i.e. twice the maximum approved dose). In this study 150 patients with NYHA Class III-IV CHF 
(left ventricular ejection fraction ≤ 35%) were treated with 3 infusions of infliximab 5 mg/kg, 10 mg/kg, or 
placebo over 6 weeks. At 38 weeks, 9 of 101 patients treated with infliximab (2 at 5 mg/kg and 7 at 10 
mg/kg) died compared to one death among the 49 patients on placebo. 
There have been post-marketing reports of worsening heart failure, with and without identifiable 
precipitating factors, in patients taking infliximab. There have also been post-marketing reports of new onset 
heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of 
these patients have been under 50 years of age. 
 
Hepatobiliary events 
In clinical studies, mild or moderate elevations of ALT and AST have been observed in patients receiving 
infliximab without progression to severe hepatic injury. Elevations of ALT ≥ 5 x Upper Limit of Normal 
(ULN) have been observed (see Table 2). Elevations of aminotransferases were observed (ALT more 
common than AST) in a greater proportion of patients receiving infliximab than in controls, both when 
infliximab was given as monotherapy and when it was used in combination with other immunosuppressive 
agents. Most aminotransferase abnormalities were transient; however, a small number of patients 
experienced more prolonged elevations. In general, patients who developed ALT and AST elevations were 
asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of 
infliximab, or modification of concomitant therapy. In post-marketing surveillance, cases of jaundice and 
hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving infliximab 
(see section 4.4). 
 
 

Table 2 
Proportion of patients with increased ALT activity in clinical studies 

Indication Number of patients
3 Median follow-up (wks)4 ≥ 3 x ULN ≥ 5 x ULN 

placebo infliximab placebo infliximab placebo infliximab placebo infliximab 
Rheumatoid 
arthritis1 375 1,087 58.1 58.3 3.2% 3.9% 0.8% 0.9% 

Crohn’s 
disease2 324 1034 53.7 54.0 2.2% 4.9% 0.0% 1.5% 

Paediatric 
Crohn’s 
disease 

N/A 139 N/A 53.0 N/A 4.4% N/A 1.5% 

Ulcerative 
colitis 242 482 30.1 30.8 1.2% 2.5% 0.4% 0.6% 

Paediatric 
Ulcerative 
colitis 

N/A 60 N/A 49.4 N/A 6.7% N/A 1.7% 

Ankylosing 
spondylitis 76 275 24.1 101.9 0.0% 9.5% 0.0% 3.6% 



20 
 

Indication Number of patients
3 Median follow-up (wks)4 ≥ 3 x ULN ≥ 5 x ULN 

placebo infliximab placebo infliximab placebo infliximab placebo infliximab 
Psoriatic 
arthritis 98 191 18.1 39.1 0.0% 6.8% 0.0% 2.1% 

Plaque 
psoriasis 281 1,175 16.1 50.1 0.4% 7.7% 0.0% 3.4% 
1 Placebo patients received methotrexate while infliximab patients received both infliximab and methotrexate.  
2 Placebo patients in the 2 Phase III studies in Crohn’s disease, ACCENT I and ACCENT II, received an initial dose of 5 mg/kg 
infliximab at study start and were on placebo in the maintenance phase. Patients who were randomised to the placebo maintenance 
group and then later crossed over to infliximab are included in the infliximab group in the ALT analysis. In the Phase IIIb trial in 
Crohn’s disease, SONIC, placebo patients received AZA 2.5 mg/kg/day as active control in addition to placebo infliximab infusions.  
3 Number of patients evaluated for ALT.  
4 Median follow-up is based on patients treated. 
 
 
Antinuclear antibodies (ANA)/Anti-double-stranded DNA (dsDNA) antibodies 
Approximately half of infliximab-treated patients in clinical studies who were ANA negative at baseline 
developed a positive ANA during the study compared with approximately one fifth of placebo-treated 
patients. Anti-dsDNA antibodies were newly detected in approximately 17% of infliximab-treated patients 
compared with 0% of placebo-treated patients. At the last evaluation, 57% of infliximab-treated patients 
remained anti-dsDNA positive. Reports of lupus and lupus-like syndromes, however, remain uncommon (see 
section 4.4). 
 
Paediatric population 
 
Juvenile rheumatoid arthritis patients 
Infliximab was studied in a clinical study in 120 patients (age range: 4-17 years old) with active juvenile 
rheumatoid arthritis despite methotrexate. Patients received 3 or 6 mg/kg infliximab as a 3-dose induction 
regimen (weeks 0, 2, 6 or weeks 14, 16, 20, respectively) followed by maintenance therapy every 8 weeks, in 
combination with methotrexate. 
 
Infusion reactions 
Infusion reactions occurred in 35% of patients with juvenile rheumatoid arthritis receiving 3 mg/kg 
compared with 17.5% of patients receiving 6 mg/kg. In the 3 mg/kg infliximab group, 4 out of 60 patients 
had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were 
among the serious infusion reactions). In the 6 mg/kg group, 2 out of 57 patients had a serious infusion 
reaction, one of whom had a possible anaphylactic reaction (see section 4.4). 
 
Immunogenicity 
Antibodies to infliximab developed in 38% of patients receiving 3 mg/kg compared with 12% of patients 
receiving 6 mg/kg. The antibody titres were notably higher for the 3 mg/kg compared to the 6 mg/kg group. 
 
Infections 
Infections occurred in 68% (41/60) of children receiving 3 mg/kg over 52 weeks, 65% (37/57) of children 
receiving infliximab 6 mg/kg over 38 weeks and 47% (28/60) of children receiving placebo over 14 weeks 
(see section 4.4). 
 
Paediatric Crohn’s disease patients 
The following adverse reactions were reported more commonly in paediatric Crohn’s disease patients in the 
REACH study (see section 5.1) than in adult Crohn’s disease patients: anaemia (10.7%), blood in stool 
(9.7%), leucopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bacterial infection 
(5.8%), and respiratory tract allergic reaction (5.8%). In addition, bone fracture (6.8%) was reported, 
however, a causal association has not been established. Other special considerations are discussed below. 
 
Infusion-related reactions 



21 
 

In REACH, 17.5% of randomised patients experienced 1 or more infusion reactions. There were no serious 
infusion reactions, and 2 subjects in REACH had non-serious anaphylactic reactions. 
 
Immunogenicity 
Antibodies to infliximab were detected in 3 (2.9%) paediatric patients. 
 
Infections 
In the REACH study, infections were reported in 56.3% of randomised subjects treated with infliximab. 
Infections were reported more frequently for subjects who received q8 week as opposed to q12 week 
infusions (73.6% and 38.0%, respectively), while serious infections were reported for 3 subjects in the 
q8 week and 4 subjects in the q12 week maintenance treatment group. The most commonly reported 
infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious 
infection was abscess. Three cases of pneumonia (1 serious) and 2 cases of herpes zoster (both non-serious) 
were reported. 
 
Paediatric ulcerative colitis patients 
Overall, the adverse reactions reported in the paediatric ulcerative colitis trial (C0168T72) and adult 
ulcerative colitis (ACT 1 and ACT 2) studies were generally consistent. In C0168T72, the most common 
adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache. 
The most common adverse event was worsening of ulcerative colitis, the incidence of which was higher in 
patients on the q12 week vs. the q8 week dosing regimen. 
 
Infusion-related reactions 
Overall, 8 (13.3%) of 60 treated patients experienced one or more infusion reactions, with 4 of 22 (18.2%) in 
the q8 week and 3 of 23 (13.0%) in the q12 week treatment maintenance group. No serious infusion 
reactions were reported. All infusion reactions were mild or moderate in intensity. 
 
Immunogenicity 
Antibodies to infliximab were detected in 4 (7.7%) patients through week 54. 
 
Infections 
Infections were reported in 31 (51.7%) of 60 treated patients in C0168T72 and 22 (36.7%) required oral or 
parenteral antimicrobial treatment. The proportion of patients with infections in C0168T72 was similar to 
that in the paediatric Crohn’s disease study (REACH) but higher than the proportion in the adults ulcerative 
colitis studies (ACT 1 and ACT 2). The overall incidence of infections in C0168T72 was 13/22 (59%) in the 
every 8 week maintenance treatment group and 14/23 (60.9%) in the every 12 week maintenance treatment 
group. Upper respiratory tract infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequently 
reported respiratory system infections. Serious infections were reported in 12% (7/60) of all treated patients. 
 
In this study, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group 
(45/60 [75.0%]) vs.15/60 [25.0%]). While the numbers of patients in each subgroup are too small to make 
any definitive conclusions about the effect of age on safety events, there were higher proportions of patients 
with serious adverse events and discontinuation due to adverse events in the younger age group than in the 
older age group. While the proportion of patients with infections was also higher in the younger age group, 
for serious infections, the proportions were similar in the two age groups. Overall proportions of adverse 
events and infusion reactions were similar between the 6 to 11 and 12 to 17 year age groups. 
 
Post-marketing experience 
Post-marketing spontaneous serious adverse reactions with infliximab in the paediatric population have 
included malignancies including hepatosplenic T-cell lymphomas, transient hepatic enzyme abnormalities, 
lupus-like syndromes, and positive auto-antibodies (see sections 4.4 and 4.8). 
 
Additional information on special populations 
Elderly 



22 
 

In rheumatoid arthritis clinical studies, the incidence of serious infections was greater in infliximab plus 
methotrexate-treated patients 65 years and older (11.3%) than in those under 65 years of age (4.6%). In 
patients treated with methotrexate alone, the incidence of serious infections was 5.2% in patients 65 years 
and older compared to 2.7% in patients under 65 (see section 4.4). 
 
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 case of overdose has been reported. Single doses up to 20 mg/kg have been administered without toxic 
effects. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunosuppressants, tumour necrosis factor alpha (TNFα) inhibitors, ATC 
code: L04AB02. 
 
Flixabi 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 
Infliximab is a chimeric human-murine monoclonal antibody that binds with high affinity to both soluble and 
transmembrane forms of TNFα but not to lymphotoxin α (TNFβ). 
 
Pharmacodynamic effects 
Infliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays. Infliximab 
prevented disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human 
TNFα and when administered after disease onset, it allowed eroded joints to heal. In vivo, infliximab rapidly 
forms stable complexes with human TNFα, a process that parallels the loss of TNFα bioactivity. 
 
Elevated concentrations of TNFα have been found in the joints of rheumatoid arthritis patients and correlate 
with elevated disease activity. In rheumatoid arthritis, treatment with infliximab reduced infiltration of 
inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular 
adhesion, chemoattraction and tissue degradation. After infliximab treatment, patients exhibited decreased 
levels of serum interleukin 6 (IL-6) and C-reactive protein (CRP), and increased haemoglobin levels in 
rheumatoid arthritis patients with reduced haemoglobin levels, compared with baseline. Peripheral blood 
lymphocytes further showed no significant decrease in number or in proliferative responses to in vitro 
mitogenic stimulation when compared with untreated patients’ cells. In psoriasis patients, treatment with 
infliximab resulted in decreases in epidermal inflammation and normalisation of keratinocyte differentiation 
in psoriatic plaques. In psoriatic arthritis, short term treatment with infliximab reduced the number of T-cells 
and blood vessels in the synovium and psoriatic skin. 
 
Histological evaluation of colonic biopsies, obtained before and 4 weeks after administration of infliximab, 
revealed a substantial reduction in detectable TNFα. Infliximab treatment of Crohn’s disease patients was 
also associated with a substantial reduction of the commonly elevated serum inflammatory marker, CRP. 
Total peripheral white blood cell counts were minimally affected in infliximab-treated patients, although 
changes in lymphocytes, monocytes and neutrophils reflected shifts towards normal ranges. Peripheral blood 

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


23 
 

mononuclear cells (PBMC) from infliximab-treated patients showed undiminished proliferative 
responsiveness to stimuli compared with untreated patients, and no substantial changes in cytokine 
production by stimulated PBMC were observed following treatment with infliximab. Analysis of lamina 
propria mononuclear cells obtained by biopsy of the intestinal mucosa showed that infliximab treatment 
caused a reduction in the number of cells capable of expressing TNFα and interferon γ. Additional 
histological studies provided evidence that treatment with infliximab reduces the infiltration of inflammatory 
cells into affected areas of the intestine and the presence of inflammation markers at these sites. Endoscopic 
studies of intestinal mucosa have shown evidence of mucosal healing in infliximab-treated patients.  
 
Clinical efficacy and safety 
Adult rheumatoid arthritis 
The efficacy of infliximab was assessed in two multicentre, randomised, double-blind, pivotal clinical 
studies: ATTRACT and ASPIRE. In both studies concurrent use of stable doses of folic acid, oral 
corticosteroids (≤ 10 mg/day) and/or non-steroidal anti-inflammatory drugs (NSAIDs) was permitted. 
 
The primary endpoints were the reduction of signs and symptoms as assessed by the American College of 
Rheumatology criteria (ACR20 for ATTRACT, landmark ACR-N for ASPIRE), the prevention of structural 
joint damage, and the improvement in physical function. A reduction in signs and symptoms was defined to 
be at least a 20% improvement (ACR20) in both tender and swollen joint counts, and in 3 of the following 
5 criteria: (1) evaluator’s global assessment, (2) patient’s global assessment, (3) functional/disability measure, 
(4) visual analogue pain scale and (5) erythrocyte sedimentation rate or C-reactive protein. ACR-N uses the 
same criteria as the ACR20, calculated by taking the lowest percent improvement in swollen joint count, 
tender joint count, and the median of the remaining 5 components of the ACR response. Structural joint 
damage (erosions and joint space narrowing) in both hands and feet was measured by the change from 
baseline in the total van der Heijde-modified Sharp score (0-440). The Health Assessment Questionnaire 
(HAQ; scale 0-3) was used to measure patients’ average change from baseline scores over time, in physical 
function. 
 
The ATTRACT study evaluated responses at 30, 54 and 102 weeks in a placebo-controlled study of 
428 patients with active rheumatoid arthritis despite treatment with methotrexate. Approximately 50% of 
patients were in functional Class III. Patients received placebo, 3 mg/kg or 10 mg/kg infliximab at weeks 0, 2 
and 6, and then every 4 or 8 weeks thereafter. All patients were on stable methotrexate doses (median 
15 mg/wk) for 6 months prior to enrolment and were to remain on stable doses throughout the study. 
Results from week 54 (ACR20, total van der Heijde-modified Sharp score and HAQ) are shown in Table 3. 
Higher degrees of clinical response (ACR50 and ACR70) were observed in all infliximab groups at 30 and 
54 weeks compared with methotrexate alone. 
 
A reduction in the rate of the progression of structural joint damage (erosions and joint space narrowing) was 
observed in all infliximab groups at 54 weeks (Table 3). 
 
The effects observed at 54 weeks were maintained through 102 weeks. Due to a number of treatment 
withdrawals, the magnitude of the effect difference between infliximab and the methotrexate alone group 
cannot be defined. 
 

Table 3 
Effects on ACR20, Structural Joint Damage and Physical Function at week 54, ATTRACT 

 Infliximabb 

 
Controla 3 mg/kg q 8 wks 

3 mg/kg 
q 4 wks 

10 mg/kg 
q 8 wks 

10 mg/kg  
q 4 wks 

All 
infliximabb 

Patients with ACR20 response/ 
Patients evaluated (%) 

15/88 
(17%) 

36/86 
(42%) 

41/86 
(48%) 

51/87 
(59%) 

48/81 
(59%) 

176/340 
(52%) 

 
Total scored (van der 
Heijde-modified Sharp score) 

      

Change from baseline (Mean ± SDc) 7.0 ± 10.3 1.3 ± 6.0 1.6 ± 8.5 0.2 ± 3.6 -0.7 ± 3.8 0.6 ± 5.9 



24 
 

 Infliximabb 

 
Controla 3 mg/kg q 8 wks 

3 mg/kg 
q 4 wks 

10 mg/kg 
q 8 wks 

10 mg/kg  
q 4 wks 

All 
infliximabb 

Median 
(Interquartile range) 

4.0  
(0.5,9.7) 

0.5 
(-1.5,3.0) 

0.1 
(-2.5,3.0) 

0.5 
(-1.5,2.0) 

-0.5 
(-3.0,1.5) 

0.0 
(-1.8,2.0) 

Patients with no deterioration/patients 
evaluated (%)c 

13/64 (20%) 34/71 (48%) 35/71 (49%) 37/77 (48%) 44/66 (67%) 150/285 (53%) 
 
HAQ change from baseline over 
timee (patients evaluated) 87 86 85 87 81 339 

Mean ± SDc 0.2 ± 0.3 0.4 ± 0.3 0.5 ± 0.4 0.5 ± 0.5 0.4 ± 0.4 0.4 ± 0.4 
a control = All patients had active RA despite treatment with stable methotrexate doses for 6 months prior to enrolment and were to 
remain on stable doses throughout the study. Concurrent use of stable doses of oral corticosteroids (≤ 10 mg/day) and/or NSAIDs 
was permitted, and folate supplementation was given. 
b all infliximab doses given in combination with methotrexate and folate with some on corticosteroids and/or NSAIDs 
c p < 0.001, for each infliximab treatment group vs. control 
d greater values indicate more joint damage. 
e HAQ = Health Assessment Questionnaire; greater values indicate less disability. 
 
The ASPIRE study evaluated responses at 54 weeks in 1,004 methotrexate naive patients with early 
(≤ 3 years disease duration, median 0.6 years) active rheumatoid arthritis (median swollen and tender joint 
count of 19 and 31, respectively). All patients received methotrexate (optimised to 20 mg/wk by week 8) and 
either placebo, 3 mg/kg or 6 mg/kg infliximab at weeks 0, 2, and 6 and every 8 weeks thereafter. Results 
from week 54 are shown in Table 4. 
 
After 54 weeks of treatment, both doses of infliximab + methotrexate resulted in statistically significantly 
greater improvement in signs and symptoms compared to methotrexate alone as measured by the proportion 
of patients achieving ACR20, 50 and 70 responses. 
 
In ASPIRE, more than 90% of patients had at least two evaluable X-rays. Reduction in the rate of 
progression of structural damage was observed at weeks 30 and 54 in the infliximab + methotrexate groups 
compared to methotrexate alone. 
 

Table 4 
Effects on ACRn, Structural Joint Damage and Physical Function at week 54, ASPIRE 

         Infliximab + MTX 
 Placebo + MTX 3 mg/kg 6 mg/kg Combined 

Subjects randomised          282        359      363         722 
Percentage ACR improvement     
Mean ± SDa 24.8 ± 59.7 37.3 ± 52.8 42.0 ± 47.3 39.6 ± 50.1 
Change from baseline in total van der 
Heijde-modified Sharp scoreb 

    

Mean ± SDa 3.70 ± 9.61 0.42 ± 5.82 0.51 ± 5.55 0.46 ± 5.68 
Median            0.43         0.00         0.00          0.00 
Improvement from baseline in HAQ 
averaged over time from week 30 to 
week 54 

    

Mean ± SDd 0.68 ± 0.63 0.80 ± 0.65 0.88 ± 0.65 0.84 ± 0.65 
 a p < 0.001, for each infliximab treatment group vs control 
 b greater values indicate more joint damage. 
 c HAQ = Health Assessment Questionnaire; greater values indicate less disability. 
 d p = 0.030 and < 0.001 for the 3 mg/kg and 6 mg/kg treatment groups respectively vs. placebo + MTX. 
 
Data to support dose titration in rheumatoid arthritis come from ATTRACT, ASPIRE and the START study. 
START was a randomised, multicentre, double-blind, 3-arm, parallel-group safety study. In one of the study 



25 
 

arms (group 2, n=329), patients with an inadequate response were allowed to dose titrate with 1.5 mg/kg 
increments from 3 up to 9 mg/kg. The majority (67%) of these patients did not require any dose titration. Of 
the patients who required a dose titration, 80% achieved clinical response and the majority (64%) of these 
required only one adjustment of 1.5 mg/kg. 
 
Adult Crohn’s disease 
Induction treatment in moderately to severely active Crohn’s disease 
The efficacy of a single dose treatment with infliximab was assessed in 108 patients with active Crohn’s 
disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 ≤ 400) in a randomised, double-blinded, placebo-
controlled, dose-response study. Of these 108 patients, 27 were treated with the recommended dosage of 
infliximab 5 mg/kg. All patients had experienced an inadequate response to prior conventional therapies. 
Concurrent use of stable doses of conventional therapies was permitted, and 92% of patients continued to 
receive these therapies. 
 
The primary endpoint was the proportion of patients who experienced a clinical response, defined as a 
decrease in CDAI by ≥ 70 points from baseline at the 4-week evaluation and without an increase in the use 
of medicinal products or surgery for Crohn’s disease. Patients who responded at week 4 were followed to 
week 12. Secondary endpoints included the proportion of patients in clinical remission at week 4 
(CDAI < 150) and clinical response over time. 
 
At week 4, following administration of a single dose, 22/27 (81%) of infliximab-treated patients receiving a 
5 mg/kg dose achieved a clinical response vs. 4/25 (16%) of the placebo-treated patients (p < 0.001). Also at 
week 4, 13/27 (48%) of infliximab-treated patients achieved a clinical remission (CDAI < 150) vs. 1/25 (4%) 
of placebo-treated patients. A response was observed within 2 weeks, with a maximum response at 4 weeks. 
At the last observation at 12 weeks, 13/27 (48%) of infliximab-treated patients were still responding. 
 
Maintenance treatment in moderately to severely active Crohn’s disease in adults 
The efficacy of repeated infusions with infliximab was studied in a 1-year clinical study (ACCENT I). 
A total of 573 patients with moderately to severely active Crohn’s disease (CDAI ≥ 220 ≤ 400) received a 
single infusion of 5 mg/kg at week 0. 178 of the 580 enrolled patients (30.7%) were defined as having severe 
disease (CDAI score > 300 and concomitant corticosteroid and/or immunosuppressants) corresponding to the 
population defined in the indication (see section 4.1). At week 2, all patients were assessed for clinical 
response and randomised to one of 3 treatment groups; a placebo maintenance group, 5 mg/kg maintenance 
group and 10 mg/kg maintenance group. All 3 groups received repeated infusions at week 2, 6 and every 
8 weeks thereafter. 
 
Of the 573 patients randomised, 335 (58%) achieved clinical response by week 2. These patients were 
classified as week-2 responders and were included in the primary analysis (see Table 5). Among patients 
classified as non-responders at week 2, 32% (26/81) in the placebo maintenance group and 42% (68/163) in 
the infliximab group achieved clinical response by week 6. There was no difference between groups in the 
number of late responders thereafter. 
 
 
The co-primary endpoints were the proportion of patients in clinical remission (CDAI < 150) at week 30 and 
time to loss of response through week 54. Corticosteroid tapering was permitted after week 6. 
 

Table 5 
Effects on response and remission rate, data from ACCENT I (week-2 responders) 



26 
 

a Reduction in CDAI ≥ 25% and ≥ 70 points.  
b CDAI < 150 at both week 30 and 54 and not receiving corticosteroids in the 3 months prior to week 54 among patients who were 
receiving corticosteroids at baseline.  
 
Beginning at week 14, patients who had responded to treatment, but subsequently lost their clinical benefit, 
were allowed to cross over to a dose of infliximab 5 mg/kg higher than the dose to which they were 
originally randomised. Eighty nine percent (50/56) of patients who lost clinical response on infliximab 
5 mg/kg maintenance therapy after week 14 responded to treatment with infliximab 10 mg/kg. 
 
Improvements in quality of life measures, a reduction in disease-related hospitalisations and corticosteroid 
use were seen in the infliximab maintenance groups compared with the placebo maintenance group at weeks 
30 and 54. 
 
Infliximab with or without AZA was assessed in a randomised, double-blind, active comparator study 
(SONIC) of 508 adult patients with moderate to severe Crohn’s disease (CDAI ≥ 220 ≤ 450) who were naive 
to biologics and immunosuppressants and had a median disease duration of 2.3 years. At baseline 27.4% of 
patients were receiving systemic corticosteroids, 14.2% of patients were receiving budesonide, and 54.3% of 
patients were receiving 5-ASA compounds. Patients were randomised to receive AZA monotherapy, 
infliximab monotherapy, or infliximab plus AZA combination therapy. Infliximab was administered at a 
dose of 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks. AZA was given at a dose of 2.5 mg/kg daily. 
 
The primary endpoint of the study was corticosteroid-free clinical remission at week 26, defined as patients 
in clinical remission (CDAI of < 150) who, for at least 3 weeks, had not taken oral systemic corticosteroids 
(prednisone or equivalent) or budesonide at a dose > 6 mg/day. For results see Table 6. The proportions of 
patients with mucosal healing at week 26 were significantly greater in the infliximab plus AZA combination 
(43.9%, p < 0.001) and infliximab monotherapy groups (30.1%, p=0.023) compared to the AZA 
monotherapy group (16.5%). 
 

Table 6 
Percent of patients achieving corticosteroid-free clinical remission at week 26, SONIC 

 AZA 
Monotherapy 

Infliximab 
Monotherapy 

Infliximab + AZA 
Combination therapy 

Week 26  

All randomised patients 30.0% (51/170) 44.4% (75/169) (p=0.006)* 
56.8% (96/169) 

(p<0.001)* 

 ACCENT I (week-2 responders) 
% of Patients 

Placebo Maintenance 
(n=110) 

Infliximab 
Maintenance 

5 mg/kg 
(n=113) 
(p value) 

Infliximab 
Maintenance 

10 mg/kg 
(n=112) 
(p value) 

Median time to loss of 
response through week 54  19 weeks 

38 weeks 
(0.002) 

> 54 weeks 
(< 0.001) 

Week 30 

Clinical Responsea  27.3 51.3 (< 0.001) 
59.1 

(< 0.001) 

Clinical Remission  20.9 38.9 (0.003) 
45.5 

(< 0.001) 

Steroid-Free Remission  10.7 (6/56) 31.0 (18/58) (0.008) 
36.8 (21/57) 

(0.001) 
Week 54 

Clinical Responsea  15.5 38.1 (< 0.001) 
47.7 

(< 0.001) 

Clinical Remission  13.6 28.3 (0.007) 
38.4 

(< 0.001) 
Sustained Steroid-Free 
Remissionb 5.7 (3/53) 

17.9 (10/56) 
(0.075) 

28.6 (16/56) 
(0.002) 



27 
 

* P-values represent each infliximab treatment group vs. AZA monotherapy 
 
Similar trends in the achievement of corticosteroid-free clinical remission were observed at week 50. 
Furthermore, improved quality of life as measured by IBDQ was observed with infliximab. 
 
Induction treatment in fistulising active Crohn’s disease 
The efficacy was assessed in a randomised, double-blinded, placebo-controlled study in 94 patients with 
fistulising Crohn’s disease who had fistulae that were of at least 3 months’ duration. Thirty one of these 
patients were treated with infliximab 5 mg/kg. Approximately 93% of the patients had previously received 
antibiotic or immunosuppressive therapy. 
 
Concurrent use of stable doses of conventional therapies was permitted, and 83% of patients continued to 
receive at least one of these therapies. Patients received three doses of either placebo or infliximab at weeks 
0, 2 and 6. Patients were followed up to 26 weeks. The primary endpoint was the proportion of patients who 
experienced a clinical response, defined as ≥ 50% reduction from baseline in the number of fistulae draining 
upon gentle compression on at least two consecutive visits (4 weeks apart), without an increase in the use of 
medicinal products or surgery for Crohn’s disease. 
 
Sixty eight percent (21/31) of infliximab-treated patients receiving a 5 mg/kg dose regimen achieved a 
clinical response vs. 26% (8/31) placebo-treated patients (p=0.002). The median time to onset of response in 
the infliximab-treated group was 2 weeks. The median duration of response was 12 weeks. Additionally, 
closure of all fistulae was achieved in 55% of infliximab-treated patients compared with 13% of placebo-
treated patients (p=0.001). 
 
Maintenance treatment in fistulising active Crohn’s disease 
The efficacy of repeated infusions with infliximab in patients with fistulising Crohn’s disease was studied in 
a 1-year clinical study (ACCENT II). A total of 306 patients received 3 doses of infliximab 5 mg/kg at week 
0, 2 and 6. At baseline, 87% of the patients had perianal fistulae, 14% had abdominal fistulae, 9% had 
rectovaginal fistulae. The median CDAI score was 180. At week 14, 282 patients were assessed for clinical 
response and randomised to receive either placebo or 5 mg/kg infliximab every 8 weeks through week 46. 
 
Week-14 responders (195/282) were analysed for the primary endpoint, which was time from randomisation 
to loss of response (see Table 7). Corticosteroid tapering was permitted after week 6. 
 

Table 7 
Effects on response rate, data from ACCENT II (week-14 responders) 

 ACCENT II (week-14 responders) 
 Placebo 

Maintenance 
(n=99) 

Infliximab 
Maintenance 

(5 mg/kg) 
(n=96) 

p-value 

Median time to loss of response through 
week 54  14 weeks > 40 weeks < 0.001 

Week 54 
Fistula Response (%)a  23.5 46.2 0.001 
Complete fistula response (%)b  19.4 36.3 0.009 
a A ≥ 50% reduction from baseline in the number of draining fistulas over a period of ≥ 4 weeks 
b Absence of any draining fistulas 
 
Beginning at week 22, patients who initially responded to treatment and subsequently lost their response 
were eligible to cross over to active re-treatment every 8 weeks at a dose of infliximab 5 mg/kg higher than 
the dose to which they were originally randomised. Among patients in the infliximab 5 mg/kg group who 
crossed over because of loss of fistula response after week 22, 57% (12/21) responded to re-treatment with 
infliximab 10 mg/kg every 8 weeks. 
 



28 
 

There was no significant difference between placebo and infliximab for the proportion of patients with 
sustained closure of all fistulas through week 54, for symptoms such as proctalgia, abscesses and urinary 
tract infection or for number of newly developed fistulas during treatment. 
 
Maintenance therapy with infliximab every 8 weeks significantly reduced disease-related hospitalisations 
and surgeries compared with placebo. Furthermore, a reduction in corticosteroid use and improvements in 
quality of life were observed. 
 
Adult ulcerative colitis 
The safety and efficacy of infliximab were assessed in two (ACT 1 and ACT 2) randomised, double-blind, 
placebo-controlled clinical studies in adult patients with moderately to severely active ulcerative colitis 
(Mayo score 6 to 12; Endoscopy subscore ≥ 2) with an inadequate response to conventional therapies [oral 
corticosteroids, aminosalicylates and/or immunomodulators (6-MP, AZA)]. Concomitant stable doses of oral 
aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted. In both studies, patients 
were randomised to receive either placebo, 5 mg/kg infliximab, or 10 mg/kg infliximab at weeks 0, 2, 6, 14 
and 22, and in ACT 1 at weeks 30, 38 and 46. Corticosteroid taper was permitted after week 8. 
 
 

Table 8 
Effects on clinical response, clinical remission and mucosal healing at weeks 8 and 30.  

Combined data from ACT 1 & 2 
 Placebo Infliximab 5 mg/kg 10 mg/kg Combined 
Subjects randomised  244 242 242 484 
Percentage of subjects in clinical response and in sustained clinical response 
Clinical response at week 8a  33.2% 66.9% 65.3% 66.1% 
Clinical response at week 30a  27.9% 49.6% 55.4% 52.5% 
Sustained response  
(clinical response at both week 
8 and week 30)a 

19.3% 45.0% 49.6% 47.3% 

Percentage of subjects in clinical remission and sustained remission 
Clinical remission at week 8a  10.2% 36.4% 29.8% 33.1% 
Clinical remission at week 30a  13.1% 29.8% 36.4% 33.1% 
Sustained remission 
(in remission at both  
week 8 and week 30)a  

5.3% 19.0% 24.4% 21.7% 

Percentage of subjects with mucosal healing 
Mucosal healing at week 8a  32.4% 61.2% 60.3% 60.7% 
Mucosal healing at week 30a  27.5% 48.3% 52.9% 50.6% 
a p < 0.001, for each infliximab treatment group vs. placebo 
 
The efficacy of infliximab through week 54 was assessed in the ACT 1 study. 
At 54 weeks, 44.9% of patients in the combined infliximab treatment group were in clinical response 
compared to 19.8% in the placebo treatment group (p < 0.001). Clinical remission and mucosal healing 
occurred in a greater proportion of patients in the combined infliximab treatment group compared to the 
placebo treatment group at week 54 (34.6% vs. 16.5%, p < 0.001 and 46.1% vs. 18.2%, p < 0.001, 
respectively). The proportions of patients in sustained response and sustained remission at week 54 were 
greater in the combined infliximab treatment group than in the placebo treatment group (37.9% vs. 14.0%, 
p < 0.001; and 20.2% vs. 6.6%, p < 0.001, respectively). 
 
A greater proportion of patients in the combined infliximab treatment group were able to discontinue 
corticosteroids while remaining in clinical remission compared to the placebo treatment group at both week 
30 (22.3% vs. 7.2%, p < 0.001, pooled ACT 1 & ACT 2 data) and week 54 (21.0% vs. 8.9%, p=0.022, 
ACT 1 data).  
 
The pooled data analysis from the ACT 1 and ACT 2 studies and their extensions, analysed from baseline 
through 54 weeks, demonstrated a reduction of ulcerative colitis-related hospitalisations and surgical 



29 
 

procedures with infliximab treatment. The number of ulcerative colitis-related hospitalisations was 
significantly lower in the 5 and 10 mg/kg infliximab treatment groups than in the placebo group (mean 
number of hospitalisations per 100 subject-years: 21 and 19 vs. 40 in the placebo group; p=0.019 and 
p=0.007, respectively). The number of ulcerative colitis-related surgical procedures was also lower in the 
5 and 10 mg/kg infliximab treatment groups than in the placebo group (mean number of surgical procedures 
per 100 subject-years: 22 and 19 vs. 34; p=0.145 and p=0.022, respectively). 
 
The proportion of subjects who underwent colectomy at any time within 54 weeks following the first 
infusion of study agent were collected and pooled from the ACT 1 and ACT 2 studies and their extensions. 
Fewer subjects underwent colectomy in the 5 mg/kg infliximab group (28/242 or 11.6% [N.S.]) and the 
10 mg/kg infliximab group (18/242 or 7.4% [p=0.011]) than in the placebo group (36/244; 14.8%). 
 
The reduction in incidence of colectomy was also examined in another randomised, double-blind study 
(C0168Y06) in hospitalised patients (n=45) with moderately to severely active ulcerative colitis who failed 
to respond to intravenous corticosteroids and who were therefore at higher risk for colectomy. Significantly 
fewer colectomies occurred within 3 months of study infusion in patients who received a single dose of 5 
mg/kg infliximab compared to patients who received placebo (29.2% vs. 66.7% respectively, p=0.017). 
 
In ACT 1 and ACT 2, infliximab improved quality of life, confirmed by statistically significant improvement 
in both a disease specific measure, IBDQ, and by improvement in the generic 36-item short form survey SF-
36. 
 
Adult ankylosing spondylitis 
Efficacy and safety of infliximab were assessed in two multicentre, double-blind, placebo-controlled studies 
in patients with active ankylosing spondylitis (Bath Ankylosing Spondylitis Disease Activity Index 
[BASDAI] score ≥ 4 and spinal pain ≥ 4 on a scale of 1-10). 
 
In the first study (P01522), which had a 3 month double-blind phase, 70 patients received either 5 mg/kg 
infliximab or placebo at weeks 0, 2, 6 (35 patients in each group). At week 12, placebo patients were 
switched to infliximab 5 mg/kg every 6 weeks up to week 54. After the first year of the study, 53 patients 
continued into an open-label extension to week 102. 
 
In the second clinical study (ASSERT), 279 patients were randomised to receive either placebo (Group 1, 
n=78) or 5 mg/kg infliximab (Group 2, n=201) at 0, 2 and 6 weeks and every 6 weeks to week 24. Thereafter, 
all subjects continued on infliximab every 6 weeks to week 96. Group 1 received 5 mg/kg infliximab. In 
Group 2, starting with the week 36 infusion, patients who had a BASDAI ≥ 3 at 2 consecutive visits, 
received 7.5 mg/kg infliximab every 6 weeks thereafter through week 96. 
 
In ASSERT, improvement in signs and symptoms was observed as early as week 2. At week 24, the number 
of ASAS 20 responders was 15/78 (19%) in the placebo group, and 123/201 (61%) in the 5 mg/kg infliximab 
group (p < 0.001). There were 95 subjects from group 2 who continued on 5 mg/kg every 6 weeks. At 
102 weeks there were 80 subjects still on infliximab treatment and among those, 71 (89%) were ASAS 20 
responders. 
 
In P01522, improvement in signs and symptoms was also observed as early as week 2. At week 12, the 
number of BASDAI 50 responders were 3/35 (9%) in the placebo group, and 20/35 (57%) in the 5 mg/kg 
group (p < 0.01). There were 53 subjects who continued on 5 mg/kg every 6 weeks. At 102 weeks there were 
49 subjects still on infliximab treatment and among those, 30 (61%) were BASDAI 50 responders. 
 
In both studies, physical function and quality of life as measured by the BASFI and the physical component 
score of the SF-36 were also improved significantly. 
 
Adult psoriatic arthritis 
Efficacy and safety were assessed in two multicentre, double-blind, placebo-controlled studies in patients 
with active psoriatic arthritis. 



30 
 

 
In the first clinical study (IMPACT), efficacy and safety of infliximab were studied in 104 patients with 
active polyarticular psoriatic arthritis. During the 16-week double-blind phase, patients received either 
5 mg/kg infliximab or placebo at weeks 0, 2, 6, and 14 (52 patients in each group). Starting at week 16, 
placebo patients were switched to infliximab and all patients subsequently received 5 mg/kg infliximab every 
8 weeks up to week 46. After the first year of the study, 78 patients continued into an open-label extension to 
week 98. 
 
In the second clinical study (IMPACT 2), efficacy and safety of infliximab were studied in 200 patients with 
active psoriatic arthritis (≥ 5 swollen joints and ≥ 5 tender joints). Forty six percent of patients continued on 
stable doses of methotrexate (≤ 25 mg/week). During the 24-week double-blind phase, patients received 
either 5 mg/kg infliximab or placebo at weeks 0, 2, 6, 14, and 22 (100 patients in each group). At week 16, 
47 placebo patients with < 10% improvement from baseline in both swollen and tender joint counts were 
switched to infliximab induction (early escape). At week 24, all placebo-treated patients crossed over to 
infliximab induction. Dosing continued for all patients through week 46. 
 
Key efficacy results for IMPACT and IMPACT 2 are shown in Table 9 below: 
 

Table 9 
Effects on ACR and PASI in IMPACT and IMPACT 2 

 
IMPACT IMPACT 2* 

Placebo 
(week 16) 

Infliximab 
(week 16) 

Infliximab 
(week 98) 

Placebo 
(week 24) 

Infliximab 
(week 24) 

Infliximab 
(week 54) 

Patients randomised 52 52 N/Aa 100 100 100 
 
ACR response  (% of patients)  
N  52 52 78 100 100 100 
ACR 20 response*  5(10%) 34 (65%) 48 (62%) 16 (16%) 54 (54%) 53 (53%) 
ACR 50 response*  0(0%) 24 (46%) 35 (45%) 4 (4%) 41(41%) 33 (33%) 
ACR 70 response*  0(0%) 15 (29%) 27 (35%) 2 (2%) 27 (27%) 20 (20%) 
PASI response (% of patients)b 
N  N/A 87 83 82 PASI 75 response**  1 (1%) 50 (60%) 40 (48.8%) 
* ITT-analysis where subjects with missing data were included as non-responders 
a Week 98 data for IMPACT includes combined placebo crossover and infliximab patients who entered the open-label extension 
b Based on patients with PASI ≥ 2.5 at baseline for IMPACT, and patients with ≥ 3% BSA psoriasis skin involvement at baseline in 
IMPACT 2 
** PASI 75 response for IMPACT not included due to low N; p < 0.001 for infliximab vs. placebo at week 24 for IMPACT 2 
 
In IMPACT and IMPACT 2, clinical responses were observed as early as week 2 and were maintained 
through week 98 and week 54 respectively. Efficacy has been demonstrated with or without concomitant use 
of methotrexate. Decreases in parameters of peripheral activity characteristic of psoriatic arthritis (such as 
number of swollen joints, number of painful/tender joints, dactylitis and presence of enthesopathy) were seen 
in the infliximab-treated patients.  
 
Radiographic changes were assessed in IMPACT 2. Radiographs of hands and feet were collected at baseline, 
weeks 24 and 54. Infliximab treatment reduced the rate of progression of peripheral joint damage compared 
with placebo treatment at the week 24 primary endpoint as measured by change from baseline in total 
modified vdH-S score (mean ± SD score was 0.82 ± 2.62 in the placebo group compared with -0.70 ± 2.53 in 
the infliximab group; p < 0.001). In the infliximab group, the mean change in total modified vdH-S score 
remained below 0 at the week 54 timepoint. 
 
Infliximab-treated patients demonstrated significant improvement in physical function as assessed by HAQ. 
Significant improvements in health-related quality of life were also demonstrated as measured by the 
physical and mental component summary scores of the SF-36 in IMPACT 2. 
 
Adult psoriasis 



31 
 

The efficacy of infliximab was assessed in two multicentre, randomised, double-blind studies: SPIRIT and 
EXPRESS. Patients in both studies had plaque psoriasis (Body Surface Area [BSA] ≥ 10% and Psoriasis 
Area and Severity Index [PASI] score ≥ 12). The primary endpoint in both studies was the percent of patients 
who achieved ≥ 75% improvement in PASI from baseline at week 10. 
 
SPIRIT evaluated the efficacy of infliximab induction therapy in 249 patients with plaque psoriasis that had 
previously received PUVA or systemic therapy. Patients received either 3 or 5 mg/kg infliximab or placebo 
infusions at weeks 0, 2 and 6. Patients with a PGA score ≥ 3 were eligible to receive an additional infusion of 
the same treatment at week 26. 
In SPIRIT, the proportion of patients achieving PASI 75 at week 10 was 71.7% in the 3 mg/kg infliximab 
group, 87.9% in the 5 mg/kg infliximab group, and 5.9% in the placebo group (p < 0.001). By week 26, 
twenty weeks after the last induction dose, 30% of patients in the 5 mg/kg group and 13.8% of patients in the 
3 mg/kg group were PASI 75 responders. Between weeks 6 and 26, symptoms of psoriasis gradually 
returned with a median time to disease relapse of > 20 weeks. No rebound was observed. 
 
EXPRESS evaluated the efficacy of infliximab induction and maintenance therapy in 378 patients with 
plaque psoriasis. Patients received 5 mg/kg infliximab- or placebo-infusions at weeks 0, 2 and 6 followed by 
maintenance therapy every 8 weeks through week 22 in the placebo group and through week 46 in the 
infliximab group. At week 24, the placebo group crossed over to infliximab induction therapy (5 mg/kg) 
followed by infliximab maintenance therapy (5 mg/kg). Nail psoriasis was assessed using the Nail Psoriasis 
Severity Index (NAPSI). Prior therapy with PUVA, methotrexate, ciclosporin, or acitretin had been received 
by 71.4% of patients, although they were not necessarily therapy resistant. Key results are presented in Table 
10. In infliximab treated subjects, significant PASI 50 responses were apparent at the first visit (week 2) and 
PASI 75 responses by the second visit (week 6). Efficacy was similar in the subgroup of patients that were 
exposed to previous systemic therapies compared to the overall study population. 
 

Table 10 
Summary of PASI response, PGA response and percent of patients with all nails cleared at weeks 10, 

24 and 50. EXPRESS 

 
Placebo → Infliximab 

5 mg/kg 
(at week 24) 

Infliximab 
5 mg/kg 

Week 10  
N  77 301 

≥ 90% improvement  1 (1.3%) 172 (57.1%)a 
≥ 75% improvement  2 (2.6%) 242 (80.4%)a 
≥ 50% improvement  6 (7.8%) 274 (91.0%) 
PGA of cleared (0) or minimal (1)  3 (3.9%) 242 (82.9%)ab 
PGA of cleared (0), minimal (1), or mild (2)  14 (18.2%) 275 (94.2%)ab 
Week 24 

N  77 276 
≥ 90% improvement  1 (1.3%) 161 (58.3%)a 
≥ 75% improvement  3 (3.9%) 227 (82.2%)a 
≥ 50% improvement  5 (6.5%) 248 (89.9%) 
PGA of cleared (0) or minimal (1)  2 (2.6%) 203 (73.6%)a 
PGA of cleared (0), minimal (1), or mild (2)  15 (19.5%) 246 (89.1%)a 
Week 50 

N  68 281 
≥ 90% improvement  34 (50.0%) 127 (45.2%) 
≥ 75% improvement  52 (76.5%) 170 (60.5%) 
≥ 50% improvement  61 (89.7%) 193 (68.7%) 
PGA of cleared (0) or minimal (1)  46 (67.6%) 149 (53.0%) 
PGA of cleared (0), minimal (1), or mild (2)  59 (86.8%) 189 (67.3%) 
All nails clearedc 
Week 10  1/65 (1.5%) 16/235 (6.8%) 
Week 24  3/65 (4.6%) 58/223 (26.0%)a 
Week 50  27/64 (42.2%) 92/226 (40.7%) 



32 
 

a p < 0.001, for each infliximab treatment group vs. control 
b n = 292 
c Analysis was based on subjects with nail psoriasis at baseline (81.8% of subjects). Mean baseline NAPSI scores were 4.6 and 4.3 in 
infliximab and placebo group. 
Significant improvements from baseline were demonstrated in DLQI (p < 0.001) and the physical and mental component scores of 
the SF 36 (p < 0.001 for each component comparison). 
 
Paediatric population 
Paediatric Crohn’s disease (6 to 17 years) 
In the REACH study, 112 patients (6 to 17 years, median age 13.0 years) with moderate to severe, active 
Crohn’s disease (median paediatric CDAI of 40) and an inadequate response to conventional therapies were 
to receive 5 mg/kg infliximab at weeks 0, 2, and 6. All patients were required to be on a stable dose of 6-MP, 
AZA or MTX (35% were also receiving corticosteroids at baseline). Patients assessed by the investigator to 
be in clinical response at week 10 were randomised and received 5 mg/kg infliximab at either q8 weeks or 
q12 weeks as a maintenance treatment regimen. If response was lost during maintenance treatment, crossing 
over to a higher dose (10 mg/kg) and/or shorter dosing interval (q8 weeks) was allowed. Thirty two (32) 
evaluable paediatric patients crossed over (9 subjects in the q8 weeks and 23 subjects in the q12 weeks 
maintenance groups). Twenty four of these patients (75.0%) regained clinical response after crossing over. 
The proportion of subjects in clinical response at week 10 was 88.4% (99/112). The proportion of subjects 
achieving clinical remission at week 10 was 58.9% (66/112). 
At week 30, the proportion of subjects in clinical remission was higher in the q8 week (59.6%, 31/52) than 
the q12 week maintenance treatment group (35.3%, 18/51; p=0.013). At week 54, the figures were 55.8% 
(29/52) and 23.5% (12/51) in the q8 weeks and q12 weeks maintenance groups, respectively (p < 0.001). 
Data about fistulas were derived from PCDAI scores. Of the 22 subjects that had fistulas at baseline, 63.6% 
(14/22), 59.1% (13/22) and 68.2% (15/22) were in complete fistula response at week 10, 30 and 54, 
respectively, in the combined q8 weeks and q12 weeks maintenance groups. 
 
In addition, statistically and clinically significant improvements in quality of life and height, as well as a 
significant reduction in corticosteroid use, were observed versus baseline. 
 
Paediatric ulcerative colitis (6 to 17 years) 
The safety and efficacy of infliximab were assessed in a multicentre, randomised, open-label, parallel-group 
clinical study (C0168T72) in 60 paediatric patients aged 6 through 17 years (median age 14.5 years) with 
moderately to severely active ulcerative colitis (Mayo score of 6 to 12; endoscopic subscore ≥ 2) with an 
inadequate response to conventional therapies. At baseline 53% of patients were receiving immunomodulator 
therapy (6-MP, AZA and/or MTX) and 62% of patients were receiving corticosteroids. Discontinuation of 
immunomodulators and corticosteroid taper were permitted after week 0. 
 
All patients received an induction regimen of 5 mg/kg infliximab at weeks 0, 2, and 6. Patients who did not 
respond to infliximab at week 8 (n=15) received no further medicinal product and returned for safety follow-
up. At week 8, 45 patients were randomised and received 5 mg/kg infliximab at either q8 weeks or q12 
weeks as a maintenance treatment regimen. 
 
The proportion of patients in clinical response at week 8 was 73.3% (44/60). Clinical response at week 8 was 
similar between those with or without concomitant immunomodulator use at baseline. Clinical remission at 
week 8 was 33.3% (17/51) as measured by the Paediatric Ulcerative Colitis Activity Index (PUCAI) score. 
 
At week 54, the proportion of patients in clinical remission as measured by the PUCAI score was 38% (8/21) 
in the q8 week maintenance group and 18% (4/22) in the q12 week maintenance treatment group. For 
patients receiving corticosteroids at baseline, the proportion of patients in remission and not receiving 
corticosteroids at week 54 was 38.5% (5/13) for the q8 week and 0% (0/13) for the q12 week maintenance 
treatment group. 
 
In this study, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group 
(45/60 vs.15/60). While the numbers of patients in each subgroup are too small to draw definitive 



33 
 

conclusions about the effect of age, there was a higher number of patients in the younger age group who 
stepped up in dose or discontinued treatment due to inadequate efficacy. 
 
Other paediatric indications 
The European Medicines Agency has waived the obligation to submit the results of studies with the 
reference medicinal product containing infliximab in all subsets of the paediatric population in rheumatoid 
arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis and Crohn's disease 
(see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Single intravenous infusions of 1, 3, 5, 10 or 20 mg/kg of infliximab yielded dose proportional increases in 
the maximum serum concentration (Cmax) and area under the concentration-time curve (AUC). The volume 
of distribution at steady state (median Vd of 3.0 to 4.1 litres) was not dependent on the administered dose and 
indicated that infliximab is predominantly distributed within the vascular compartment. No time-dependency 
of the Pharmacokinetics was observed. The elimination pathways for infliximab have not been characterised. 
Unchanged infliximab was not detected in urine. No major age- or weight-related differences in clearance or 
volume of distribution were observed in rheumatoid arthritis patients. The pharmacokinetics of infliximab in 
elderly patients has not been studied. Studies have not been performed in patients with liver or renal disease. 
 
At single doses of 3, 5, or 10 mg/kg, the median Cmax values were 77, 118 and 277 micrograms/mL, 
respectively. The median terminal half-life at these doses ranged from 8 to 9.5 days. In most patients, 
infliximab could be detected in the serum for at least 8 weeks after the recommended single dose of 5 mg/kg 
for Crohn’s disease and the rheumatoid arthritis maintenance dose of 3 mg/kg every 8 weeks. 
 
Repeated administration of infliximab (5 mg/kg at 0, 2 and 6 weeks in fistulising Crohn’s disease, 3 or 
10 mg/kg every 4 or 8 weeks in rheumatoid arthritis) resulted in a slight accumulation of infliximab in serum 
after the second dose. No further clinically relevant accumulation was observed. In most fistulising Crohn’s 
disease patients, infliximab was detected in serum for 12 weeks (range 4-28 weeks) after administration of 
the regimen. 
 
Paediatric population 
Population pharmacokinetic analysis based on data obtained from patients with ulcerative colitis (N=60), 
Crohn’s disease (N=112), juvenile rheumatoid arthritis (N=117) and Kawasaki disease (N=16) with an 
overall age range from 2 months to 17 years indicated that exposure to infliximab was dependent on body 
weight in a non-linear way. Following administration of 5 mg/kg infliximab every 8 weeks, the predicted 
median steady-state infliximab exposure (area under concentration-time curve at steady state, AUCss) in 
paediatric patients aged 6 years to 17 years was approximately 20% lower than the predicted median steady-
state drug exposure in adults. The median AUCss in paediatric patients aged 2 years to less than 6 years was 
predicted to be approximately 40% lower than that in adults, although the number of patients supporting this 
estimate is limited. 
 
5.3 Preclinical safety data 
 
Infliximab does not cross react with TNFα from species other than human and chimpanzees. Therefore, 
conventional preclinical safety data with infliximab are limited. In a developmental toxicity study conducted 
in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα, there 
was no indication of maternal toxicity, embryotoxicity or teratogenicity. In a fertility and general 
reproductive function study, the number of pregnant mice was reduced following administration of the same 
analogous antibody. It is not known whether this finding was due to effects on the males and/or the females. 
In a 6-month repeated dose toxicity study in mice, using the same analogous antibody against mouse TNFα, 
crystalline deposits were observed on the lens capsule of some of the treated male mice. No specific 
ophthalmologic examinations have been performed in patients to investigate the relevance of this finding for 
humans. 



34 
 

Long-term studies have not been performed to evaluate the carcinogenic potential of infliximab. Studies in 
mice deficient in TNFα demonstrated no increase in tumours when challenged with known tumour initiators 
and/or promoters. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sucrose 
Polysorbate 80 
Monobasic sodium phosphate monohydrate 
Dibasic sodium phosphate heptahydrate 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
Before reconstitution 
4 years at 2°C – 8°C. 
 
Flixabi may be stored at temperatures up to a maximum of 25°C for a single period of up to 6 months, but 
not exceeding the original expiry date. The new expiry date must be written on the carton. Upon removal 
from refrigerated storage, Flixabi must not be returned to refrigerated storage. 
  
After reconstitution and dilution: 
Chemical and physical in use stability of the diluted solution has been demonstrated for up to 34 days at 2°C 
to 8°C and for an additional 24 hours at 25°C after removal from refrigeration. From a microbiological point 
of view, the infusion solution should be administered immediately, in use storage times and conditions prior 
to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless 
reconstitution/dilution has been taken place in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C - 8°C). 
 
For storage conditions up to 25°C before reconstitution of the medicinal product, see section 6.3. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Type 1 glass vial with a rubber stopper and aluminium crimp protected by a plastic cap. 
 
Flixabi is available in packs containing 1, 2, 3, 4, and 5 vial(s). Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
1. Calculate the dose and the number of Flixabi vials needed. Each Flixabi vial contains 100 mg infliximab. 

Calculate the total volume of reconstituted Flixabi solution required. 
 



35 
 

2. Under aseptic conditions, reconstitute each Flixabi vial with 10 ml of water for injections, using a 
syringe equipped with a 21-gauge (0.8 mm) or smaller needle. Remove flip-top from the vial and wipe 
the top with a 70% alcohol swab. Insert the syringe needle into the vial through the centre of the rubber 
stopper and direct the stream of water for injections to the glass wall of the vial. Gently swirl the 
solution by rotating the vial to dissolve the lyophilised powder. Avoid prolonged or vigorous agitation. 
DO NOT SHAKE. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted 
solution to stand for 5 minutes. Check that the solution is colourless to light yellow and opalescent. The 
solution may develop a few fine translucent particles, as infliximab is a protein. Do not use if opaque 
particles, discolouration, or other foreign particles are present. 

 
3. Dilute the total volume of the reconstituted Flixabi solution dose to 250 ml with sodium chloride 9 

mg/ml (0.9%) solution for infusion. Do not dilute the reconstituted Flixabi solution with any other 
diluent. The dilution can be accomplished by withdrawing a volume of the sodium chloride 9 mg/ml 
(0.9%) solution for infusion from the 250-ml glass bottle or infusion bag equal to the volume of 
reconstituted Flixabi. Slowly add the total volume of reconstituted Flixabi solution to the 250-ml 
infusion bottle or bag. Gently mix. For volumes greater than 250 ml, either use a larger infusion bag (e.g. 
500 ml, 1000 ml) or use multiple 250 ml infusion bags to ensure that the concentration of the infusion 
solution does not exceed 4 mg/ml. If stored refrigerated after reconstitution and dilution, the infusion 
solution must be allowed to equilibrate at room temperature to 25 °C for 3 hours prior to Step 4 
(infusion). Storage beyond 24 hours at 2 °C to 8 °C applies to preparation of Flixabi in the infusion bag 
only. 

 
4. Administer the infusion solution over a period of not less than the infusion time recommended (see 

section 4.2). Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter 
(pore size 1.2 micrometre or less). Since no preservative is present, it is recommended that the 
administration of the solution for infusion is to be started as soon as possible and within 3 hours of 
reconstitution and dilution. If not used immediately, in use storage times and conditions prior to use are 
the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless 
reconstitution/dilution has been taken place in controlled and validated aseptic conditions (see section 
6.3 above). Do not store any unused portion of the infusion solution for reuse. 
 

5. No physical biochemical compatibility studies have been conducted to evaluate the co-administration of 
Flixabi with other agents. Do not infuse Flixabi concomitantly in the same intravenous line with other 
agents. 
 

6. Visually inspect Flixabi for particulate matter or discolouration prior to administration. Do not use if 
visibly opaque particles, discolouration or foreign particles are observed. 
 

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

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616 LR Delft 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/16/1106/001 
EU/1/16/1106/002 
EU/1/16/1106/003 



36 
 

EU/1/16/1106/004 
EU/1/16/1106/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26/05/2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 
 



37 
 

 
 
 
 
 
 
 
 
 

ANNEX II 

 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER 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 
 

 



38 
 

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

Name and address of the manufacturer of the biological active substance  

Biogen (Denmark) Manufacturing ApS 
Biogen Alle’ 1 
3400 Hillerod 
DENMARK 
 
Samsung BioLogics Co., Ltd. 
300, Songdo bio-daero 
Yeonsu-gu, Incheon City, 21987, 
Korea, Republic of 
 
Name and address of the manufacturer responsible for batch release 

Biogen (Denmark) Manufacturing ApS 
Biogen Alle’ 1 
3400 Hillerod 
DENMARK 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

• Periodic safety update reports (PSURs)  
 

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

USE OF THE MEDICINAL PRODUCT 

• Risk management plan (RMP) 
 

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

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

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



39 
 

important (pharmacovigilance or risk minimisation) milestone being reached.  

 

• Additional risk minimisation measures 
 

The educational programme consists of a patient reminder card to be held by the patient. The card is aimed at 
both serving as a reminder to record the dates and outcomes of specific tests and to facilitate the patient 
sharing of special information with healthcare professionals(s) (HCPs) treating the patient about on-going 
treatment with the product. 
 
The patient reminder card shall contain the following key messages: 
 
• A reminder to patients to show the patient reminder card to all treating HCPs, including in conditions 

of emergency, and a message for HCPs that the patient is using Flixabi 
 
• A statement that the brand name and batch number should be recorded 
 
• Provision to record the type, date, and result of TB screenings 
 
• That treatment with Flixabi may increase the risks of serious infections/sepsis, opportunistic infections, 

tuberculosis, hepatitis B reactivation, and BCG breakthrough in infants with in utero exposure to 
infliximab, and when to seek attention from a HCP 

 
• Contact details of the prescriber



40 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



41 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



42 
 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Flixabi 100 mg powder for concentrate for solution for infusion 
infliximab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 100 mg of infliximab. 
After reconstitution one mL contains 10 mg infliximab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sucrose, polysorbate 80, monobasic sodium phosphate monohydrate and dibasic sodium 
phosphate heptahydrate. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial 
2 vials 
3 vials 
4 vials 
5 vials 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous use. 
Reconstitute and dilute before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 



43 
 

 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
Can be stored at room temperature (up to 25°C) for a single period up to 6 months. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616 LR Delft 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1106/001 1 vial 
EU/1/16/1106/002 2 vials  
EU/1/16/1106/003 3 vials 
EU/1/16/1106/004 4 vials  
EU/1/16/1106/005 5 vials  
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 



44 
 

Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



45 
 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Flixabi 100 mg powder for concentrate 
infliximab 
Intravenous use <IV> 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
100 mg 
 
 
6. OTHER 
 
 



46 
 

 

Flixabi 100 mg 
Infliximab 

 
Patient Reminder Card 

 
Name patient:  
Name doctor:  
Telephone number doctor:  
 
This patient reminder card contains important safety 
information that you need to be aware of before and 
during treatment with Flixabi.  
 
Show this card to any doctor involved in your 
treatment.  
 
Please read the Flixabi ‘Package Leaflet’ carefully 
before you start using this medicine.  
 
Date of Flixabi therapy initiation:  
 
 
Current administrations:  
 
 
It is important that you and your doctor record the 
brand name and batch number of your medicine.  
 
Ask your doctor to record the type and date of last 
screening(s) for TB below:  
Test: 
Date: 
Result:  
 
Please make sure you also have a list of all other 
medicines that you are using with you at any visit to 
a healthcare professional.  
 
List of allergies:  
 
List of other medicines:  
 
 
 
 

Infections  
 
Before treatment with Flixabi  
• Tell your doctor if you have an infection even if 

it is a very minor one.  
• It is very important that you tell your doctor if 

you have ever had tuberculosis (TB), or if you 
have been in close contact with someone who 
has had TB. Your doctor will test you to see if 
you have TB. Ask your doctor to record the type 
and date of your last screening(s) for TB on the 
card.  

• Tell your doctor if you have hepatitis B or if you 
know or suspect you are a carrier of the hepatitis 
B virus.  

 
During treatment with Flixabi  
• Tell your doctor straight away if you have signs 

of an infection. Signs include a fever, feeling 
tired, (persistent) cough, shortness of breath, 
weight loss, night sweats, diarrhea, wounds, 
dental problems, burning when urinating or ‘flu-
like’ signs.  

 
Pregnancy and Vaccinations  
 
• In case you have received Flixabi while you 

were pregnant, it is important that you inform 
your baby’s doctor about it before your baby 
receives any vaccine. Your baby should not 
receive a ‘live vaccine’, such as BCG (used to 
prevent tuberculosis) within 6 months after 
birth.  

 
Keep this card with you for 4 months after your dose 
of Flixabi, or in case of pregnancy for at least 6 
months after the birth of your baby. Side effects may 
occur a long time after your last dose. 

 



47 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



48 
 

Package leaflet: Information for the user 
 

Flixabi 100 mg powder for concentrate for solution for infusion 
infliximab 

 
 

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 

you need to be aware of before and during your treatment with Flixabi. 
• If you have any further questions, ask your doctor. 
• 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. This includes any possible side effects not listed in this 

leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Flixabi is and what it is used for 
2. What you need to know before you use Flixabi 
3. How Flixabi will be given 
4. Possible side effects 
5. How to store Flixabi 
6. Contents of the pack and other information 
 
1. What Flixabi is and what it is used for 
 
Flixabi contains the active substance infliximab. Infliximab is a monoclonal antibody – a type of protein that 
attaches to a specific target in the body called TNF (tumour necrosis factor) alpha. 
 
Flixabi belongs to a group of medicines called ‘TNF blockers’. It is used in adults for the following 
inflammatory diseases: 
• Rheumatoid arthritis 
• Psoriatic arthritis 
• Ankylosing spondylitis (Bechterew’s disease) 
• Psoriasis. 

 
Flixabi is also used in adults and children 6 years of age or older for: 
• Crohn’s disease 
• Ulcerative colitis. 

 
Flixabi works by selectively attaching to TNF alpha and blocking its action. TNF alpha is involved in 
inflammatory processes of the body so blocking it can reduce the inflammation in your body. 
 
Rheumatoid arthritis 
Rheumatoid arthritis is an inflammatory disease of the joints. If you have active rheumatoid arthritis you will 
first be given other medicines. If these medicines do not work well enough, you will be given Flixabi which 
you will take in combination with another medicine called methotrexate to: 
• Reduce the signs and symptoms of your disease, 
• Slow down the damage in your joints, 



49 
 

• Improve your physical function. 
 
Psoriatic arthritis 
Psoriatic arthritis is an inflammatory disease of the joints, usually accompanied by psoriasis. If you have 
active psoriatic arthritis you will first be given other medicines. If these medicines do not work well enough, 
you will be given Flixabi to: 
• Reduce the signs and symptoms of your disease, 
• Slow down the damage in your joints, 
• Improve your physical function. 

 
Ankylosing spondylitis (Bechterew’s disease) 
Ankylosing spondylitis is an inflammatory disease of the spine. If you have ankylosing spondylitis you will 
first be given other medicines. If these medicines do not work well enough, you will be given Flixabi to: 
• Reduce the signs and symptoms of your disease, 
• Improve your physical function. 

 
Psoriasis 
Psoriasis is an inflammatory disease of the skin. If you have moderate to severe plaque psoriasis, you will 
first be given other medicines or treatments, such as phototherapy. If these medicines or treatments do not 
work well enough, you will be given Flixabi to reduce the signs and symptoms of your disease. 
 
Ulcerative colitis 
Ulcerative colitis is an inflammatory disease of the bowel. If you have ulcerative colitis you will first be 
given other medicines. If these medicines do not work well enough, you will be given Flixabi to treat your 
disease. 
 
Crohn’s disease 
Crohn’s disease is an inflammatory disease of the bowel. If you have Crohn’s disease you will first be given 
other medicines. If these medicines do not work well enough, you will be given Flixabi to: 
• Treat active Crohn’s disease, 
• Reduce the number of abnormal openings (fistulae) between your bowel and your skin that have not 

been controlled by other medicines or surgery. 
 
2. What you need to know before you use Flixabi 
 
You should not be given Flixabi if 
• You are allergic to infliximab or any of the other ingredients of this medicine (listed in section 6). 
• You are allergic (hypersensitive) to proteins that come from mice. 
• You have tuberculosis (TB) or another serious infection such as pneumonia or sepsis. 
• You have heart failure that is moderate or severe. 

 
Do not use Flixabi if any of the above applies to you. If you are not sure, talk to your doctor before you are 
given Flixabi. 
 
Warnings and precautions 
Talk to your doctor before or during treatment with Flixabi if you have: 
 

Had treatment with any medicine containing infliximab before 
• Tell your doctor if you have had treatment with medicines containing infliximab in the past and are 

now starting Flixabi treatment again. 
• If you have had a break in your treatment with infliximab of more than 16 weeks, there is a higher 

risk for allergic reactions when you start the treatment again. 
 
Infections 
• Tell your doctor before you are given Flixabi if you have an infection even if it is a very minor one. 



50 
 

• Tell your doctor before you are given Flixabi if you have ever lived in or travelled to an area where 
infections called histoplasmosis, coccidioidomycosis, or blastomycosis are common. These 
infections are caused by specific types of fungi that can affect the lungs or other parts of your body. 

• You may get infections more easily when you are being treated with Flixabi. If you are 65 or older, 
you have a greater risk. 

• These infections may be serious and include tuberculosis, infections caused by viruses, fungi, 
bacteria, or other organisms in the environment and sepsis that may be life-threatening. 

Tell your doctor straight away if you get signs of infection during treatment with Flixabi. Signs include 
fever, cough, flu-like signs, feeling unwell, red or hot skin, wounds or dental problems. Your doctor 
may recommend temporarily stopping Flixabi. 
 
Tuberculosis (TB) 
• It is very important that you tell your doctor if you have ever had TB or if you have been in close 

contact with someone who has had or has TB. 
• Your doctor will test you to see if you have TB. Cases of TB have been reported in patients treated 

with Flixabi, even in patients who have already been treated with medicines for TB. Your doctor 
will record these tests on your patient reminder card. 

• If your doctor feels that you are at risk for TB, you may be treated with medicines for TB before 
you are given Flixabi. 

Tell your doctor straight away if you get signs of TB during treatment with Flixabi. Signs include 
persistent cough, weight loss, feeling tired, fever, night sweats. 
 
Hepatitis B virus  
• Tell your doctor before you are given Flixabi if you are a carrier of hepatitis B or have ever had it. 
• Tell your doctor if you think you might be at risk of contracting hepatitis B. 
• Your doctor should test you for hepatitis B virus. 
• Treatment with TNF blockers such as Flixabi may result in reactivation of hepatitis B virus in 

patients who carry this virus, which can be life-threatening in some cases. 
 
Heart problems 
• Tell your doctor if you have any heart problems, such as mild heart failure. 
• Your doctor will want to closely monitor your heart. 
Tell your doctor straight away if you get new or worsening signs of heart failure during treatment with 
Flixabi. Signs include shortness of breath or swelling of your feet. 
 
Cancer and lymphoma 
• Tell your doctor before you are given Flixabi if you have or have ever had lymphoma (a type of 

blood cancer) or any other cancer. 
• Patients with severe rheumatoid arthritis, who have had the disease for a long time, may be at 

higher risk of developing lymphoma. 
• Children and adults taking Flixabi may have an increased risk of developing lymphoma or another 

cancer. 
• Some patients who have received TNF-blockers, including Flixabi have developed a rare type of 

cancer called hepatosplenic T-cell lymphoma. Of these patients, most were teenage boys or young 
men and most had either Crohn’s disease or ulcerative colitis. This type of cancer has usually 
resulted in death. Almost all patients had also received medicines containing azathioprine or 6-
mercaptopurine in addition to TNF-blockers. 

• Some patients treated with infliximab have developed certain kinds of skin cancer. If there are any 
changes in your skin or growths on the skin during or after therapy, tell your doctor. 

• Some women being treated for rheumatoid arthritis with infliximab have developed cervical cancer. 
For women taking infliximab including those over 60 years of age, your doctor may recommend 
regular screening for cervical cancer. 

 
Lung disease or heavy smoking 



51 
 

• Tell your doctor before you are given Flixabi if you have a lung disease called Chronic Obstructive 
Pulmonary Disease (COPD) or if you are a heavy smoker. 

• Patients with COPD and patients who are heavy smokers may have a higher risk of developing 
cancer with Flixabi treatment. 

 
Nervous system disease 
• Tell your doctor if you have or have ever had a problem that affects your nervous system before 

you are given Flixabi. This includes multiple sclerosis, Guillain-Barre syndrome, if you have fits or 
have been diagnosed with ‘optic neuritis’. 

Tell your doctor straight away if you get symptoms of a nerve disease during treatment with Flixabi. 
Signs include changes in your vision, weakness in your arms or legs, numbness or tingling in any part of 
your body. 
 
Abnormal skin openings 
• Tell your doctor if you have any abnormal skin openings (fistulae) before you are given Flixabi. 
 
Vaccinations 
• Talk to your doctor if you recently have had or are due to have a vaccine. 
• You should receive recommended vaccinations before starting Flixabi treatment. You may receive 

some vaccines during treatment with Flixabi but you should not receive live vaccines (vaccines that 
contain a living but weakened infectious agent) while using Flixabi because they may cause 
infections. 

• If you received Flixabi while you were pregnant, your baby may also be at higher risk for getting 
an infection with live vaccines for up to six months after birth. It is important that you tell your 
baby's doctors and other health care professionals about your Flixabi use so they can decide when 
your baby should receive any vaccine, including live vaccines such as BCG (used to prevent 
tuberculosis). For more information see section on Pregnancy and breast-feeding. 

 
Therapeutic infectious agents 
• Talk to your doctor if you have recently received or are scheduled to receive treatment with a 

therapeutic infectious agent (such as BCG instillation used for the treatment of cancer). 
 
Operations or dental procedures 
• Tell your doctor if you are going to have any operations or dental procedures. 
• Tell your surgeon or dentist that you are having treatment with Flixabi by showing them your 

patient reminder card. 
 

Liver problems 
• Some patients receiving infliximab have developed serious liver problems. 
Tell your doctor straight away if you get symptoms of liver problems during treatment with Flixabi. 
Signs include yellowing of the skin and eyes, dark-brown coloured urine, pain or swelling in the upper 
right side of the stomach area, joint pain, skin rashes, or fever. 

 
Low blood counts 
• In some patients receiving infliximab, the body may not make enough of the blood cells that help 
fight infections or help stop bleeding. 
Tell your doctor straight away if you get symptoms of low blood counts during treatment with Flixabi. 
Signs include persistent fever, bleeding or bruising more easily, small red or purple spots caused by 
bleeding under the skin, or looking pale. 

 
Immune system disorder 
• Some patients receiving infliximab have developed symptoms of an immune system disorder called 
lupus. 
Tell your doctor straight away if you develop symptoms of lupus during treatment with Flixabi. Signs 
include joint pain or a rash on cheeks or arms that is sensitive to the sun. 



52 
 

Children and adolescents 
The information above also applies to children and adolescents. In addition: 
• Some children and teenage patients who have received TNF-blockers such as Flixabi have 

developed cancers, including unusual types, which sometimes resulted in death. 
• More children taking Flixabi developed infections as compared to adults. 
• Children should receive recommended vaccinations before starting Flixabi treatment.  

Children may receive some vaccines during treatment with Flixabi but should not receive live 
vaccines while using Flixabi. 

 
If you are not sure if any of the above applies to you, talk to your doctor before you are given Flixabi. 
 
Other medicines and Flixabi 
Patients who have inflammatory diseases already take medicines to treat their problem. These medicines may 
cause side effects. Your doctor will advise you what other medicines you must keep using while you are 
having Flixabi. 
 
Tell your doctor if you are using or have recently used any other medicines, including any other medicines to 
treat Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or 
psoriasis or medicines obtained without a prescription, such as vitamins and herbal medicines. 
 
In particular, tell your doctor if you are using any of the following medicines: 
• Medicines that affect your immune system. 
• Kineret (anakinra). Flixabi and Kineret should not be used together. 
• Orencia (abatacept). Flixabi and Orencia should not be used together. 

 
While using Flixabi you should not receive live vaccines. If you were using Flixabi during pregnancy, tell 
your baby’s doctor and other healthcare professionals caring for your baby about your Flixabi use before the 
baby receives any vaccines. 
 
If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before using Flixabi. 
 
Pregnancy and breast-feeding, and fertility 
• If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor for advice before taking this medicine. Flixabi should only be used during pregnancy if 
your doctor feels it is necessary for you. 

• You should avoid getting pregnant when you are being treated with Flixabi and for 6 months after you 
stop being treated with it. Discuss the use of contraception during this time with your doctor. 

• Do not breast-feed when you are being treated with Flixabi or for 6 months after your last treatment 
with Flixabi. 

• If you received Flixabi 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 healthcare professionals about your Flixabi 
use before your baby is given any vaccine. If you received Flixabi while pregnant, giving BCG vaccine 
(used to prevent tuberculosis) to your baby within 6 months after birth may result in infection with 
serious complications, including death. Live vaccines such as BCG should not be given to your baby 
within 6 months after birth. For more information see section on vaccination. 

• Severely decreased numbers of white blood cells have been reported in infants born to women treated 
with Flixabi during pregnancy. If your baby has continual fevers or infections, contact your baby’s 
doctor immediately. 

 
Driving and using machines 
Flixabi is not likely to affect your ability to drive or use tools or machines. If you feel tired, dizzy, or unwell 
after having Flixabi, do not drive or use any tools or machines. 
 
Flixabi contains sodium 



53 
 

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-
free’.However, before Flixabi is given to you, it is mixed with a solution that contains sodium. Talk to your 
doctor if you are on a low salt diet. 
 
3. How Flixabi will be given 
 
Rheumatoid arthritis 
The usual dose is 3 mg for every kg of body weight. 
 
Psoriatic arthritis, ankylosing spondylitis (Bechterew’s disease), psoriasis, ulcerative colitis and 
Crohn's disease 
The usual dose is 5 mg for every kg of body weight. 
 
How Flixabi is given 
• Flixabi will be given to you by your doctor or nurse. 
• Your doctor or nurse will prepare the medicine for infusion. 
• The medicine will be given as an infusion (drip) (over 2 hours) into one of your veins, usually in your 

arm. After the third treatment, your doctor may decide to give your dose of Flixabi over 1 hour. 
• You will be monitored while you are given Flixabi and also for 1 to 2 hours afterwards. 

 
How much Flixabi is given 
• The doctor will decide your dose  and how often you will be given Flixabi. This will depend on your 

disease, weight and how well you respond to Flixabi. 
• The table below shows how often you will usually have this medicine after your first dose. 

 
2nd dose  2 weeks after your 1stdose 
3rd dose 6 weeks after your 1stdose 
Further doses  Every 6 to 8 weeks depending on your disease  

 
Use in children and adolescents 
Flixabi should only be used in children and adolescents if they are being treated for Crohn`s disease or 
ulcerative colitis. These children must be 6 years of age or older. 
 
If you are given too much Flixabi 
As this medicine is being given by your doctor or nurse, it is unlikely that you will be given too much. There 
are no known side effects of having too much of Flixabi. 
 
If you forget or miss your Flixabi infusion 
If you forget or miss an appointment to receive Flixabi, make another appointment as soon as possible. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
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 patients may experience serious side effects and may require treatment. 
Side effects may also occur after your treatment with Flixabi has stopped. 
 
Tell your doctor straight away if you notice any of the following: 
• Signs of an allergic reaction such as swelling of your face, lips, mouth or throat which may cause 

difficulty in swallowing or breathing, skin rash, hives, swelling of the hands, feet or ankles. Some of 
these reactions may be serious or life-threatening. An allergic reaction could happen within 2 hours of 
your injection or later. More signs of allergic side effects that may happen up to 12 days after your 
injection include pain in the muscles, fever, joint or jaw pain, sore throat or headache. 



54 
 

• Signs of a heart problem such as chest discomfort or pain, arm pain, stomach pain, shortness of 
breath, anxiety, lightheadedness, dizziness, fainting, sweating, nausea (feeling sick), vomiting, 
fluttering or pounding in your chest, a fast or a slow heartbeat, and swelling of your feet. 

• Signs of infection (including TB) such as fever, feeling tired, cough which may be persistent, 
shortness of breath, flu-like symptoms, weight loss, night sweats, diarrhoea, wounds, collection of pus 
in the gut or around the anus (abscess), dental problems or burning sensation when urinating 

• Possible signs of cancer including but not limited to swelling of lymph nodes, weight loss, fever, 
unusual skin nodules, changes in moles or skin colouring, or unusual vaginal bleeding 

• Signs of a lung problem such as coughing, breathing difficulties or tightness in the chest 
• Signs of a nervous system problem (including eye problems) such as signs of a stroke (sudden 

numbness or weakness of your face, arm or leg, especially on one side of your body; sudden confusion, 
trouble speaking or understanding; trouble seeing in one or both eyes, trouble walking, dizziness, loss 
of balance or coordination or a severe headache), fits, tingling/numbness in any part of your body, or 
weakness in arms or legs, changes in eyesight such as double vision or other eye problems 

• Signs of a liver problem (including hepatitis B infection when you have had hepatitis B in the past) 
such as yellowing of the skin or eyes, dark-brown coloured urine, pain or swelling in the upper right 
side of the stomach area, joint pain, skin rashes, or fever 

• Signs of an immune system disorder such as joint pain or a rash on cheeks or arms that is sensitive 
to the sun (lupus) or cough, shortness of breath, fever or skin rash (sarcoidosis) 

• Signs of low blood counts such as persistent fever, bleeding or bruising more easily, small red or 
purple spots caused by bleeding under the skin, or looking pale. 

• Signs of serious skin problems such as reddish-target-like spots or circular patches often with central 
blisters on the trunk, large areas of peeling and shedding (exfoliating) skin, ulcers of mouth, throat, 
nose, genitals and eyes or small pus-filled bumps that can spread over the body. These skin reactions 
can be accompanied by fever. 

 
Tell your doctor straight away if you notice any of the above. 
 
The following side effects have been observed with infliximab: 
 
Very common: may affect more than 1 in 10 people 
• Stomach pain, feeling sick 
• Viral infections such as herpes or flu 
• Upper respiratory infections such as sinusitis 
• Headache 
• Side effect due to an infusion 
• Pain. 

 
Common: may affect up to 1 10 people 
• Changes in how your liver works, increase in liver enzymes (shown in blood tests) 
• Lung or chest infections such as bronchitis or pneumonia 
• Difficult or painful breathing, chest pain 
• Bleeding in the stomach or intestines, diarrhoea, indigestion, heartburn, constipation 
• Nettle-type rash (hives), itchy rash or dry skin 
• Balance problems or feeling dizzy 
• Fever, increased sweating 
• Circulation problems such as low or high blood pressure 
• Bruising, hot flush or nosebleed, warm, red skin (flushing) 
• Feeling tired or weak 
• Bacterial infections such as blood poisoning, abscess or infection of the skin (cellulitis) 
• Infection of the skin due to a fungus 
• Blood problems such as anaemia or low white blood cell count 
• Swollen lymph nodes 
• Depression, problems sleeping 
• Eye problems, including red eyes and infections 



55 
 

• Fast heart beat (tachycardia) or palpitations 
• Pain in the joints, muscles or back 
• Urinary tract infection 
• Psoriasis, skin problems such as eczema and hair loss 
• Reactions at the injection site such as pain, swelling, redness or itching 
• Chills, a build up of fluid under the skin causing swelling 
• Feeling numb or having a tingling feeling. 

 
Uncommon: may affect up to1 in 100 people 
• Shortage of blood supply, swelling of a vein 
• Collection of blood outside the blood vessels (haematoma) or bruising 
• Skin problems such as blistering, warts, abnormal skin colouration or pigmentation, or swollen lips, or 

thickening of the skin, or red, scaly and flaky skin 
• Severe allergic reactions (e.g. anaphylaxis), an immune system disorder called lupus, allergic reactions 

to foreign proteins 
• Wounds taking longer to heal 
• Swelling of the liver (hepatitis) or gall bladder, liver damage 
• Feeling forgetful, irritable, confused, nervous 
• Eye problems including blurred or reduced vision, puffy eyes or sties 
• New or worsening heart failure, slow heart rate 
• Fainting 
• Convulsions, nerve problems 
• A hole in the bowel or blockage of the intestine, stomach pain or cramps 
• Swelling of your pancreas (pancreatitis) 
• Fungal infections such as yeast infection or fungal infection of the nails 
• Lung problems (such as oedema) 
• Fluid around the lungs (pleural effusion) 
• Narrowed airway in the lungs, causing difficulty breathing 
• Inflamed lining of the lung, causing sharp chest pains that feel worse with breathing (pleurisy) 
• Tuberculosis 
• Kidney infections 
• Low platelet count, too many white blood cells 
• Infections of the vagina. 
• Blood test result showing ‘antibodies’ against your own body. 

 
Rare: may affect up to 1 in 1,000 people 
• A type of blood cancer (lymphoma) 
• Your blood not supplying enough oxygen to your body, circulation problems such as narrowing of a 

blood vessel 
• Inflammation of the lining of the brain (meningitis) 
• Infections due to a weakened immune system 
• Hepatitis B infection when you have had hepatitis B in the past 
• Inflamed liver caused by a problem with the immune system (autoimmune hepatitis) 
• Liver problem that causes yellowing of the skin or eyes (jaundice) 
• Abnormal tissue swelling or growth 
• Severe allergic reaction that may cause loss of consciousness and could be life-threatening 

(anaphylactic shock) 
• Swelling of small blood vessels (vasculitis) 
• Immune disorders that could affect the lungs, skin and lymph nodes (such as sarcoidosis) 
• Collections of immune cells resulting from an inflammatory response (granulomatous lesions) 
• Lack of interest or emotion 
• Serious skin problems such as toxic epidermal necrolysis, Stevens-Johnson Syndrome and acute 

generalised exanthematous pustulosis  



56 
 

• Other skin problems such as erythema multiforme, lichenoid reactions (itchy reddish-purple skin rash 
and/or threadlike white-grey lines on mucous membranes), blisters and peeling skin, or boils 
(furunculosis) 

• Serious nervous system disorders such as transverse myelitis, multiple sclerosis-like disease, optic 
neuritis and Guillain-Barré syndrome 

• Inflammation in the eye that may cause changes in the vision, including blindness 
• Fluid in the lining of the heart (pericardial effusion) 
• Serious lung problems (such as interstitial lung disease) 
• Melanoma (a type of skin cancer). 
• Cervical cancer 
• Low blood counts, including a severely decreased number of white blood cells. 
• Small red or purple spots caused by bleeding under the skin 
• Abnormal values of a blood protein called ‘complement factor’ which is part of the immune system. 

 
Not known: frequency cannot be estimated from the available data 
• Cancer in children and adults 
• A rare blood cancer affecting mostly teenage boys or young men (hepatosplenic T-cell lymphoma) 
• Liver failure 
• Merkel cell carcinoma (a type of skin cancer) 
• Worsening of a condition called dermatomyositis (seen as a skin rash accompanying muscle 

weakness) 
• Heart attack 
• Stroke 
• Temporary loss of sight during or within 2 hours of infusion 
• Infection due to a live vaccine because of a weakened immune system. 

 
Additional side effects in children and adolescents 
Children and adolescents who took infliximab for Crohn’s disease showed some differences in side effects 
compared with adults who took infliximab for Crohn's disease. The side effects that happened more in 
children were: low red blood cells (anaemia), blood in stool, low overall levels of white blood cells 
(leucopenia), redness or blushing (flushing), viral infections, low levels of white blood cells that fight 
infection (neutropenia), bone fracture, bacterial infection and allergic reactions of the breathing tract. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. 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 Flixabi 
 
Flixabi will be stored by the health professionals at the hospital or clinic. The storage details should you need 
them are as follows: 
• 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 and the carton after “EXP”. 

The expiry date refers to the last day of that month. 
• Store in a refrigerator (2°C - 8°C). 
• This medicine can also be stored in the original carton outside of refrigerated storage up to a 

maximum of 25°C for a single period of up to six months. In this situation, do not return to 
refrigerated storage again. Write the new expiry date on the carton including day/month/year. 
Discard this medicine if not used by the new expiry date or the expiry date printed on the carton, 
whichever is earlier. 

• It is recommended that when Flixabi is prepared for infusion, it is used as soon as possible (within 
3 hours). However, if the solution is prepared in germ-free conditions, it can be stored in the 

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


57 
 

refrigerator at 2°C to 8°C up to 34 days and for an additional 24 hours at 25°C after removal from 
refrigeration. 

• Do not use this medicine if it is discoloured or if there are particles present. 
 
 
6. Contents of the pack and other information 
 
What Flixabi contains 
• The active substance is infliximab. Each vial contains 100 mg of infliximab. After preparation each 

mL contains 10 mg of infliximab. 
• The other ingredients are sucrose, polysorbate 80, monobasic sodium phosphate monohydrate and 

dibasic sodium phosphate heptahydrate. 
 
What Flixabi looks like and contents of the pack 
Flixabi is supplied as a glass vial containing a powder for concentrate for solution for infusion. The powder 
is white. 
Flixabi is produced in packs of 1, 2, 3, 4, or 5 vial(s). Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder  
Samsung Bioepis NL B.V. 
Olof Palmestraat 10 
2616 LR Delft 
The Netherlands 
 
Manufacturer 
Biogen (Denmark) Manufacturing ApS 
Biogen Allé 1 
3400 Hillerød 
Denmark  
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien  
Biogen Belgium NV/S.A  
Tél/Tel: + 32 (0)2 808 5947 

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

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

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

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

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

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

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

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

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

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

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



58 
 

  

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

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

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

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

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

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

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

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

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

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

Ísland  
Icepharma hf. 
Sími: + 354 800 9836 
 

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

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

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

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

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

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

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

 
This leaflet was last revised in {MM/YYYY}. 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 



59 
 

 
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The following information is intended for healthcare professionals only: 
 
Patients treated with Flixabi should be given the patient reminder card. 
 
Instructions for use and handling – storage conditions 
 
Store at 2°C - 8°C. 
 
Flixabi may be stored at temperatures up to a maximum of 25°C for a single period of up to 6 months, but 
not exceeding the original expiry date. The new expiry date must be written on the carton. Upon removal 
from refrigerated storage, Flixabi must not be returned to refrigerated storage. 
 
Instructions for use and handling – reconstitution, dilution and administration  
 
In order to improve the traceability of biological medicinal products, the tradename and batch number of the 
administered medicinal product should be clearly recorded. 
 
1. Calculate the dose and the number of Flixabi vials needed. Each Flixabi vial contains 100 mg infliximab. 

Calculate the total volume of reconstituted Flixabi solution required. 
 
2. Under aseptic conditions, reconstitute each Flixabi vial with 10 ml of water for injections, using a 

syringe equipped with a 21-gauge (0.8 mm) or smaller needle. Remove flip-top from the vial and wipe 
the top with a 70% alcohol swab. Insert the syringe needle into the vial through the centre of the rubber 
stopper and direct the stream of water for injections to the glass wall of the vial. Gently swirl the 
solution by rotating the vial to dissolve the lyophilised powder. Avoid prolonged or vigorous agitation. 
DO NOT SHAKE. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted 
solution to stand for 5 minutes. Check that the solution is colourless to light yellow and opalescent. The 
solution may develop a few fine translucent particles, as infliximab is a protein. Do not use if opaque 
particles, discolouration, or other foreign particles are present. 

 
3. Dilute the total volume of the reconstituted Flixabi solution dose to 250 ml with sodium chloride 9 

mg/ml (0.9%) solution for infusion. Do not dilute the reconstituted Flixabi solution with any other 
diluent. The dilution can be accomplished by withdrawing a volume of the sodium chloride 9 mg/ml 
(0.9%) solution for infusion from the 250-ml glass bottle or infusion bag equal to the volume of 
reconstituted Flixabi. Slowly add the total volume of reconstituted Flixabi solution to the 250-ml 
infusion bottle or bag. Gently mix. For volumes greater than 250 ml, either use a larger infusion bag (e.g. 
500 ml, 1000 ml) or use multiple 250 ml infusion bags to ensure that the concentration of the infusion 
solution does not exceed 4 mg/ml. If stored refrigerated after reconstitution and dilution, the infusion 
solution must be allowed to equilibrate at room temperature to 25 °C for 3 hours prior to Step 4 
(infusion). Storage beyond 24 hours at 2 °C to 8 °C applies to preparation of Flixabi in the infusion bag 
only. 

 
4. Administer the infusion solution over a period of not less than the infusion time recommended. Use only 

an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 1.2 
micrometre or less). Since no preservative is present, it is recommended that the administration of the 
solution for infusion is to be started as soon as possible and within 3 hours of reconstitution and dilution. 
If not used immediately, in use storage times and conditions prior to use are the responsibility of the user 
and would normally not be longer than 24 hours at 2 °C to 8 °C, unless reconstitution/dilution has been 
taken place in controlled and validated aseptic conditions. Do not store any unused portion of the 
infusion solution for reuse. 

 
5. No physical biochemical compatibility studies have been conducted to evaluate the co-administration of 

Flixabi with other agents. Do not infuse Flixabi concomitantly in the same intravenous line with other 
agents. 



60 
 

 
6. Visually inspect Flixabi for particulate matter or discolouration prior to administration. Do not use if 

visibly opaque particles, discolouration or foreign particles are observed. 
 

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


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER 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