FLIXABI 100mg powder for concentrate infusion solution medication leaflet

Flixabi 100 mg powder for concentrate for solution for infusion

Each 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.

Powder for concentrate for solution for infusion (powder for concentrate)

White powder.

Flixabi, in combination with methotrexate, is indicated for the reduction of signs and symptoms as well asthe 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 orother 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).

Flixabi is indicated for: treatment of moderately to severely active Crohn’s disease, in adult patients who have not respondeddespite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; orwho 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 fulland adequate course of therapy with conventional treatment (including antibiotics, drainage andimmunosuppressive therapy).

Flixabi is indicated for treatment of severe, active Crohn’s disease in children and adolescents aged 6 to17 years, who have not responded to conventional therapy including a corticosteroid, an immunomodulatorand 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.

Flixabi is indicated for treatment of moderately to severely active ulcerative colitis in adult patients whohave 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.

Flixabi is indicated for treatment of severely active ulcerative colitis in children and adolescents aged 6 to17 years, who have had an inadequate response to conventional therapy including corticosteroids and 6-MPor AZA, or who are intolerant to or have medical contraindications for such therapies.

Flixabi is indicated for treatment of severe, active ankylosing spondylitis, in adult patients who haveresponded inadequately to conventional therapy.

Flixabi is indicated for treatment of active and progressive psoriatic arthritis in adult patients when theresponse 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 iscontraindicated.

Infliximab has been shown to improve physical function in patients with psoriatic arthritis, and to reduce therate of progression of peripheral joint damage as measured by X-ray in patients with polyarticularsymmetrical subtypes of the disease (see section 5.1).

Flixabi is indicated for treatment of moderate to severe plaque psoriasis in adult patients who failed torespond to, or who have a contraindication to, or are intolerant to other systemic therapy includingciclosporin, methotrexate or psoralen ultra-violet A (PUVA) (see section 5.1).

Flixabi treatment is to be initiated and supervised by qualified physicians experienced in the diagnosis andtreatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis orpsoriasis. Flixabi should be administered intravenously. Flixabi infusions should be administered byqualified healthcare professionals trained to detect any infusion-related issues. Patients treated with Flixabishould be given the package leaflet and the patient reminder card.

During Flixabi treatment, other concomitant therapies, e.g. corticosteroids and immunosuppressants shouldbe optimised.

Adults (≥ 18 years)

Rheumatoid arthritis3 mg/kg given based on the body weight (bw) as an intravenous infusion followed by additional 3 mg/kg bwinfusion 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 apatient has an inadequate response or loses response after this period, consideration may be given to increasethe dose step-wise by approximately 1.5 mg/kg bw, up to a maximum of 7.5 mg/kg bw every 8 weeks.

Alternatively, administration of 3 mg/kg bw as often as every 4 weeks may be considered. If adequateresponse is achieved, patients should be continued on the selected dose or dose frequency. Continued therapyshould be carefully reconsidered in patients who show no evidence of therapeutic benefit within the first 12weeks of treatment or after dose adjustment.

Moderately to severely active Crohn’s disease5 mg/kg bw given as an intravenous infusion followed by an additional 5 mg/kg bw infusion 2 weeks afterthe first infusion. If a patient does not respond after 2 doses, no additional treatment with infliximab shouldbe given. Available data do not support further infliximab treatment, in patients not responding within 6weeks of the initial infusion.

In responding patients, the alternative strategies for continued treatment are: Maintenance: Additional infusion of 5 mg/kg bw at 6 weeks after the initial dose, followed by infusionsevery 8 weeks or Re-administration: Infusion of 5 mg/kg bw 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 bw butwho 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 benefitafter dose adjustment.

Fistulising, active Crohn’s disease5 mg/kg bw given as an intravenous infusion followed by additional 5 mg/kg bw infusions at 2 and 6 weeksafter the first infusion. If a patient does not respond after 3 doses, no additional treatment with infliximabshould be given.

In responding patients, the alternative strategies for continued treatment are: Maintenance: Additional infusions of 5 mg/kg bw every 8 weeks or Re-administration: Infusion of 5 mg/kg bw if signs and symptoms of the disease recur followed byinfusions of 5 mg/kg bw 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 bw butwho 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 benefitafter dose adjustment.

In Crohn’s disease, experience with re-administration if signs and symptoms of disease recur is limited andcomparative data on the benefit/risk of the alternative strategies for continued treatment are lacking.

Ulcerative colitis5 mg/kg bw given as an intravenous infusion followed by additional 5 mg/kg bw infusion doses at 2 and 6weeks 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. threedoses. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeuticbenefit within this time period.

Ankylosing spondylitis5 mg/kg bw given as an intravenous infusion followed by additional 5 mg/kg bw infusion doses at 2 and 6weeks after the first infusion, then every 6 to 8 weeks. If a patient does not respond by 6 weeks (i.e. after 2doses), no additional treatment with infliximab should be given.

Psoriatic arthritis5 mg/kg bw given as an intravenous infusion followed by additional 5 mg/kg bw infusion doses at 2 and 6weeks after the first infusion, then every 8 weeks thereafter.

Psoriasis5 mg/kg bw given as an intravenous infusion followed by additional 5 mg/kg bw infusion doses at 2 and 6weeks 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 infliximab should be given.

If the signs and symptoms of disease recur, infliximab can be re-administered within 16 weeks following thelast infusion. In clinical studies, delayed hypersensitivity reactions have been uncommon and have occurredafter 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 appliesto both Crohn’s disease patients and rheumatoid arthritis patients.

The safety and efficacy of re-administration, other than every 8 weeks, has not been established (see sections4.4 and 4.8).

The safety and efficacy of re-administration, other than every 6 to 8 weeks, has not been established (seesections 4.4 and 4.8).

The safety and efficacy of re-administration, other than every 8 weeks, has not been established (see sections4.4 and 4.8).

Limited experience from re-treatment with one single infliximab dose in psoriasis after an interval of20 weeks suggests reduced efficacy and a higher incidence of mild to moderate infusion-related reactionswhen 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 higherincidence of infusion-related reactions, including serious ones, when compared to 8-weekly maintenancetreatment (see section 4.8).

In case maintenance therapy is interrupted, and there is a need to restart treatment, use of a re-inductionregimen is not recommended (see section 4.8). In this situation, infliximab should be re-initiated as a singledose followed by the maintenance dose recommendations described above.

Specific studies of infliximab in elderly patients have not been conducted. No major age-related differencesin clearance or volume of distribution were observed in clinical studies. No dose adjustment is required (seesection 5.2). For more information about the safety of infliximab in elderly patients (see sections 4.4 and4.8).

Infliximab has not been studied in these patient populations. No dose recommendations can be made (seesection 5.2).

Crohn’s disease (6 to 17 years)5 mg/kg bw given as an intravenous infusion followed by additional 5 mg/kg bw infusion doses at 2 and 6weeks after the first infusion, then every 8 weeks thereafter. Available data do not support further infliximabtreatment in children and adolescents not responding within the first 10 weeks of treatment (see section 5.1).

Some patients may require a shorter dosing interval to maintain clinical benefit, while for others a longerdosing interval may be sufficient. Patients who have had their dose interval shortened to less than 8 weeksmay be at greater risk for adverse reactions. Continued therapy with a shortened interval should be carefullyconsidered in those patients who show no evidence of additional therapeutic benefit after a change in dosinginterval.

The safety and efficacy of infliximab have not been studied in children with Crohn’s disease below the ageof 6 years. Currently available pharmacokinetic data are described in section 5.2 but no recommendation ona posology can be made in children younger than 6 years.

Ulcerative colitis (6 to 17 years)5 mg/kg bw given as an intravenous infusion followed by additional 5 mg/kg bw infusion doses at 2 and 6weeks after the first infusion, then every 8 weeks thereafter. Available data do not support further infliximabtreatment 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 ageof 6 years. Currently available pharmacokinetic data are described in section 5.2 but no recommendation ona posology can be made in children younger than 6 years.

The safety and efficacy of infliximab in children and adolescents younger than 18 years for the indication ofpsoriasis have not been established. Currently available data are described in section 5.2 but norecommendation on a posology can be made.

The safety and efficacy of infliximab in children and adolescents younger than 18 years for the indications ofjuvenile 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.

The safety and efficacy of infliximab in children and adolescents younger than 18 years for the indication ofjuvenile rheumatoid arthritis have not been established. Currently available data are described in sections 4.8and 5.2 but no recommendation on a posology can be made.

Infliximab should be administered intravenously over a 2-hour period. All patients administered infliximabare to be observed for at least 1-2 hours post-infusion for acute infusion-related reactions. Emergencyequipment, 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 ratemay be slowed in order to decrease the risk of infusion-related reactions especially if infusion-relatedreactions have occurred previously (see section 4.4).

In carefully selected adult patients who have tolerated at least 3 initial 2-hour infusions of infliximab(induction phase) and are receiving maintenance therapy, consideration may be given to administeringsubsequent infusions over a period of not less than 1 hour. If an infusion-related reaction occurs inassociation with a shortened infusion, a slower infusion rate may be considered for future infusions iftreatment is to be continued. Shortened infusions at doses > 6 mg/kg bw have not been studied (see section4.8).

For preparation and administration instructions, see section 6.6.

Hypersensitivity to the active substance, to other murine proteins, or to any of the excipients listed in section6.1.

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).

In order to improve the traceability of biological medicinal products, the name and the batch number of theadministered product should be clearly recorded.

Infusion-related reactions (IRR) and hypersensitivity

Infliximab has been associated with acute infusion-related reactions, including anaphylactic shock, anddelayed hypersensitivity reactions (see section 4.8).

Acute infusion-related reactions including anaphylactic reactions may develop during (within seconds) orwithin a few hours following infusion. If acute infusion-related reactions occur, the infusion must beinterrupted immediately. Emergency equipment, such as adrenaline, antihistamines, corticosteroids and anartificial airway must be available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisoneand/or paracetamol to prevent mild and transient effects.

Antibodies to infliximab may develop and have been associated with an increased frequency of infusion-related reactions. A low proportion of the infusion-related reactions was serious allergic reactions. Anassociation between development of antibodies to infliximab and reduced duration of response has also beenobserved. Concomitant administration of immunomodulators has been associated with lower incidence ofantibodies to infliximab and a reduction in the frequency of infusion-related reactions. The effect ofconcomitant immunomodulator therapy was more profound in episodically-treated patients than in patientsgiven maintenance therapy. Patients who discontinue immunosuppressants prior to or during infliximabtreatment are at greater risk of developing these antibodies. Antibodies to infliximab cannot always bedetected in serum samples. If serious reactions occur, symptomatic treatment must be given and furtherinfliximab infusions must not be administered (see section 4.8).

In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest an increasedrisk for delayed hypersensitivity with increasing infliximab-free interval. Patients should be advised to seekimmediate medical advice if they experience any delayed adverse reaction (see section 4.8). If patients arere-treated after a prolonged period, they must be closely monitored for signs and symptoms of delayedhypersensitivity.

Patients must be monitored closely for infections including tuberculosis or other severe infections such assepsis, abscesses, and opportunistic infections before, during and after treatment with infliximab. Becausethe elimination of infliximab may take up to six months, monitoring should be continued throughout thisperiod. Further treatment with infliximab must not be given if a patient develops a serious infection or sepsis.

Caution should be exercised when considering the use of infliximab in patients with chronic infection or ahistory of recurrent infections, including concomitant immunosuppressive therapy. Patients should beadvised 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 experienceshows 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. Earlyrecognition of atypical clinical presentations of serious infections and of typical clinical presentation of rareand unusual infections is critical in order to minimise delays in diagnosis and treatment.

Patients taking TNF-blockers are more susceptible to serious infections.

Tuberculosis, mycobacterial infection, bacterial infections, including sepsis and pneumonia, invasive fungal,viral, and other opportunistic infections have been observed in patients treated with infliximab. Some ofthese infections have been fatal; the most frequently reported opportunistic infections with a mortality rate of> 5% include aspergillosis, candidiasis, listeriosis and pneumocystosis.

Patients who develop a new infection while undergoing treatment with infliximab, should be monitoredclosely and undergo a complete diagnostic evaluation. Administration of infliximab should be discontinuedif a patient develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapyshould be initiated until the infection is controlled.

There have been reports of active tuberculosis in patients receiving infliximab. It should be noted that in themajority of these reports tuberculosis was extrapulmonary, presenting as either local or disseminated disease.

Before starting treatment with infliximab, all patients must be evaluated for both active and inactive (‘latent’)tuberculosis. This evaluation should include a detailed medical history with personal history of tuberculosisor 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 conductof these tests should be recorded in the patient’s reminder card. Prescribers are reminded of the risk of falsenegative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.

If active tuberculosis is diagnosed, infliximab therapy must not be initiated (see section 4.3).

If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should beconsulted. In all situations described below, the benefit/risk balance of infliximab therapy should be verycarefully considered.

If inactive (‘latent’) tuberculosis is diagnosed, treatment for latent tuberculosis must be started withantituberculosis therapy before the initiation of infliximab, and in accordance with local recommendations.

In patients who have several or significant risk factors for tuberculosis and have a negative test for latenttuberculosis, antituberculosis therapy should be considered before the initiation of infliximab.

Use of anti-tuberculosis therapy should also be considered before the initiation of infliximab in patients witha 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 infliximab during and aftertreatment 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 infliximab treatment.

In patients treated with infliximab, an invasive fungal infection such as aspergillosis, candidiasis,pneumocystosis, histoplasmosis, coccidioidomycosis or blastomycosis should be suspected if they develop aserious systemic illness, and a physician with expertise in the diagnosis and treatment of invasive fungalinfections should be consulted at an early stage when investigating these patients.

Invasive fungal infections may present as disseminated rather than localised disease, and antigen andantibody testing may be negative in some patients with active infection. Appropriate empiric antifungaltherapy should be considered while a diagnostic workup is being performed taking into account both the riskfor severe fungal infection and the risks of antifungal therapy.

For patients who have resided in or travelled to regions where invasive fungal infections such ashistoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of infliximabtreatment should be carefully considered before initiation of infliximab therapy.

Patients with fistulising Crohn’s disease with acute suppurative fistulas must not initiate infliximab therapyuntil a source for possible infection, specifically abscess, has been excluded (see section 4.3).

Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including infliximab, who arechronic carriers of this virus. Some cases have had fatal outcome.

Patients should be tested for HBV infection before initiating treatment with infliximab. For patients who testpositive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B isrecommended. Carriers of HBV who require treatment with infliximab should be closely monitored for signsand symptoms of active HBV infection throughout therapy and for several months following termination oftherapy. Adequate data of treating patients who are carriers of HBV with antiviral therapy in conjunctionwith TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBVreactivation, infliximab should be stopped and effective antiviral therapy with appropriate supportivetreatment should be initiated.

Cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have beenobserved in the post-marketing experience of infliximab. Isolated cases of liver failure resulting in livertransplantation or death have occurred. Patients with symptoms or signs of liver dysfunction should beevaluated for evidence of liver injury. If jaundice and/or ALT elevations ≥ 5 times the upper limit of normaldevelop(s), infliximab should be discontinued, and a thorough investigation of the abnormality should beundertaken.

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 ofthe nature of the adverse reactions seen with combination of etanercept and anakinra therapy, similartoxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, thecombination of infliximab and anakinra is not recommended.

In clinical studies concurrent administration of TNF-antagonists and abatacept has been associated with anincreased risk of infections including serious infections compared to TNF-antagonists alone, withoutincreased clinical benefit. The combination of infliximab and abatacept is not recommended.

There is insufficient information regarding the concomitant use of infliximab with other biologicaltherapeutics used to treat the same conditions as infliximab. The concomitant use of infliximab with thesebiologics is not recommended because of the possibility of an increased risk of infection, and other potentialpharmacological interactions.

Switching between biological DMARDS

Care should be taken and patients should continue to be monitored when switching from one biologic toanother, since overlapping biological activity may further increase the risk for adverse reactions, includinginfection.

It is recommended that patients, if possible, be brought up to date with all vaccinations in agreement withcurrent vaccination guidelines prior to initiating infliximab therapy. Patients on infliximab may receiveconcurrent vaccinations, except for live vaccines (see sections 4.5 and 4.6).

In a subset of 90 adult patients with rheumatoid arthritis from the ASPIRE study a similar proportion ofpatients in each treatment group (methotrexate plus: placebo [n = 17], 3 mg/kg [n = 27] or 6 mg/kginfliximab [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’sdisease) suggest that non-live vaccinations received during treatment with anti-TNF therapies, includinginfliximab, may elicit a lower immune response than in patients not receiving anti-TNF therapy.

In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with livevaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines can result inclinical infections, including disseminated infections. The concurrent administration of live vaccines withinfliximab 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. A twelve month waitingperiod following birth is recommended before the administration of live vaccines to infants exposed in uteroto infliximab. If infant infliximab serum levels are undetectable or infliximab administration was limited tothe first trimester of pregnancy, administration of a live vaccine might be considered at an earlier timepoint ifthere is a clear clinical benefit for the individual infant (see section 4.6).

Administration of a live vaccine to a breastfed infant while the mother is receiving infliximab is notrecommended unless infant infliximab serum levels are undetectable (see section 4.6).

Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation forthe treatment of cancer) could result in clinical infections, including disseminated infections. It isrecommended that therapeutic infectious agents not be given concurrently with infliximab.

The relative deficiency of TNFα caused by anti-TNF therapy may result in the initiation of an autoimmuneprocess. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment withinfliximab and is positive for antibodies against double-stranded DNA, further treatment with infliximabmust not be given (see section 4.8).

Use of TNF-blocking agents, including infliximab, has been associated with cases of new onset orexacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinatingdisorders, including multiple sclerosis, and peripheral demyelinating disorders, including Guillain-Barrésyndrome. In patients with pre-existing or recent onset of demyelinating disorders, the benefits and risks ofanti-TNF treatment should be carefully considered before initiation of infliximab therapy. Discontinuation ofinfliximab should be considered if these disorders develop.

In the controlled portions of clinical studies of TNF-blocking agents, more cases of malignancies includinglymphoma 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 ininfliximab-treated patients was higher than expected in the general population, but the occurrence oflymphoma was rare. In the post-marketing setting, cases of leukaemia have been reported in patients treatedwith a TNF-antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoidarthritis 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 chronicobstructive pulmonary disease (COPD), more malignancies were reported in infliximab-treated patientscompared with control patients. All patients had a history of heavy smoking. Caution should be exercised inconsidering 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 patientstreated with a TNF-blocking agent cannot be excluded (see section 4.8). Caution should be exercised whenconsidering TNF-blocking therapy for patients with a history of malignancy or when considering continuingtreatment in patients who develop a malignancy.

Caution should also be exercised in patients with psoriasis and a medical history of extensiveimmunosuppressant therapy or prolonged PUVA treatment.

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 yearsof age) treated with TNF-blocking agents (initiation of therapy ≤ 18 years of age), including infliximab in thepost-marketing setting. Approximately half the cases were lymphomas. The other cases represented a varietyof different malignancies and included rare malignancies usually associated with immunosuppression. A riskfor 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 treatedwith TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a very aggressivedisease course and is usually fatal. Almost all patients had received treatment with AZA or 6-MPconcomitantly with or immediately prior to a TNF-blocker. The vast majority of infliximab cases haveoccurred in patients with Crohn’s disease or ulcerative colitis and most were reported in adolescent or youngadult males. The potential risk with the combination of AZA or 6-MP and infliximab should be carefullyconsidered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated withinfliximab 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 patientswith risk factors for skin cancer.

A population-based retrospective cohort study using data from Swedish national health registries found anincreased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab comparedto biologics-naïve patients or the general population, including those over 60 years of age. Periodic screeningshould 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 ofdysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy andthroughout their disease course. This evaluation should include colonoscopy and biopsies per localrecommendations. Current data do not indicate that infliximab treatment influences the risk for developingdysplasia or colon cancer.

Since the possibility of increased risk of cancer development in patients with newly diagnosed dysplasiatreated with infliximab is not established, the risk and benefits of continued therapy to the individual patientsshould be carefully considered by the clinician.

Infliximab should be used with caution in patients with mild heart failure (NYHA class I/II). Patients shouldbe closely monitored and infliximab must not be continued in patients who develop new or worseningsymptoms of heart failure (see sections 4.3 and 4.8).

There have been reports of pancytopenia, leucopenia, neutropenia, and thrombocytopenia in patientsreceiving TNF-blockers, including infliximab. All patients should be advised to seek immediate medicalattention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising,bleeding, pallor). Discontinuation of infliximab therapy should be considered in patients with confirmedsignificant haematologic abnormalities.

The long half-life of infliximab should be taken into consideration if a surgical procedure is planned. Apatient who requires surgery while on infliximab should be closely monitored for infectious and non-infectious complications, and appropriate actions should be taken (see section 4.8).

Failure to respond to treatment for Crohn’s disease may indicate the presence of a fixed fibrotic stricture thatmay require surgical treatment. There is no evidence to suggest that infliximab worsens or causes fibroticstrictures.

The incidence of serious infections in infliximab-treated patients 65 years and older was greater than in thoseunder 65 years of age. Some of those had a fatal outcome. Particular attention regarding the risk for infectionshould be paid when treating the elderly (see section 4.8).

In clinical studies, infections have been reported in a higher proportion of paediatric patients compared toadult patients (see section 4.8).

It is recommended that paediatric patients, if possible, be brought up to date with all vaccinations inagreement with current vaccination guidelines prior to initiating infliximab therapy. Paediatric patients oninfliximab may receive concurrent vaccinations, except for live vaccines (see sections 4.5 and 4.6).

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 yearsof age) treated with TNF-blocking agents (initiation of therapy ≤ 18 years of age), including infliximab in thepost-marketing setting. Approximately half the cases were lymphomas. The other cases represented a varietyof different malignancies and included rare malignancies usually associated with immunosuppression. A riskfor the development of malignancies in children and adolescents treated with TNF-blockers cannot beexcluded.

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 diseasecourse and is usually fatal. Almost all patients had received treatment with AZA or6-MP concomitantly with or immediately prior to a TNF-blocker. The vast majority of infliximab cases haveoccurred in patients with Crohn’s disease or ulcerative colitis and most were reported in adolescent or youngadult males. The potential risk with the combination of AZA or 6-MP and infliximab should be carefullyconsidered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with infliximabcannot be excluded (see section 4.8).

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Flixabi is however, diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion. This should be takeninto consideration for patients on a controlled sodium diet (see section 6.6).

Polysorbate 80

This medicinal product contains 0.5 mg of polysorbate 80 in each vial (20 mL vial) which is equivalent to0.5 mg/10 mL upon reconstitution with 10 mL Water for Injection. Polysorbates may cause allergicreactions. Tell your doctor if you have any known allergies.

No interaction studies have been performed.

In rheumatoid arthritis, psoriatic arthritis and Crohn's disease patients, there are indications that concomitantuse of methotrexate and other immunomodulators reduces the formation of antibodies against infliximab andincreases the plasma concentrations of infliximab. However, the results are uncertain due to limitations in themethods used for serum analyses of infliximab and antibodies against infliximab.

Corticosteroids do not appear to affect the pharmacokinetics of infliximab to a clinically relevant extent.

The combination of infliximab with other biological therapeutics used to treat the same conditions asinfliximab, including anakinra and abatacept, is not recommended (see section 4.4).

It is recommended that live vaccines not be given concurrently with infliximab. It is also recommended thatlive vaccines not be given to infants after in utero exposure to infliximab for 12 months following birth. Ifinfant infliximab serum levels are undetectable or infliximab administration was limited to the first trimesterof pregnancy, administration of a live vaccine might be considered at an earlier timepoint if there is a clearclinical benefit for the individual infant (see section 4.4).

Administration of a live vaccine to a breastfed infant while the mother is receiving infliximab is notrecommended unless infant infliximab serum levels are undetectable (see sections 4.4 and 4.6).

It is recommended that therapeutic infectious agents not be given concurrently with infliximab (see section4.4).

Women of childbearing potential should consider the use of adequate contraception to prevent pregnancyand continue its use for at least 6 months after the last infliximab treatment.

The moderate number of prospectively collected pregnancies exposed to infliximab resulting in live birthwith known outcomes, including approximately 1,100 exposed during the first trimester, does not indicate anincrease 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 exposedduring pregnancy to infliximab (with or without immunomodulators/corticosteroids, 270 pregnancies) ascompared to women exposed to immunomodulators and/or corticosteroids only (6,460 pregnancies). Thepotential contribution of exposure to infliximab and/or the severity of the underlying disease in theseoutcomes remains unclear.

Due to its inhibition of TNFα, infliximab administered during pregnancy could affect normal immuneresponses in the newborn. In a developmental toxicity study conducted in mice using an analogous antibodythat 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 clearlyneeded.

Infliximab crosses the placenta and has been detected in the serum of infants up to 12 months followingbirth. After in utero exposure to infliximab, infants may be at increased risk of infection, including seriousdisseminated infection that can become fatal. Administration of live vaccines (e.g. BCG vaccine) to infantsexposed to infliximab in utero is not recommended for 12 months after birth (see sections 4.4 and 4.5). Ifinfant infliximab serum levels are undetectable or infliximab administration was limited to the first trimesterof pregnancy, administration of a live vaccine might be considered at an earlier timepoint if there is a clearclinical benefit for the individual infant. Cases of agranulocytosis have also been reported (see section 4.8).

Limited data from published literature indicate infliximab has been detected at low levels in human milk atconcentrations up to 5% of the maternal serum level. Infliximab has also been detected in infant serum afterexposure to infliximab via breast milk. While systemic exposure in a breastfed infant is expected to be lowbecause infliximab is largely degraded in the gastrointestinal tract, the administration of live vaccines to abreastfed infant when the mother is receiving infliximab is not recommended unless infant infliximab serumlevels are undetectable. Infliximab could be considered for use during breast-feeding.

There are insufficient preclinical data to draw conclusions on the effects of infliximab on fertility and generalreproductive function (see section 5.3).

Flixabi has minor influence on the ability to drive and use machines, e.g. dizziness, vertigo (see section 4.8).

Upper respiratory tract infection was the most common adverse drug reaction (ADR) reported in clinicaltrials, occurring in 25.3% of infliximab-treated patients compared with 16.5% of control patients. The mostserious ADRs associated with the use of TNF blockers that have been reported for infliximab include HBVreactivation, CHF (congestive heart failure), serious infections (including sepsis, opportunistic infections and

TB), serum sickness (delayed hypersensitivity reactions), haematologic reactions, systemic lupuserythematosus/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-related reactions (see section 4.4).

Table 1 lists ADRs based on experience from clinical studies as well as adverse reactions, some with fataloutcome, reported from post-marketing experience. Within the organ system classes, adverse reactions arelisted under headings of frequency using the following categories: very common (≥ 1/10); common (≥ 1/100to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), notknown (cannot be estimated from the available data). Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

Table 1

Adverse reactions in clinical studies and from post-marketing experience

Very Common: Viral infection (e.g. influenza, herpes virusinfection).

Common: Bacterial infections (e.g. sepsis, cellulitis,abscess).

Uncommon: Tuberculosis, fungal infections (e.g. candidiasis,onychomycosis).

Rare: Meningitis, opportunistic infections (such as invasive fungalinfections [pneumocystosis, histoplasmosis, aspergillosis,coccidioidomycosis, cryptococcosis, blastomycosis], bacterialinfections [atypical mycobacterial, listeriosis, salmonellosis],and viral infections [cytomegalovirus]), parasitic infections,hepatitis B reactivation.

Not known: Vaccine breakthrough infection (after in utero exposure toinfliximab)*.

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 andyoung adult males with Crohn’s disease or ulcerative colitis),

Merkel cell carcinoma, Kaposi’s sarcoma.

Common: Neutropenia, leucopenia, anaemia, lymphadenopathy.

Uncommon: Thrombocytopenia, lymphopenia, lymphocytosis.

Rare: Agranulocytosis (including infants exposed in utero toinfliximab), thrombotic thrombocytopenic purpura,pancytopenia, haemolytic anaemia, idiopathicthrombocytopenic purpura.

Common: Allergic respiratory symptom.

Uncommon: Anaphylactic reaction, lupus-like syndrome, serum sicknessor serum sickness-like reaction.

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

Uncommon: Dyslipidaemia.

Common: Depression, insomnia.

Uncommon: Amnesia, agitation, confusion, somnolence, nervousness.

Rare: Apathy.

Very common: Headache.

Common: Vertigo, dizziness, hypoaesthesia, paraesthesia.

Uncommon: Seizure, neuropathy.

Rare: Transverse myelitis, central nervous system demyelinatingdisorders (multiple sclerosis-like disease and optic neuritis),peripheral demyelinating disorders (such as Guillain-Barrésyndrome, chronic inflammatory demyelinatingpolyneuropathy and multifocal motor neuropathy).

Not known: Cerebrovascular accidents in close temporal association withinfusion.

Common: Conjunctivitis.

Uncommon: Keratitis, periorbital oedema, hordeolum.

Rare: Endophthalmitis.

Not known: Transient visual loss occurring during or within 2 hours ofinfusion.

Common: Tachycardia, palpitation.

Uncommon: Cardiac failure (new onset or worsening), arrhythmia,syncope, bradycardia.

Rare: Cyanosis, pericardial effusion.

Not known: Myocardial ischaemia/myocardial infarction.

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

Uncommon: Peripheral ischaemia, thrombophlebitis, haematoma.

Rare: Circulatory failure, petechia, vasospasm.

Very common: Upper respiratory tract infection, sinusitis.

Common: Lower respiratory tract infection (e.g. bronchitis, pneumonia),dyspnoea, epistaxis.

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

Rare: Interstitial lung disease (including rapidly progressivedisease, lung fibrosis and pneumonitis).

Very common: Abdominal pain, nausea.

Common: Gastrointestinal haemorrhage, diarrhoea, dyspepsia,gastroesophageal reflux, constipation.

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

Common: Hepatic function abnormal, transaminases increased.

Uncommon: Hepatitis, hepatocellular damage, cholecystitis.

Rare: Autoimmune hepatitis, jaundice.

Not known: Liver failure.

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 bullousdermatosis (LABD), acute generalised exanthematouspustulosis (AGEP), lichenoid reactions.

Not known: Worsening of symptoms of dermatomyositis.

Common: Arthralgia, myalgia, back pain.

Common: Urinary tract infection.

Uncommon: Pyelonephritis.

Uncommon: Vaginitis.

Very common: Infusion-related reaction, pain.

Common: Chest pain, fatigue, fever, injection site reaction, chills,oedema.

Uncommon: Impaired healing.

Rare: Granulomatous lesion.

Uncommon: Autoantibody positive, weight increased1.

Rare: Complement factor abnormal.

Injury, poisoning, and procedural complications

Not known: Post-procedural complication (including infectious and non-infectious complications)

* including bovine tuberculosis (disseminated BCG infection), see section 4.41 At month 12 of the controlled period for adult clinical trials across all indications, the median weight increase was3.50 kg for infliximab-treated subjects vs. 3.00 kg for placebo-treated subjects. The median weight increase forinflammatory bowel disease indications was 4.14 kg for infliximab-treated subjects vs. 3.00 kg for placebo-treatedsubjects, and the median weight increase for rheumatology indications was 3.40 kg for infliximab-treated subjects vs.3.00 kg for placebo-treated subjects.

An infusion-related reaction was defined in clinical studies as any adverse event occurring during an infusionor within 1 hour after an infusion. In Phase III clinical studies, 18% of infliximab-treated patients comparedwith 5% of placebo-treated patients experienced an infusion-related reaction. Overall, a higher proportion ofpatients receiving infliximab monotherapy experienced an infusion-related reaction compared to patientsreceiving infliximab with concomitant immunomodulators. Approximately 3% of patients discontinuedtreatment due to infusion-related reactions and all patients recovered with or without medical therapy. Ofinfliximab-treated patients who had an infusion-related reaction during the induction period, through week 6,27% experienced an infusion-related reaction during the maintenance period, week 7 through week 54. Ofpatients who did not have an infusion-related reaction during the induction period, 9% experienced aninfusion-related reaction during the maintenance period.

In a clinical study of patients with rheumatoid arthritis (ASPIRE), infusions were to be administered over2 hours for the first 3 infusions. The duration of subsequent infusions could be shortened to not less than40 minutes in patients who did not experience serious infusion-related reactions. In this trial, sixty sixpercent of the patients (686 out of 1,040) received at least one shortened infusion of 90 minutes or less and44% of the patients (454 out of 1,040) received at least one shortened infusion of 60 minutes or less. Of theinfliximab-treated patients who received at least one shortened infusion, infusion-related reactions occurredin 15% of patients and serious infusion-related reactions occurred in 0.4% of patients.

In a clinical study of patients with Crohn’s disease (SONIC), infusion-related reactions occurred in16.6% (27/163) of patients receiving infliximab monotherapy, 5% (9/179) of patients receiving infliximab incombination with AZA, and 5.6% (9/161) of patients receiving AZA monotherapy. One serious infusion-related reaction (< 1%) occurred in a patient on infliximab monotherapy.

In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngeal oedemaand 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 closetemporal association with infusion of infliximab; cerebrovascular accidents have also been reported in closetemporal association with infusion of infliximab.

Infusion-related reactions following re-administration of infliximab

A clinical study in patients with moderate to severe psoriasis was designed to assess the efficacy and safetyof long-term maintenance therapy versus re-treatment with an induction regimen of infliximab (maximum offour infusions at 0, 2, 6 and 14 weeks) following disease flare. Patients did not receive any concomitantimmunosuppressant therapy. In the re-treatment arm, 4% (8/219) of patients experienced a serious infusion-related reaction versus < 1% (1/222) on maintenance therapy. The majority of serious infusion-relatedreactions occurred during the second infusion at week 2. The interval between the last maintenance dose andthe 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 othertreatment instituted with complete resolution of signs and symptoms.

In clinical studies delayed hypersensitivity reactions have been uncommon and have occurred afterinfliximab-free intervals of less than 1 year. In the psoriasis studies, delayed hypersensitivity reactionsoccurred early in the treatment course. Signs and symptoms included myalgia and/or arthralgia with feverand/or rash, with some patients experiencing pruritus, facial, hand or lip oedema, dysphagia, urticaria, sorethroat and headache.

There are insufficient data on the incidence of delayed hypersensitivity reactions after infliximab-freeintervals of more than 1 year but limited data from clinical studies suggest an increased risk for delayedhypersensitivity 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), theincidence of serum sickness-like reactions was 2.4%.

Patients who developed antibodies to infliximab were more likely (approximately 2-3 fold) to developinfusion-related reactions. Use of concomitant immunosuppressant agents appeared to reduce the frequencyof infusion-related reactions.

In clinical studies using single and multiple infliximab doses ranging from 1 to 20 mg/kg, antibodies toinfliximab were detected in 14% of patients with any immunosuppressant therapy, and in 24% of patientswithout immunosuppressant therapy. In rheumatoid arthritis patients who received the recommendedrepeated treatment dose regimens with methotrexate, 8% of patients developed antibodies to infliximab. Inpsoriatic arthritis patients who received 5 mg/kg with and without methotrexate, antibodies occurred overallin 15% of patients (antibodies occurred in 4% of patients receiving methotrexate and in 26% of patients notreceiving 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% ofpatients not receiving immunosuppressants. The antibody incidence was 2-3 fold higher for patients treatedepisodically. Due to methodological limitations, a negative assay did not exclude the presence of antibodiesto infliximab. Some patients who developed high titres of antibodies to infliximab had evidence of reducedefficacy. In psoriasis patients treated with infliximab as a maintenance regimen in the absence ofconcomitant immunomodulators, approximately 28% developed antibodies to infliximab (see section 4.4).

Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral, and otheropportunistic infections have been observed in patients receiving infliximab. Some of these infections havebeen fatal; the most frequently reported opportunistic infections with a mortality rate of > 5% includepneumocystosis, candidiasis, listeriosis and aspergillosis (see section 4.4).

In clinical studies 36% of infliximab-treated patients were treated for infections compared with 25% ofplacebo-treated patients.

In rheumatoid arthritis clinical studies, the incidence of serious infections including pneumonia was higher ininfliximab plus methotrexate-treated patients compared with methotrexate alone especially at doses of6 mg/kg or greater (see section 4.4).

In post-marketing spontaneous reporting, infections are the most common serious adverse reaction. Some ofthe cases have resulted in a fatal outcome. Nearly 50% of reported deaths have been associated withinfection. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis and tuberculosis with extra-pulmonary location have been reported (see section 4.4).

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 lymphomasand 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 (seesection 4.4).

In an exploratory clinical study involving patients with moderate to severe COPD who were either currentsmokers or ex-smokers, 157 adult patients were treated with infliximab at doses similar to those used inrheumatoid arthritis and Crohn’s disease. Nine of these patients developed malignancies, including1 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;incidence 1.3% [95% CI 0.03%-7.0%]). The majority of the malignancies developed in the lung or head andneck.

A population-based retrospective cohort study found an increased incidence of cervical cancer in womenwith rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the generalpopulation, 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 treatedwith infliximab with the vast majority of cases occurring in Crohn’s disease and ulcerative colitis, and mostof whom were adolescent or young adult males (see section 4.4).

In a Phase II study aimed at evaluating infliximab in CHF, higher incidence of mortality due to worsening ofheart failure were seen in patients treated with infliximab, especially those treated with the higher dose of10 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, orplacebo over 6 weeks. At 38 weeks, 9 of 101 patients treated with infliximab (2 at 5 mg/kg and 7 at10 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 identifiableprecipitating factors, in patients taking infliximab. There have also been post-marketing reports of new onsetheart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some ofthese patients have been under 50 years of age.

In clinical studies, mild or moderate elevations of ALT and AST have been observed in patients receivinginfliximab 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 morecommon than AST) in a greater proportion of patients receiving infliximab than in controls, both wheninfliximab was given as monotherapy and when it was used in combination with other immunosuppressiveagents. Most aminotransferase abnormalities were transient; however, a small number of patientsexperienced more prolonged elevations. In general, patients who developed ALT and AST elevations wereasymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation ofinfliximab, or modification of concomitant therapy. In post-marketing surveillance, cases of jaundice andhepatitis, 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

Number of patients3 Median follow-up

Indication (wks)4 ≥ 3 x ULN ≥ 5 x ULNplacebo infliximab placebo infliximab placebo infliximab placebo infliximab

Rheumatoidarthritis1 375 1,087 58.1 58.3 3.2% 3.9% 0.8% 0.9%

Crohn’sdisease2 324 1,034 53.7 54.0 2.2% 4.9% 0.0% 1.5%

Paediatric

Crohn’s N/A 139 N/A 53.0 N/A 4.4% N/A 1.5%disease

Ulcerativecolitis 242 482 30.1 30.8 1.2% 2.5% 0.4% 0.6%

Paediatric

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

Ankylosingspondylitis 76 275 24.1 101.9 0.0% 9.5% 0.0% 3.6%

Psoriaticarthritis 98 191 18.1 39.1 0.0% 6.8% 0.0% 2.1%

Plaquepsoriasis 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/kginfliximab at study start and were on placebo in the maintenance phase. Patients who were randomised to the placebo maintenancegroup 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.

Approximately half of infliximab-treated patients in clinical studies who were ANA negative at baselinedeveloped a positive ANA during the study compared with approximately one fifth of placebo-treatedpatients. Anti-dsDNA antibodies were newly detected in approximately 17% of infliximab-treated patientscompared with 0% of placebo-treated patients. At the last evaluation, 57% of infliximab-treated patientsremained anti-dsDNA positive. Reports of lupus and lupus-like syndromes, however, remain uncommon (seesection 4.4).

Infliximab was studied in a clinical study in 120 patients (age range: 4-17 years old) with active juvenilerheumatoid arthritis despite methotrexate. Patients received 3 or 6 mg/kg infliximab as a 3-dose inductionregimen (weeks 0, 2, 6 or weeks 14, 16, 20, respectively) followed by maintenance therapy every 8 weeks, incombination with methotrexate.

Infusion-related reactions occurred in 35% of patients with juvenile rheumatoid arthritis receiving 3 mg/kgcompared with 17.5% of patients receiving 6 mg/kg. In the 3 mg/kg infliximab group, 4 out of 60 patientshad a serious infusion-related reaction and 3 patients reported a possible anaphylactic reaction (2 of whichwere among the serious infusion-related reactions). In the 6 mg/kg group, 2 out of 57 patients had a seriousinfusion-related reaction, one of whom had a possible anaphylactic reaction (see section 4.4).

Antibodies to infliximab developed in 38% of patients receiving 3 mg/kg compared with 12% of patientsreceiving 6 mg/kg. The antibody titres were notably higher for the 3 mg/kg compared to the 6 mg/kg group.

Infections occurred in 68% (41/60) of children receiving 3 mg/kg over 52 weeks, 65% (37/57) of childrenreceiving infliximab 6 mg/kg over 38 weeks and 47% (28/60) of children receiving placebo over 14 weeks(see section 4.4).

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.

In REACH, 17.5% of randomised patients experienced 1 or more infusion-related reactions. There were noserious infusion-related reactions, and 2 subjects in REACH had non-serious anaphylactic reactions.

Antibodies to infliximab were detected in 3 (2.9%) paediatric patients.

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 weekinfusions (73.6% and 38.0%, respectively), while serious infections were reported for 3 subjects in theq8 week and 4 subjects in the q12 week maintenance treatment group. The most commonly reportedinfections were upper respiratory tract infection and pharyngitis, and the most commonly reported seriousinfection was abscess. Three cases of pneumonia (1 serious) and 2 cases of herpes zoster (both non-serious)were reported.

Overall, the adverse reactions reported in the paediatric ulcerative colitis trial (C0168T72) and adultulcerative colitis (ACT 1 and ACT 2) studies were generally consistent. In C0168T72, the most commonadverse 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 inpatients on the q12 week vs. the q8 week dosing regimen.

Overall, 8 (13.3%) of 60 treated patients experienced one or more infusion-related 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 seriousinfusion-related reactions were reported. All infusion-related reactions were mild or moderate in intensity.

Antibodies to infliximab were detected in 4 (7.7%) patients through week 54.

Infections were reported in 31 (51.7%) of 60 treated patients in C0168T72 and 22 (36.7%) required oral orparenteral antimicrobial treatment. The proportion of patients with infections in C0168T72 was similar tothat in the paediatric Crohn’s disease study (REACH) but higher than the proportion in the adults ulcerativecolitis studies (ACT 1 and ACT 2). The overall incidence of infections in C0168T72 was 13/22 (59%) in theevery 8 week maintenance treatment group and 14/23 (60.9%) in the every 12 week maintenance treatmentgroup. Upper respiratory tract infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequentlyreported 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 makeany definitive conclusions about the effect of age on safety events, there were higher proportions of patientswith serious adverse events and discontinuation due to adverse events in the younger age group than in theolder 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 adverseevents and infusion-related reactions were similar between the 6 to 11 and 12 to 17 year age groups.

Post-marketing spontaneous serious adverse reactions with infliximab in the paediatric population haveincluded 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

In rheumatoid arthritis clinical studies, the incidence of serious infections was greater in infliximab plusmethotrexate-treated patients 65 years and older (11.3%) than in those under 65 years of age (4.6%). Inpatients treated with methotrexate alone, the incidence of serious infections was 5.2% in patients 65 yearsand older compared to 2.7% in patients under 65 (see section 4.4).

Reporting of s uspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national r eporting system listedin Appendix V.

No case of overdose has been reported. Single doses up to 20 mg/kg have been administered without toxiceffects.

Pharmacotherapeutic group: Immunosuppressants, tumour necrosis factor alpha (TNFα) inhibitors, ATCcode: L04AB02.

Flixabi is a biosimilar medicinal product. Detailed information is available on the website of the European

Medicines Agency https://www.ema.europa.eu.

Infliximab is a chimeric human-murine monoclonal antibody that binds with high affinity to both soluble andtransmembrane forms of TNFα but not to lymphotoxin α (TNFβ).

Infliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays. Infliximabprevented 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 rapidlyforms 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 correlatewith elevated disease activity. In rheumatoid arthritis, treatment with infliximab reduced infiltration ofinflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellularadhesion, chemoattraction and tissue degradation. After infliximab treatment, patients exhibited decreasedlevels of serum interleukin 6 (IL-6) and C-reactive protein (CRP), and increased haemoglobin levels inrheumatoid arthritis patients with reduced haemoglobin levels, compared with baseline. Peripheral bloodlymphocytes further showed no significant decrease in number or in proliferative responses to in vitromitogenic stimulation when compared with untreated patients’ cells. In psoriasis patients, treatment withinfliximab resulted in decreases in epidermal inflammation and normalisation of keratinocyte differentiationin psoriatic plaques. In psoriatic arthritis, short term treatment with infliximab reduced the number of T-cellsand 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 wasalso 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, althoughchanges in lymphocytes, monocytes and neutrophils reflected shifts towards normal ranges. Peripheral bloodmononuclear cells (PBMC) from infliximab-treated patients showed undiminished proliferativeresponsiveness to stimuli compared with untreated patients, and no substantial changes in cytokineproduction by stimulated PBMC were observed following treatment with infliximab. Analysis of laminapropria mononuclear cells obtained by biopsy of the intestinal mucosa showed that infliximab treatmentcaused a reduction in the number of cells capable of expressing TNFα and interferon γ. Additionalhistological studies provided evidence that treatment with infliximab reduces the infiltration of inflammatorycells into affected areas of the intestine and the presence of inflammation markers at these sites. Endoscopicstudies of intestinal mucosa have shown evidence of mucosal healing in infliximab-treated patients.

Adult rheumatoid arthritis

The efficacy of infliximab was assessed in two multicentre, randomised, double-blind, pivotal clinicalstudies: ATTRACT and ASPIRE. In both studies concurrent use of stable doses of folic acid, oralcorticosteroids (≤ 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 structuraljoint damage, and the improvement in physical function. A reduction in signs and symptoms was defined tobe at least a 20% improvement (ACR20) in both tender and swollen joint counts, and in 3 of the following5 criteria: (1) evaluator’s global assessment, (2) patient’s global assessment, (3) functional/disabilitymeasure, (4) visual analogue pain scale and (5) erythrocyte sedimentation rate or C-reactive protein. ACR-Nuses the same criteria as the ACR20, calculated by taking the lowest percent improvement in swollen jointcount, tender joint count, and the median of the remaining 5 components of the ACR response. Structuraljoint damage (erosions and joint space narrowing) in both hands and feet was measured by the change frombaseline 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 physicalfunction.

The ATTRACT study evaluated responses at 30, 54 and 102 weeks in a placebo-controlled study of428 patients with active rheumatoid arthritis despite treatment with methotrexate. Approximately 50% ofpatients were in functional Class III. Patients received placebo, 3 mg/kg or 10 mg/kg infliximab at weeks 0, 2and 6, and then every 4 or 8 weeks thereafter. All patients were on stable methotrexate doses (median15 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 and54 weeks compared with methotrexate alone.

A reduction in the rate of the progression of structural joint damage (erosions and joint space narrowing) wasobserved 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 treatmentwithdrawals, the magnitude of the effect difference between infliximab and the methotrexate alone groupcannot be defined.

Table 3

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

Infliximabb

Controla 3 mg/kg 3 mg/kg 10 mg/kg 10 mg/kg Allq 8 wks q 4 wks q 8 wks q 4 wks infliximabb

Patients with ACR20 response/ 15/88 36/86 41/86 51/87 48/81 176/340

Patients evaluated (%) (17%) (42%) (48%) (59%) (59%) (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

Median 4.0 0.5 0.1 0.5 -0.5 0.0(Interquartile range) (0.5,9.7) (-1.5,3.0) (-2.5,3.0) (-1.5,2.0) (-3.0,1.5) (-1.8,2.0)

Patients with no deterioration/patientsc 13/64 (20%) 34/71 (48%) 35/71 (49%) 37/77 (48%) 44/66 (67%) 150/285evaluated (%) (53%)

HAQ change from baseline overtimee (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 ± 0.4a control = All patients had active RA despite treatment with stable methotrexate doses for 6 months prior to enrolment and were toremain on stable doses throughout the study. Concurrent use of stable doses of oral corticosteroids (≤ 10 mg/day) and/or NSAIDswas permitted, and folate supplementation was given.

b all infliximab doses given in combination with methotrexate and folate with some on corticosteroids and/or NSAIDsc p < 0.001, for each infliximab treatment group vs. controld 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 jointcount of 19 and 31, respectively). All patients received methotrexate (optimised to 20 mg/wk by week 8) andeither placebo, 3 mg/kg or 6 mg/kg infliximab at weeks 0, 2, and 6 and every 8 weeks thereafter. Resultsfrom week 54 are shown in Table 4.

After 54 weeks of treatment, both doses of infliximab + methotrexate resulted in statistically significantlygreater improvement in signs and symptoms compared to methotrexate alone as measured by the proportionof 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 ofprogression of structural damage was observed at weeks 30 and 54 in the infliximab + methotrexate groupscompared 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 derb

Heijde-modified Sharp score

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 HAQaveraged over time from week 30 toweek 54

Mean ± SDd 0.68 ± 0.63 0.80 ± 0.65 0.88 ± 0.65 0.84 ± 0.65a p < 0.001, for each infliximab treatment group vs controlb 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 6mg/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 studyarms (group 2, n=329), patients with an inadequate response were allowed to dose titrate with 1.5 mg/kgincrements from 3 up to 9 mg/kg. The majority (67%) of these patients did not require any dose titration. Ofthe patients who required a dose titration, 80% achieved clinical response and the majority (64%) of theserequired only one adjustment of 1.5 mg/kg.

The efficacy of a single dose treatment with infliximab was assessed in 108 patients with active Crohn’sdisease (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 ofinfliximab 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 toreceive these therapies.

The primary endpoint was the proportion of patients who experienced a clinical response, defined as adecrease in CDAI by ≥ 70 points from baseline at the 4-week evaluation and without an increase in the use ofmedicinal products or surgery for Crohn’s disease. Patients who responded at week 4 were followed to week12. 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 a5 mg/kg dose achieved a clinical response vs. 4/25 (16%) of the placebo-treated patients (p < 0.001). Also atweek 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.

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 asingle infusion of 5 mg/kg at week 0. 178 of the 580 enrolled patients (30.7%) were defined as having severedisease (CDAI score > 300 and concomitant corticosteroid and/or immunosuppressants) corresponding to thepopulation defined in the indication (see section 4.1). At week 2, all patients were assessed for clinicalresponse and randomised to one of 3 treatment groups; a placebo maintenance group, 5 mg/kg maintenancegroup and 10 mg/kg maintenance group. All 3 groups received repeated infusions at week 2, 6 and every8 weeks thereafter.

Of the 573 patients randomised, 335 (58%) achieved clinical response by week 2. These patients wereclassified as week-2 responders and were included in the primary analysis (see Table 5). Among patientsclassified as non-responders at week 2, 32% (26/81) in the placebo maintenance group and 42% (68/163) inthe infliximab group achieved clinical response by week 6. There was no difference between groups in thenumber of late responders thereafter.

The co-primary endpoints were the proportion of patients in clinical remission (CDAI < 150) at week 30 andtime 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)

ACCENT I (week-2 responders)% of Patients

Infliximab Infliximab

Placebo Maintenance Maintenance Maintenance5 mg/kg 10 mg/kg(n=110) (n=113) (n=112)(p value) (p value)

Median time to loss of 38 weeks > 54 weeksresponse through week 54 19 weeks (0.002) (< 0.001)

Week 30

Clinical Responsea 27.3 51.3 59.1(< 0.001) (< 0.001)

Clinical Remission 20.9 38.9 45.5(0.003) (< 0.001)

Steroid-Free Remission 10.7 (6/56) 31.0 (18/58) 36.8 (21/57)(0.008) (0.001)

Week 54

Clinical Responsea 15.5 38.1 47.7(< 0.001) (< 0.001)

Clinical Remission 13.6 28.3 38.4(0.007) (< 0.001)

Sustained Steroid-Free

Remissionb 5.7 (3/53) 17.9 (10/56) 28.6 (16/56)(0.075) (0.002)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 werereceiving 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 wereoriginally randomised. Eighty nine percent (50/56) of patients who lost clinical response on infliximab5 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 corticosteroiduse were seen in the infliximab maintenance groups compared with the placebo maintenance group at weeks30 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 naiveto biologics and immunosuppressants and had a median disease duration of 2.3 years. At baseline 27.4% ofpatients were receiving systemic corticosteroids, 14.2% of patients were receiving budesonide, and 54.3% ofpatients were receiving 5-ASA compounds. Patients were randomised to receive AZA monotherapy,infliximab monotherapy, or infliximab plus AZA combination therapy. Infliximab was administered at adose 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 patientsin 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 ofpatients 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 AZAmonotherapy group (16.5%).

Table 6

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

AZA Infliximab Infliximab + AZA

Monotherapy Monotherapy Combination therapy

Week 26

All randomised patients 30.0% (51/170) 44.4% (75/169) 56.8% (96/169)(p=0.006)* (p<0.001)*

* 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.

The efficacy was assessed in a randomised, double-blinded, placebo-controlled study in 94 patients withfistulising Crohn’s disease who had fistulae that were of at least 3 months’ duration. Thirty one of thesepatients were treated with infliximab 5 mg/kg. Approximately 93% of the patients had previously receivedantibiotic or immunosuppressive therapy.

Concurrent use of stable doses of conventional therapies was permitted, and 83% of patients continued toreceive at least one of these therapies. Patients received three doses of either placebo or infliximab at weeks0, 2 and 6. Patients were followed up to 26 weeks. The primary endpoint was the proportion of patients whoexperienced a clinical response, defined as ≥ 50% reduction from baseline in the number of fistulae drainingupon gentle compression on at least two consecutive visits (4 weeks apart), without an increase in the use ofmedicinal products or surgery for Crohn’s disease.

Sixty eight percent (21/31) of infliximab-treated patients receiving a 5 mg/kg dose regimen achieved aclinical response vs. 26% (8/31) placebo-treated patients (p=0.002). The median time to onset of response inthe 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).

The efficacy of repeated infusions with infliximab in patients with fistulising Crohn’s disease was studied ina 1-year clinical study (ACCENT II). A total of 306 patients received 3 doses of infliximab 5 mg/kg at week0, 2 and 6. At baseline, 87% of the patients had perianal fistulae, 14% had abdominal fistulae, 9% hadrectovaginal fistulae. The median CDAI score was 180. At week 14, 282 patients were assessed for clinicalresponse 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 randomisationto 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 Infliximab

Maintenance Maintenance(n=99) (5 mg/kg) p-value(n=96)

Median time to loss of response throughweek 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 0.009a A ≥ 50% reduction from baseline in the number of draining fistulas over a period of ≥ 4 weeksb Absence of any draining fistulas

Beginning at week 22, patients who initially responded to treatment and subsequently lost their responsewere eligible to cross over to active re-treatment every 8 weeks at a dose of infliximab 5 mg/kg higher thanthe dose to which they were originally randomised. Among patients in the infliximab 5 mg/kg group whocrossed over because of loss of fistula response after week 22, 57% (12/21) responded to re-treatment withinfliximab 10 mg/kg every 8 weeks.

There was no significant difference between placebo and infliximab for the proportion of patients withsustained closure of all fistulas through week 54, for symptoms such as proctalgia, abscesses and urinarytract infection or for number of newly developed fistulas during treatment.

Maintenance therapy with infliximab every 8 weeks significantly reduced disease-related hospitalisationsand surgeries compared with placebo. Furthermore, a reduction in corticosteroid use and improvements inquality of life were observed.

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 [oralcorticosteroids, aminosalicylates and/or immunomodulators (6-MP, AZA)]. Concomitant stable doses of oralaminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted. In both studies, patientswere randomised to receive either placebo, 5 mg/kg infliximab, or 10 mg/kg infliximab at weeks 0, 2, 6, 14and 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 Infliximab5 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 19.3% 45.0% 49.6% 47.3%week 8 and week 30)a

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 5.3% 19.0% 24.4% 21.7%week 8 and week 30)a

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 responsecompared to 19.8% in the placebo treatment group (p < 0.001). Clinical remission and mucosal healingoccurred in a greater proportion of patients in the combined infliximab treatment group compared to theplacebo 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 weregreater 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 discontinuecorticosteroids while remaining in clinical remission compared to the placebo treatment group at both week30 (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 baselinethrough 54 weeks, demonstrated a reduction of ulcerative colitis-related hospitalisations and surgicalprocedures with infliximab treatment. The number of ulcerative colitis-related hospitalisations wassignificantly lower in the 5 and 10 mg/kg infliximab treatment groups than in the placebo group (meannumber of hospitalisations per 100 subject-years: 21 and 19 vs. 40 in the placebo group; p=0.019 andp=0.007, respectively). The number of ulcerative colitis-related surgical procedures was also lower in the5 and 10 mg/kg infliximab treatment groups than in the placebo group (mean number of surgical proceduresper 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 firstinfusion 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 the10 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 failedto respond to intravenous corticosteroids and who were therefore at higher risk for colectomy. Significantlyfewer colectomies occurred within 3 months of study infusion in patients who received a single dose of5 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 improvementin both a disease specific measure, IBDQ, and by improvement in the generic 36-item short form survey SF-36.

Efficacy and safety of infliximab were assessed in two multicentre, double-blind, placebo-controlled studiesin 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/kginfliximab or placebo at weeks 0, 2, 6 (35 patients in each group). At week 12, placebo patients wereswitched to infliximab 5 mg/kg every 6 weeks up to week 54. After the first year of the study, 53 patientscontinued 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/kginfliximab. In Group 2, starting with the week 36 infusion, patients who had a BASDAI ≥ 3 at 2 consecutivevisits, 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 numberof ASAS 20 responders was 15/78 (19%) in the placebo group, and 123/201 (61%) in the 5 mg/kg infliximabgroup (p < 0.001). There were 95 subjects from group 2 who continued on 5 mg/kg every 6 weeks. At102 weeks there were 80 subjects still on infliximab treatment and among those, 71 (89%) were ASAS 20responders.

In P01522, improvement in signs and symptoms was also observed as early as week 2. At week 12, thenumber of BASDAI 50 responders were 3/35 (9%) in the placebo group, and 20/35 (57%) in the 5 mg/kggroup (p < 0.01). There were 53 subjects who continued on 5 mg/kg every 6 weeks. At 102 weeks there were49 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 componentscore of the SF-36 were also improved significantly.

Efficacy and safety were assessed in two multicentre, double-blind, placebo-controlled studies in patientswith active psoriatic arthritis.

In the first clinical study (IMPACT), efficacy and safety of infliximab were studied in 104 patients withactive polyarticular psoriatic arthritis. During the 16-week double-blind phase, patients received either5 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 every8 weeks up to week 46. After the first year of the study, 78 patients continued into an open-label extension toweek 98.

In the second clinical study (IMPACT 2), efficacy and safety of infliximab were studied in 200 patients withactive psoriatic arthritis (≥ 5 swollen joints and ≥ 5 tender joints). Forty six percent of patients continued onstable doses of methotrexate (≤ 25 mg/week). During the 24-week double-blind phase, patients receivedeither 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 wereswitched to infliximab induction (early escape). At week 24, all placebo-treated patients crossed over toinfliximab 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 Infliximab Infliximab Placebo Infliximab Infliximab(week 16) (week 16) (week 98) (week 24) (week 24) (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 87 83 82

PASI 75 response** 1 (1%) 50 (60%) 40 (48.8%)

* ITT-analysis where subjects with missing data were included as non-respondersa Week 98 data for IMPACT includes combined placebo crossover and infliximab patients who entered the open-label extensionb 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 maintainedthrough week 98 and week 54, respectively. Efficacy has been demonstrated with or without concomitant useof methotrexate. Decreases in parameters of peripheral activity characteristic of psoriatic arthritis (such asnumber of swollen joints, number of painful/tender joints, dactylitis and presence of enthesopathy) were seenin the infliximab-treated patients.

Radiographic changes were assessed in IMPACT 2. Radiographs of hands and feet were collected atbaseline, weeks 24 and 54. Infliximab treatment reduced the rate of progression of peripheral joint damagecompared with placebo treatment at the week 24 primary endpoint as measured by change from baseline intotal 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-Sscore 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 thephysical and mental component summary scores of the SF-36 in IMPACT 2.

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 patientswho 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 hadpreviously received PUVA or systemic therapy. Patients received either 3 or 5 mg/kg infliximab or placeboinfusions at weeks 0, 2 and 6. Patients with a PGA score ≥ 3 were eligible to receive an additional infusion ofthe 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 infliximabgroup, 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 the3 mg/kg group were PASI 75 responders. Between weeks 6 and 26, symptoms of psoriasis graduallyreturned 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 withplaque psoriasis. Patients received 5 mg/kg infliximab- or placebo-infusions at weeks 0, 2 and 6 followed bymaintenance therapy every 8 weeks through week 22 in the placebo group and through week 46 in theinfliximab 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 receivedby 71.4% of patients, although they were not necessarily therapy resistant. Key results are presented in Table10. 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 wereexposed 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 Infliximab5 mg/kg(at week 24) 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 a(2) 15 (19.5%) 246 (89.1%)

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%)a p < 0.001, for each infliximab treatment group vs. controlb n = 292c Analysis was based on subjects with nail psoriasis at baseline (81.8% of subjects). Mean baseline NAPSI scores were 4.6 and 4.3 ininfliximab and placebo group.

Significant improvements from baseline were demonstrated in DLQI (p < 0.001) and the physical and mentalcomponent scores of the SF 36 (p < 0.001 for each component comparison).

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 wereto 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 tobe in clinical response at week 10 were randomised and received 5 mg/kg infliximab at either q8 weeks orq12 weeks as a maintenance treatment regimen. If response was lost during maintenance treatment, crossingover 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 weeksmaintenance 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 subjectsachieving 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) thanthe 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 asignificant reduction in corticosteroid use, were observed versus baseline.

The safety and efficacy of infliximab were assessed in a multicentre, randomised, open-label, parallel-groupclinical study (C0168T72) in 60 paediatric patients aged 6 through 17 years (median age 14.5 years) withmoderately to severely active ulcerative colitis (Mayo score of 6 to 12; endoscopic subscore ≥ 2) with aninadequate response to conventional therapies. At baseline 53% of patients were receiving immunomodulatortherapy (6-MP, AZA and/or MTX) and 62% of patients were receiving corticosteroids. Discontinuation ofimmunomodulators 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 notrespond 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 q12weeks 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 wassimilar between those with or without concomitant immunomodulator use at baseline. Clinical remission atweek 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. Forpatients receiving corticosteroids at baseline, the proportion of patients in remission and not receivingcorticosteroids at week 54 was 38.5% (5/13) for the q8 week and 0% (0/13) for the q12 week maintenancetreatment 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 definitiveconclusions about the effect of age, there was a higher number of patients in the younger age group whostepped up in dose or discontinued treatment due to inadequate efficacy.

The European Medicines Agency has waived the obligation to submit the results of studies with thereference medicinal product containing infliximab in all subsets of the paediatric population in rheumatoidarthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis and Crohn's disease(see section 4.2 for information on paediatric use).

Single intravenous infusions of 1, 3, 5, 10 or 20 mg/kg of infliximab yielded dose proportional increases inthe maximum serum concentration (Cmax) and area under the concentration-time curve (AUC). The volumeof distribution at steady state (median Vd of 3.0 to 4.1 litres) was not dependent on the administered dose andindicated that infliximab is predominantly distributed within the vascular compartment. No time-dependencyof 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 orvolume of distribution were observed in rheumatoid arthritis patients. The pharmacokinetics of infliximab inelderly 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/kgfor 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 or10 mg/kg every 4 or 8 weeks in rheumatoid arthritis) resulted in a slight accumulation of infliximab in serumafter the second dose. No further clinically relevant accumulation was observed. In most fistulising Crohn’sdisease patients, infliximab was detected in serum for 12 weeks (range 4-28 weeks) after administration ofthe regimen.

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 anoverall age range from 2 months to 17 years indicated that exposure to infliximab was dependent on bodyweight in a non-linear way. Following administration of 5 mg/kg infliximab every 8 weeks, the predictedmedian steady-state infliximab exposure (area under concentration-time curve at steady state, AUCss) inpaediatric 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 waspredicted to be approximately 40% lower than that in adults, although the number of patients supporting thisestimate is limited.

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 conductedin mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα, therewas no indication of maternal toxicity, embryotoxicity or teratogenicity. In a fertility and generalreproductive function study, the number of pregnant mice was reduced following administration of the sameanalogous 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 specificophthalmologic examinations have been performed in patients to investigate the relevance of this finding forhumans.

Long-term studies have not been performed to evaluate the carcinogenic potential of infliximab. Studies inmice deficient in TNFα demonstrated no increase in tumours when challenged with known tumour initiatorsand/or promoters.

Sucrose

Polysorbate 80 (E 433)

Monobasic sodium phosphate monohydrate (for pH-adjustment)

Dibasic sodium phosphate heptahydrate (for pH-adjustment)

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

Before reconstitution4 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, butnot exceeding the original expiry date. The new expiry date must be written on the carton. Upon removalfrom refrigerated storage, Flixabi must not be returned to refrigerated storage.

Chemical and physical in use stability of the diluted solution has been demonstrated for up to 34 days at 2 °Cto 8 °C and for an additional 24 hours at 25 °C after removal from refrigeration. From a microbiologicalpoint of view, the infusion solution should be administered immediately, in use storage times and conditionsprior 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.

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.

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, or 5 vial(s).

Not all pack sizes may be marketed.

1. Calculate the dose and the number of Flixabi vials needed. Each Flixabi vial contains 100 mginfliximab. 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 asyringe equipped with a 21-gauge (0.8 mm) or smaller needle. Remove flip-top from the vial and wipethe top with a 70% alcohol swab. Insert the syringe needle into the vial through the centre of the rubberstopper and direct the stream of water for injections to the glass wall of the vial. Gently swirl thesolution 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 reconstitutedsolution to stand for 5 minutes. Check that the solution is colourless to light yellow and opalescent. Thesolution may develop a few fine translucent particles, as infliximab is a protein. Do not use if opaqueparticles, discolouration, or other foreign particles are present.

3. Dilute the total volume of the reconstituted Flixabi solution dose to 250 mL with sodium chloride9 mg/mL (0.9%) solution for infusion. Do not dilute the reconstituted Flixabi solution with any otherdiluent. 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 ofreconstituted Flixabi. Slowly add the total volume of reconstituted Flixabi solution to the 250 mLinfusion bottle or bag. Gently mix. For volumes greater than 250 mL, either use a larger infusion bag(e.g. 500 mL, 1,000 mL) or use multiple 250 mL infusion bags to ensure that the concentration of theinfusion solution does not exceed 4 mg/mL. If stored refrigerated after reconstitution and dilution, theinfusion 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 bagonly.

4. Administer the infusion solution over a period of not less than the infusion time recommended (seesection 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 theadministration of the solution for infusion is to be started as soon as possible and within 3 hours ofreconstitution and dilution. If not used immediately, in use storage times and conditions prior to use arethe responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unlessreconstitution/dilution has been taken place in controlled and validated aseptic conditions (see section6.3 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 otheragents.

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

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

Samsung Bioepis NL B.V.

Olof Palmestraat 102616 LR Delft

The Netherlands

EU/1/16/1106/001

EU/1/16/1106/002

EU/1/16/1106/003

EU/1/16/1106/004

EU/1/16/1106/005

Date of first authorisation: 26 May 2016

Date of latest renewal: 11 Feb 2021

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