INFLECTRA 100mg powder for concentrate infusion solution medication leaflet

Inflectra 100 mg powder for concentrate for solution for infusion

One vial contains 100 mg of infliximab*. After reconstitution each mL contains 10 mg of infliximab.

* Infliximab is a chimeric human-murine IgG1 monoclonal antibody produced in murine hybridomacells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

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

The powder is white.

Inflectra, in combination with methotrexate, is indicated for the reduction of signs and symptoms aswell as the improvement in physical function in:

* adult patients with active disease when the response to disease-modifying antirheumatic drugs(DMARDs), including methotrexate, has been inadequate.

* adult patients with severe, active and progressive disease not previously treated withmethotrexate or other DMARDs.

In these patient populations, a reduction in the rate of the progression of joint damage, as measured by

X-ray, has been demonstrated (see section 5.1).

Inflectra is indicated for:

* treatment of moderately to severely active Crohn’s disease, in adult patients who have notresponded despite a full and adequate course of therapy with a corticosteroid and/or animmunosuppressant; or who are intolerant to or have medical contraindications for suchtherapies.

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

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

Inflectra is indicated for treatment of moderately to severely active ulcerative colitis in adult patientswho have had an inadequate response to conventional therapy including corticosteroids and6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medicalcontraindications for such therapies.

Inflectra is indicated for treatment of severely active ulcerative colitis in children and adolescents aged6 to 17 years, who have had an inadequate response to conventional therapy including corticosteroidsand 6-MP or AZA, or who are intolerant to or have medical contraindications for such therapies.

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

Inflectra is indicated for treatment of active and progressive psoriatic arthritis in adult patients whenthe response to previous DMARD therapy has been inadequate.

Inflectra 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 toreduce the rate of progression of peripheral joint damage as measured by X-ray in patients withpolyarticular symmetrical subtypes of the disease (see section 5.1).

Inflectra is indicated for treatment of moderate to severe plaque psoriasis in adult patients who failedto respond 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).

Inflectra treatment is to be initiated and supervised by qualified physicians experienced in thediagnosis and treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis,psoriatic arthritis or psoriasis. Inflectra should be administered intravenously. Inflectra infusionsshould be administered by qualified healthcare professionals trained to detect any infusion-relatedissues. Patients treated with Inflectra should be given the package leaflet and the patient remindercard.

During Inflectra treatment, other concomitant therapies, e.g. corticosteroids and immunosuppressantsshould be optimised.

Rheumatoid arthritis3 mg/kg given as an intravenous infusion followed by additional 3 mg/kg infusion doses at 2 and6 weeks after the first infusion, then every 8 weeks thereafter.

Inflectra 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 toincrease the dose step-wise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kg every8 weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may be considered. Ifadequate response is achieved, patients should be continued on the selected dose or dose frequency.

Continued therapy should be carefully reconsidered in patients who show no evidence of therapeuticbenefit within the first 12 weeks of treatment or after dose adjustment.

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

In responding patients, the alternative strategies for continued treatment are:

* Maintenance: Additional infusion of 5 mg/kg at 6 weeks after the initial dose, followed byinfusions every 8 weeks or

* Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur (see‘Re-administration’ below and section 4.4).

Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg butwho lost response indicate that some patients may regain response with dose escalation (seesection 5.1). Continued therapy should be carefully reconsidered in patients who show no evidence oftherapeutic benefit after dose adjustment.

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

In responding patients, the alternative strategies for continued treatment are:

* Maintenance: Additional infusions of 5 mg/kg every 8 weeks or

* Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur followed byinfusions of 5 mg/kg every 8 weeks (see ‘Re-administration’ below and section 4.4).

Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg butwho lost response indicate that some patients may regain response with dose escalation (seesection 5.1). Continued therapy should be carefully reconsidered in patients who show no evidence oftherapeutic benefit after dose adjustment.

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

Ulcerative colitis5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and6 weeks after the first infusion, then every 8 weeks thereafter.

Available data suggest that the clinical response is usually achieved within 14 weeks of treatment, i.e.

three doses. Continued therapy should be carefully reconsidered in patients who show no evidence oftherapeutic benefit within this time period.

Ankylosing spondylitis5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and6 weeks after the first infusion, then every 6 to 8 weeks. If a patient does not respond by 6 weeks (i.e.

after 2 doses), no additional treatment with infliximab should be given.

Psoriatic arthritis5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and6 weeks after the first infusion, then every 8 weeks thereafter.

Psoriasis5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and6 weeks after the first infusion, then every 8 weeks thereafter. If a patient shows no response after14 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 weeksfollowing the last infusion. In clinical studies, delayed hypersensitivity reactions have been uncommonand have occurred after infliximab-free intervals of less than 1 year (see sections 4.4 and 4.8). Thesafety and efficacy of re-administration after an infliximab-free interval of more than 16 weeks has notbeen established. This applies to 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 (seesections 4.4 and 4.8).

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

The safety and efficacy of re-administration, other than every 8 weeks, has not been established (seesections 4.4 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 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 ahigher incidence of infusion reactions, including serious ones, when compared to 8-weeklymaintenance treatment (see section 4.8).

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

Specific studies of infliximab in elderly patients have not been conducted. No major age-relateddifferences in clearance or volume of distribution were observed in clinical studies. No doseadjustment is required (see section 5.2). For more information about the safety of infliximab in elderlypatients (see sections 4.4 and 4.8).

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

Crohn’s disease (6 to 17 years)5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and6 weeks after the first infusion, then every 8 weeks thereafter. Available data do not support furtherinfliximab treatment 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 alonger dosing interval may be sufficient. Patients who have had their dose interval shortened to lessthan 8 weeks may be at greater risk for adverse reactions. Continued therapy with a shortened intervalshould be carefully considered in those patients who show no evidence of additional therapeuticbenefit after a change in dosing interval.

The safety and efficacy of infliximab have not been studied in children with Crohn’s disease below theage of 6 years. Currently available pharmacokinetic data are described in section 5.2 but norecommendation on a posology can be made in children younger than 6 years.

Ulcerative colitis (6 to 17 years)5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and6 weeks after the first infusion, then every 8 weeks thereafter. Available data do not support furtherinfliximab treatment in paediatric patients not responding within the first 8 weeks of treatment (seesection 5.1).

The safety and efficacy of infliximab have not been studied in children with ulcerative colitis belowthe age of 6 years. Currently available pharmacokinetic data are described in section 5.2 but norecommendation on a 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 theindication of psoriasis have not been established. Currently available data are described in section 5.2but no recommendation on a posology can be made.

The safety and efficacy of infliximab in children and adolescents younger than 18 years for theindications of juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis have not beenestablished. Currently available data are described in section 5.2 but no recommendation on aposology can be made.

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

Infliximab should be administered intravenously over a 2 hour period. All patients administeredinfliximab are to be observed for at least 1-2 hours post-infusion for acute infusion-related reactions.

Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway mustbe available. Patients may be pre-treated with e.g. an antihistamine, hydrocortisone and/or paracetamoland infusion rate may be slowed in order to decrease the risk of infusion-related reactions especially ifinfusion-related reactions 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 reaction occurs in associationwith a shortened infusion, a slower infusion rate may be considered for future infusions if treatment isto be continued. Shortened infusions at doses >6 mg/kg have not been studied (see section 4.8).

For preparation and administration instructions, see section 6.6.

Hypersensitivity to the active substance, to other murine proteins, or to any of the excipients listed insection 6.1.

Patients with tuberculosis or other severe infections such as sepsis, abscesses, and opportunisticinfections (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 numberof the administered product should be clearly recorded.

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

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

Antibodies to infliximab may develop and have been associated with an increased frequency ofinfusion reactions. A low proportion of the infusion reactions was serious allergic reactions. Anassociation between development of antibodies to infliximab and reduced duration of response hasalso been observed. Concomitant administration of immunomodulators has been associated with lowerincidence of antibodies to infliximab and a reduction in the frequency of infusion reactions. The effectof concomitant immunomodulator therapy was more profound in episodically-treated patients than inpatients given maintenance therapy. Patients who discontinue immunosuppressants prior to or duringinfliximab treatment are at greater risk of developing these antibodies. Antibodies to infliximab cannotalways be detected in serum samples. If serious reactions occur, symptomatic treatment must be givenand further infliximab infusions must not be administered (see section 4.8).

In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest anincreased risk for delayed hypersensitivity with increasing infliximab-free interval. Patients should beadvised to seek immediate medical advice if they experience any delayed adverse reaction (see section4.8). If patients are re-treated after a prolonged period, they must be closely monitored for signs andsymptoms of delayed hypersensitivity.

Patients must be monitored closely for infections including tuberculosis before, during and aftertreatment with infliximab. Because the elimination of infliximab may take up to six months,monitoring should be continued throughout this period. Further treatment with infliximab must not begiven if a patient develops a serious infection or sepsis.

Caution should be exercised when considering the use of infliximab in patients with chronic infectionor a history of recurrent infections, including concomitant immunosuppressive therapy. Patientsshould be advised of and avoid exposure to potential risk factors for infection as appropriate.

Tumour necrosis factor alpha (TNFα) mediates inflammation and modulates cellular immuneresponses. Experimental data show that TNFα is essential for the clearing of intracellular infections.

Clinical experience shows that host defence against infection is compromised in some patients treatedwith 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 presentationof rare and unusual infections is critical in order to minimise delays in diagnosis and treatment.

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

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

Patients who develop a new infection while undergoing treatment with infliximab, should bemonitored closely and undergo a complete diagnostic evaluation. Administration of infliximab shouldbe discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobialor antifungal therapy should be initiated until the infection is controlled.

There have been reports of active tuberculosis in patients receiving infliximab. It should be noted thatin the majority of these reports tuberculosis was extrapulmonary, presenting as either local ordisseminated 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 historyof tuberculosis or possible previous contact with tuberculosis and previous and/or currentimmunosuppressive 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 mayapply). It is recommended that the conduct of these tests should be recorded in the patient’s remindercard. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially inpatients 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 bevery carefully 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 localrecommendations.

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

Use of antituberculosis therapy should also be considered before the initiation of infliximab in patientswith a past history of latent or active tuberculosis in whom an adequate course of treatment cannot beconfirmed.

Some cases of active tuberculosis have been reported in patients treated with infliximab during andafter treatment for latent tuberculosis.

All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis(e.g. persistent cough, wasting/weight loss, low-grade fever) appear during or after infliximabtreatment.

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

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

For patients who have resided in or travelled to regions where invasive fungal infections such 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 infliximabtherapy until 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 are chronic carriers of this virus. Some cases have had fatal outcome.

Patients should be tested for HBV infection before initiating treatment with infliximab. For patientswho test positive for HBV infection, consultation with a physician with expertise in the treatment ofhepatitis B is recommended. Carriers of HBV who require treatment with infliximab should be closelymonitored for signs and symptoms of active HBV infection throughout therapy and for several monthsfollowing termination of therapy. Adequate data of treating patients who are carriers of HBV withantiviral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are notavailable. In patients who develop HBV reactivation, infliximab should be stopped and effectiveantiviral therapy with appropriate supportive treatment 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 inliver transplantation or death have occurred. Patients with symptoms or signs of liver dysfunctionshould be evaluated for evidence of liver injury. If jaundice and/or ALT elevations ≥ 5 times the upperlimit of normal develop(s), infliximab should be discontinued, and a thorough investigation of theabnormality should be undertaken.

Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra andanother TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone.

Because of the nature of the adverse reactions seen with combination of etanercept and anakinratherapy, similar toxicities may also result from the combination of anakinra and other TNFα-blockingagents. Therefore, the combination of infliximab and anakinra is not recommended.

In clinical studies concurrent administration of TNF-antagonists and abatacept has been associatedwith an increased risk of infections including serious infections compared to TNF-antagonists alone,without increased 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 withthese biologics is not recommended because of the possibility of an increased risk of infection, andother potential pharmacological interactions.

Care should be taken and patients should continue to be monitored when switching from one biologicto another, since overlapping biological activity may further increase the risk for adverse reactions,including infection.

It is recommended that patients, if possible, be brought up to date with all vaccinations in agreementwith current vaccination guidelines prior to initiating Inflectra therapy. Patients on infliximab mayreceive concurrent 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 proportionof patients 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 titres to a polyvalent pneumococcalvaccine, indicating that infliximab did not interfere with T-cell independent humoral immuneresponses. However, studies from the published literature in various indications (e.g. rheumatoidarthritis, psoriasis, Crohn’s disease) suggest that non-live vaccinations received during treatment withanti-TNF therapies, including infliximab, may elicit a lower immune response than in patients notreceiving anti-TNF therapy.

In patients receiving anti-TNF therapy, limited data are available on the response to vaccination withlive vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines canresult in clinical infections, including disseminated infections. The concurrent administration of livevaccines with infliximab 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 twelvemonth waiting period following birth is recommended before the administration of live vaccines toinfants exposed in utero to infliximab. If infant infliximab serum levels are undetectable or infliximabadministration was limited to the first trimester of pregnancy, administration of a live vaccine might beconsidered at an earlier timepoint if there is a clear clinical benefit for the individual infant (seesection 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 bladderinstillation for the treatment of cancer) could result in clinical infections, including disseminatedinfections. It is recommended that therapeutic infectious agents not be given concurrently withinfliximab.

The relative deficiency of TNFα caused by anti-TNF therapy may result in the initiation of anautoimmune process. If a patient develops symptoms suggestive of a lupus-like syndrome followingtreatment with infliximab and is positive for antibodies against double-stranded DNA, furthertreatment with infliximab must 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 systemdemyelinating disorders, including multiple sclerosis, and peripheral demyelinating disorders,including Guillain-Barré syndrome. In patients with pre-existing or recent onset of demyelinatingdisorders, the benefits and risks of anti-TNF treatment should be carefully considered before initiationof infliximab therapy. Discontinuation of infliximab should be considered if these disorders develop.

In the controlled portions of clinical studies of TNF-blocking agents, more cases of malignanciesincluding lymphoma have been observed among patients receiving a TNF blocker compared withcontrol patients. During clinical studies of infliximab across all approved indications the incidence oflymphoma in infliximab-treated patients was higher than expected in the general population, but theoccurrence of lymphoma was rare. In the post-marketing setting, cases of leukaemia have beenreported in patients treated with a TNF-antagonist. There is an increased background risk forlymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active,inflammatory disease, which complicates risk estimation.

In an exploratory clinical study evaluating the use of infliximab in patients with moderate to severechronic obstructive pulmonary disease (COPD), more malignancies were reported ininfliximab-treated patients compared with control patients. All patients had a history of heavysmoking. Caution should be exercised in considering treatment of patients with increased risk formalignancy due to heavy smoking.

With the current knowledge, a risk for the development of lymphomas or other malignancies inpatients treated with a TNF-blocking agent cannot be excluded (see section 4.8). Caution should beexercised when considering TNF-blocking therapy for patients with a history of malignancy or whenconsidering continuing treatment 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 to22 years of age) treated with TNF-blocking agents (initiation of therapy ≤ 18 years of age), includinginfliximab in the post-marketing setting. Approximately half the cases were lymphomas. The othercases represented a variety of different malignancies and included rare malignancies usually associatedwith immunosuppression. A risk for the development of malignancies in patients treated with

TNF-blockers cannot be excluded.

Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patientstreated with TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a veryaggressive disease course 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 infliximabcases have occurred in patients with Crohn’s disease or ulcerative colitis and most were reported inadolescent or young adult males. The potential risk with the combination of AZA or 6-MP andinfliximab should be carefully considered. A risk for the development for hepatosplenic T-celllymphoma in patients treated with infliximab cannot be excluded (see section 4.8).

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blockertherapy, including infliximab (see section 4.8). Periodic skin examination is recommended,particularly for patients with risk factors for skin cancer.

A population-based retrospective cohort study using data from Swedish national health registriesfound an increased incidence of cervical cancer in women with rheumatoid arthritis treated withinfliximab compared to biologics-naïve patients or the general population, including those over60 years of age. Periodic screening should continue in women treated with infliximab, including thoseover 60 years of age.

All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (forexample, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had aprior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervalsbefore therapy and throughout their disease course. This evaluation should include colonoscopy andbiopsies per local recommendations. Current data do not indicate that infliximab treatment influencesthe risk for developing dysplasia or colon cancer.

Since the possibility of increased risk of cancer development in patients with newly diagnoseddysplasia treated with infliximab is not established, the risk and benefits of continued therapy to theindividual patients should be carefully considered by the clinician.

Infliximab should be used with caution in patients with mild heart failure (NYHA class I/II). Patientsshould be closely monitored and infliximab must not be continued in patients who develop new orworsening symptoms 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 immediatemedical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistentfever, bruising, bleeding, pallor). Discontinuation of infliximab therapy should be considered inpatients with confirmed significant haematologic abnormalities.

The long half-life of infliximab should be taken into consideration if a surgical procedure is planned.

A patient who requires surgery while on infliximab should be closely monitored for infectious andnon-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 fibroticstricture that may require surgical treatment. There is no evidence to suggest that infliximab worsensor causes fibrotic strictures.

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

In clinical studies, infections have been reported in a higher proportion of paediatric patients comparedto adult 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 patientson infliximab 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 to22 years of age) treated with TNF-blocking agents (initiation of therapy ≤ 18 years of age), includinginfliximab in the post-marketing setting. Approximately half the cases were lymphomas. The othercases represented a variety of different malignancies and included rare malignancies usually associatedwith immunosuppression. A risk for the development of malignancies in children and adolescentstreated with TNF-blockers cannot be excluded.

Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with

TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a very 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 oryoung adult males. The potential risk with the combination of AZA or 6-MP and infliximab should becarefully considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treatedwith infliximab cannot be excluded (see section 4.8).

Inflectra contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially ‘sodium-free’. Inflectrais however, diluted in sodium chloride 9 mg/ml (0.9%) solution for infusion. This should be taken intoconsideration for patients on a controlled sodium diet (see section 6.6).

No interaction studies have been performed.

In rheumatoid arthritis, psoriatic arthritis and Crohn’s disease patients, there are indications thatconcomitant use of methotrexate and other immunomodulators reduces the formation of antibodiesagainst infliximab and increases the plasma concentrations of infliximab. However, the results areuncertain due to limitations in the methods used for serum analyses of infliximab and antibodiesagainst infliximab.

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

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 alsorecommended that live vaccines not be given to infants after in utero exposure to infliximab for12 months following birth. If infant infliximab serum levels are undetectable or infliximabadministration was limited to the first trimester of pregnancy, administration of a live vaccine might beconsidered at an earlier timepoint if there is a clear clinical benefit for the individual infant (seesection 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 (seesection 4.4).

Women of childbearing potential should consider the use of adequate contraception to preventpregnancy and 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 livebirth with known outcomes, including approximately 1,100 exposed during the first trimester, does notindicate an increase in the rate of malformation in the newborn.

Based on an observational study from Northern Europe, an increased risk (OR, 95% CI; p-value) for

C-section (1.50, 1.14-1.96; p = 0.0032), preterm birth (1.48, 1.05-2.09; p = 0.024), small forgestational age (2.79, 1.54-5.04; p = 0.0007), and low birth weight (2.03, 1.41-2.94; p = 0.0002) wasobserved in women exposed during pregnancy to infliximab (with or withoutimmunomodulators/corticosteroids, 270 pregnancies) as compared to women exposed toimmunomodulators and/or corticosteroids only (6,460 pregnancies). The potential contribution ofexposure to infliximab and/or the severity of the underlying disease in these outcomes remainsunclear.

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 analogousantibody that selectively inhibits the functional activity of mouse TNFα, there was no indication ofmaternal toxicity, embryotoxicity or teratogenicity (see section 5.3).

The available clinical experience is limited. Infliximab should only be used during pregnancy ifclearly needed.

Infliximab crosses the placenta and has been detected in the serum of infants up to 12 monthsfollowing birth. After in utero exposure to infliximab, infants may be at increased risk of infection,including serious disseminated infection that can become fatal. Administration of live vaccines(e.g. BCG vaccine) to infants exposed to infliximab in utero is not recommended for 12 months afterbirth (see sections 4.4 and 4.5). If infant infliximab serum levels are undetectable or infliximabadministration was limited to the first trimester of pregnancy, administration of a live vaccine might beconsidered at an earlier timepoint if there is a clear clinical benefit for the individual infant. Cases ofagranulocytosis have also been reported (see section 4.8).

Limited data from published literature indicate infliximab has been detected at low levels in humanmilk at concentrations up to 5% of the maternal serum level. Infliximab has also been detected ininfant serum after exposure to infliximab via breast milk. While systemic exposure in a breastfedinfant is expected to be low because infliximab is largely degraded in the gastrointestinal tract, theadministration of live vaccines to a breastfed infant when the mother is receiving infliximab is notrecommended unless infant infliximab serum levels are undetectable. Infliximab could be consideredfor use during breast-feeding.

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

Inflectra may have a minor influence on the ability to drive and use machines. Dizziness may occurfollowing administration of infliximab (see section 4.8).

Upper respiratory tract infection was the most common adverse drug reaction (ADR) reported inclinical trials, occurring in 25.3% of infliximab-treated patients compared with 16.5% of controlpatients. The most serious ADRs associated with the use of TNF blockers that have been reported forinfliximab include HBV reactivation, CHF (congestive heart failure), serious infections (includingsepsis, opportunistic infections and TB), serum sickness (delayed hypersensitivity reactions),haematologic reactions, systemic lupus erythematosus/lupus-like syndrome, demyelinating disorders,hepatobiliary events, lymphoma, HSTCL, leukaemia, Merkel cell carcinoma, melanoma, paediatricmalignancy, sarcoidosis/sarcoid-like reaction, intestinal or perianal abscess (in Crohn’s disease), andserious infusion reactions (see section 4.4).

Table 1 lists the ADRs based on experience from clinical studies as well as adverse reactions, somewith fatal outcome, reported from post-marketing experience. Within the organ system classes,adverse reactions are listed under headings of frequency using the following categories: very common(≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to< 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Withineach frequency grouping, undesirable effects are presented 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 virus infection).

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

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

Rare: Meningitis, opportunistic infections (such as invasive fungal infections[pneumocystosis, histoplasmosis, aspergillosis, coccidioidomycosis,cryptococcosis, blastomycosis], bacterial infections [atypicalmycobacterial, 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 and youngadult males with Crohn’s disease or ulcerative colitis), Merkel cellcarcinoma, Kaposi’s sarcoma.

Common: Neutropenia, leucopenia, anaemia, lymphadenopathy.

Uncommon: Thrombocytopenia, lymphopenia, lymphocytosis.

Rare: Agranulocytosis (including infants exposed in utero to infliximab),thrombotic thrombocytopenic purpura, pancytopenia, haemolyticanaemia, idiopathic thrombocytopenic purpura.

Common: Allergic respiratory symptom.

Uncommon: Anaphylactic reaction, lupus-like syndrome, serum sickness or serumsickness-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 demyelinating disorders(multiple sclerosis-like disease and optic neuritis), peripheraldemyelinating disorders (such as Guillain-Barré syndrome, chronicinflammatory demyelinating polyneuropathy and multifocal motorneuropathy).

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

Common: Conjunctivitis.

Uncommon: Keratitis, periorbital oedema, hordeolum.

Rare: Endophthalmitis.

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

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 progressive disease, lungfibrosis and pneumonitis).

Very common: Abdominal pain, nausea.

Common: Gastrointestinal haemorrhage, diarrhoea, dyspepsia, gastroesophagealreflux, 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, dryskin, fungal dermatitis, eczema, alopecia.

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

Rare: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythemamultiforme, furunculosis, linear IgA bullous dermatosis (LABD),acute generalised exanthematous pustulosis (AGEP), lichenoidreactions.

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-infectiouscomplications).

* 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 medianweight increase was 3.50 kg for infliximab-treated subjects vs. 3.00 kg for placebo-treated subjects.

The median weight increase for inflammatory bowel disease indications was 4.14 kg forinfliximab-treated subjects vs. 3.00 kg for placebo-treated subjects, and the median weight increasefor rheumatology indications was 3.40 kg for infliximab-treated subjects vs. 3.00 kg forplacebo-treated subjects.

Description of selected adverse drug reactions

An infusion-related reaction was defined in clinical studies as any adverse event occurring during aninfusion or within 1 hour after an infusion. In Phase III clinical studies, 18% of infliximab-treatedpatients compared with 5% of placebo-treated patients experienced an infusion-related reaction.

Overall, a higher proportion of patients receiving infliximab monotherapy experienced aninfusion-related reaction compared to patients receiving infliximab with concomitantimmunomodulators. Approximately 3% of patients discontinued treatment due to infusion-relatedreactions and all patients recovered with or without medical therapy. Of infliximab-treated patientswho had an infusion reaction during the induction period, through week 6, 27% experienced aninfusion reaction during the maintenance period, week 7 through week 54. Of patients who did nothave an infusion reaction during the induction period, 9% experienced an infusion reaction during themaintenance period.

In a clinical study of patients with rheumatoid arthritis (ASPIRE), infusions were to be administeredover 2 hours for the first 3 infusions. The duration of subsequent infusions could be shortened to notless than 40 minutes in patients who did not experience serious infusion reactions. In this trial,sixty-six percent of the patients (686 out of 1,040) received at least one shortened infusion of90 minutes or less and 44% of the patients (454 out of 1,040) received at least one shortened infusionof 60 minutes or less. Of the infliximab-treated patients who received at least one shortened infusion,infusion-related reactions occurred in 15% of patients and serious infusion reactions occurred in 0.4%of patients.

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

In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngealoedema and severe bronchospasm, and seizure have been associated with infliximab administration(see section 4.4).

Cases of transient visual loss occurring during or within 2 hours of infliximab infusion have beenreported. Events (some fatal) of myocardial ischaemia/infarction and arrhythmia have been reported,some in close temporal association with infusion of infliximab, cerebrovascular accidents have alsobeen reported in close temporal association with infusion of infliximab.

A clinical study in patients with moderate to severe psoriasis was designed to assess the efficacy andsafety of long-term maintenance therapy versus re-treatment with an induction regimen of infliximab(maximum of four infusions at 0, 2, 6 and 14 weeks) following disease flare. Patients did not receiveany concomitant immunosuppressant therapy. In the re-treatment arm, 4% (8/219) of patientsexperienced a serious infusion reaction versus < 1% (1/222) on maintenance therapy. The majority ofserious infusion reactions occurred during the second infusion at week 2. The interval between the lastmaintenance dose and the first re-induction dose ranged from 35-231 days. Symptoms included, butwere not limited to, dyspnoea, urticaria, facial oedema, and hypotension. In all cases, infliximabtreatment was discontinued and/or other treatment instituted with complete resolution of signs andsymptoms.

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 withfever and/or rash, with some patients experiencing pruritus, facial, hand or lip oedema, dysphagia,urticaria, sore throat and headache.

There are insufficient data on the incidence of delayed hypersensitivity reactions after infliximab-freeintervals of more than 1 year but limited data from clinical studies suggest an increased risk fordelayed hypersensitivity with increasing infliximab-free interval (see section 4.4).

In a 1-year clinical study with repeated infusions in patients with Crohn’s disease (ACCENT I study),the incidence of serum sickness-like reactions was 2.4%.

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 thefrequency of infusion-related reactions.

In clinical studies using single and multiple infliximab doses ranging from 1 to 20 mg/kg, antibodiesto infliximab were detected in 14% of patients with any immunosuppressant therapy, and in 24% ofpatients without immunosuppressant therapy. In rheumatoid arthritis patients who received therecommended repeated treatment dose regimens with methotrexate, 8% of patients developedantibodies to infliximab. In psoriatic arthritis patients who received 5 mg/kg with and withoutmethotrexate, antibodies occurred overall in 15% of patients (antibodies occurred in 4% of patientsreceiving methotrexate and in 26% of patients not receiving methotrexate at baseline). In Crohn’sdisease patients who received maintenance treatment, antibodies to infliximab occurred overall in3.3% of patients receiving immunosuppressants and in 13.3% of patients not receivingimmunosuppressants. The antibody incidence was 2-3 fold higher for patients treated episodically.

Due to methodological limitations, a negative assay did not exclude the presence of antibodies toinfliximab. Some patients who developed high titres of antibodies to infliximab had evidence ofreduced efficacy. In psoriasis patients treated with infliximab as a maintenance regimen in the absenceof concomitant immunomodulators, approximately 28% developed antibodies to infliximab (seesection 4.4: “Infusion reactions and hypersensitivity”).

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

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

In rheumatoid arthritis clinical studies, the incidence of serious infections including pneumonia washigher in infliximab plus methotrexate-treated patients compared with methotrexate alone especially atdoses of 6 mg/kg or greater (see section 4.4).

In post-marketing spontaneous reporting, infections are the most common serious adverse reaction.

Some of the cases have resulted in a fatal outcome. Nearly 50% of reported deaths have beenassociated with infection. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis andtuberculosis 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 patientyears, 5 cases of lymphomas and 26 non-lymphoma malignancies were detected as compared with nolymphomas and 1 non-lymphoma malignancy in 1,600 placebo-treated patients representing941 patient years.

In long-term safety follow-up of clinical studies with infliximab of up to 5 years, representing6,234 patients-years (3,210 patients), 5 cases of lymphoma and 38 cases of non-lymphomamalignancies were reported.

Cases of malignancies, including lymphoma, have also been reported in the post-marketing setting(see section 4.4).

In an exploratory clinical study involving patients with moderate to severe COPD who were eithercurrent smokers or ex-smokers, 157 adult patients were treated with infliximab at doses similar tothose used in rheumatoid arthritis and Crohn’s disease. Nine of these patients developed malignancies,including 1 lymphoma. The median duration of follow-up was 0.8 years (incidence 5.7% [95% CI2.65%-10.6%]. There was one reported malignancy amongst 77 control patients (median duration offollow-up 0.8 years; incidence 1.3% [95% CI 0.03%-7.0%]). The majority of the malignanciesdeveloped in the lung or head and neck.

A population-based retrospective cohort study found an increased incidence of cervical cancer inwomen with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or thegeneral population, including those over 60 years of age (see section 4.4).

In addition, post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patientstreated with infliximab with the vast majority of cases occurring in Crohn’s disease and ulcerativecolitis, and most of 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 toworsening of heart failure were seen in patients treated with infliximab, especially those treated withthe higher dose of 10 mg/kg (i.e. twice the maximum approved dose). In this study 150 patients with

NYHA Class III-IV CHF (left ventricular ejection fraction ≤ 35%) were treated with 3 infusions ofinfliximab 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 38 weeks, 9 of 101 patients treated withinfliximab (2 at 5 mg/kg and 7 at 10 mg/kg) died compared to one death among the 49 patients onplacebo.

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 newonset heart failure, including heart failure in patients without known pre-existing cardiovasculardisease. Some of these patients have been under 50 years of age.

In clinical studies, mild or moderate elevations of ALT and AST have been observed in patientsreceiving infliximab without progression to severe hepatic injury. Elevations of ALT ≥5 x Upper

Limit of Normal (ULN) have been observed (see Table 2). Elevations of aminotransferases wereobserved (ALT more common than AST) in a greater proportion of patients receiving infliximab thanin controls, both when infliximab was given as monotherapy and when it was used in combinationwith other immunosuppressive agents. Most aminotransferase abnormalities were transient; however,a small number of patients experienced more prolonged elevations. In general, patients who developed

ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with eithercontinuation or discontinuation of infliximab, or modification of concomitant therapy. Inpost-marketing surveillance, cases of jaundice and hepatitis, some with features of autoimmunehepatitis, 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 Median follow-up≥3 x ULN ≥5 x ULNpatients3 (wks)4

Indicationinflixim inflixim inflixim infliximplacebo placebo placebo placeboab ab ab ab

Rheumatoid1 375 1,087 58.1 58.3 3.2% 3.9% 0.8% 0.9%arthritis

Crohn’s324 1,034 53.7 54.0 2.2% 4.9% 0.0% 1.5%disease2

Paediatric

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

Number of Median follow-up3 4 ≥3 x ULN ≥5 x ULNpatients (wks)

Indicationinflixim inflixim inflixim infliximplacebo placebo placebo placeboab ab ab ab

Ulcerative242 482 30.1 30.8 1.2% 2.5% 0.4% 0.6%colitis

Paediatric

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

Ankylosing76 275 24.1 101.9 0.0% 9.5% 0.0% 3.6%spondylitis

Psoriatic98 191 18.1 39.1 0.0% 6.8% 0.0% 2.1%arthritis

Plaque281 1,175 16.1 50.1 0.4% 7.7% 0.0% 3.4%psoriasis1 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 initialdose of 5 mg/kg infliximab at study start and were on placebo in the maintenance phase. Patients who wererandomised to the placebo maintenance group and then later crossed over to infliximab are included in theinfliximab group in the ALT analysis. In the Phase IIIb trial in Crohn’s disease, SONIC, placebo patientsreceived 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 atbaseline developed a positive ANA during the study compared with approximately one fifth ofplacebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately 17% ofinfliximab-treated patients compared with 0% of placebo-treated patients. At the last evaluation, 57%of infliximab-treated patients remained anti-dsDNA positive. Reports of lupus and lupus-likesyndromes, however, remain uncommon (see section 4.4).

Infliximab was studied in a clinical study in 120 patients (age range: 4-17 years old) with activejuvenile rheumatoid arthritis despite methotrexate. Patients received 3 or 6 mg/kg infliximab as a3-dose induction regimen (weeks 0, 2, 6 or weeks 14, 16, 20, respectively) followed by maintenancetherapy every 8 weeks, in combination with methotrexate.

Infusion reactions

Infusion 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 of60 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2of which were among the serious infusion reactions). In the 6 mg/kg group, 2 out of 57 patients had aserious infusion 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% ofpatients receiving 6 mg/kg. The antibody titres were notably higher for the 3 mg/kg compared to the6 mg/kg group.

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

The following adverse reactions were reported more commonly in paediatric Crohn’s disease patientsin the REACH study (see section 5.1) than in adult Crohn’s disease patients: anaemia (10.7%), bloodin 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 specialconsiderations are discussed below.

In REACH, 17.5% of randomised patients experienced 1 or more infusion reactions. There were noserious infusion 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 withinfliximab. Infections were reported more frequently for subjects who received q8 week as opposed toq12 week infusions (73.6% and 38.0%, respectively), while serious infections were reported for3 subjects in the q8 week and 4 subjects in the q12 week maintenance treatment group. The mostcommonly reported infections were upper respiratory tract infection and pharyngitis, and the mostcommonly reported serious infection was abscess. Three cases of pneumonia (1 serious) and 2 cases ofherpes 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 mostcommon adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever,and headache. The most common adverse event was worsening of ulcerative colitis, the incidence ofwhich was higher in patients on the q12 week vs. the q8 week dosing regimen.

Overall, 8 (13.3%) of 60 treated patients experienced one or more infusion reactions, with 4 of 22(18.2%) in the q8 week and 3 of 23 (13.0%) in the q12 week treatment maintenance group. No seriousinfusion reactions were reported. All infusion 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%) requiredoral or parenteral antimicrobial treatment. The proportion of patients with infections in C0168T72 wassimilar to that in the paediatric Crohn’s disease study (REACH) but higher than the proportion in theadults ulcerative colitis studies (ACT 1 and ACT 2). The overall incidence of infections in C0168T72was 13/22 (59%) in the every 8 week maintenance treatment group and 14/23 (60.9%) in the every12 week maintenance treatment group. Upper respiratory tract infection (7/60 [12%]) and pharyngitis(5/60 [8%]) were the most frequently reported respiratory system infections. Serious infections werereported 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 tomake any definitive conclusions about the effect of age on safety events, there were higher proportionsof patients with serious adverse events and discontinuation due to adverse events in the younger agegroup than in the older age group. While the proportion of patients with infections was also higher inthe younger age group, for serious infections, the proportions were similar in the two age groups.

Overall proportions of adverse events and infusion reactions were similar between the 6 to 11 and 12to 17 year age groups.

Post-marketing spontaneous serious adverse reactions with infliximab in the paediatric populationhave included malignancies including hepatosplenic T-cell lymphomas, transient hepatic enzymeabnormalities, lupus-like syndromes, and positive auto-antibodies (see sections 4.4 and 4.8).

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

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 reporting systemlisted in Appendix V.

No case of overdose has been reported. Single doses up to 20 mg/kg have been administered withouttoxic effects.

Pharmacotherapeutic group: immunosuppressants, tumour necrosis factor alpha (TNFα) inhibitors,

ATC code: L04AB02.

Inflectra 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 bothsoluble and transmembrane 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 ofhuman TNFα and when administered after disease onset, it allowed eroded joints to heal. In vivo,infliximab rapidly forms stable complexes with human TNFα, a process that parallels the loss of TNFαbioactivity.

Elevated concentrations of TNFα have been found in the joints of rheumatoid arthritis patients andcorrelate with elevated disease activity. In rheumatoid arthritis, treatment with infliximab reducedinfiltration of inflammatory cells into inflamed areas of the joint as well as expression of moleculesmediating cellular adhesion, chemoattraction and tissue degradation. After infliximab treatment,patients exhibited decreased levels of serum interleukin 6 (IL-6) and C-reactive protein (CRP), andincreased haemoglobin levels in rheumatoid arthritis patients with reduced haemoglobin levels,compared with baseline. Peripheral blood lymphocytes further showed no significant decrease innumber or in proliferative responses to in vitro mitogenic stimulation when compared with untreatedpatients’ cells. In psoriasis patients, treatment with infliximab resulted in decreases in epidermalinflammation and normalisation of keratinocyte differentiation in psoriatic plaques. In psoriaticarthritis, short term treatment with infliximab reduced the number of T-cells and blood vessels in thesynovium and psoriatic skin.

Histological evaluation of colonic biopsies, obtained before and 4 weeks after administration ofinfliximab, revealed a substantial reduction in detectable TNFα. Infliximab treatment of Crohn’sdisease patients was also associated with a substantial reduction of the commonly elevated seruminflammatory marker, CRP. Total peripheral white blood cell counts were minimally affected ininfliximab-treated patients, although changes in lymphocytes, monocytes and neutrophils reflectedshifts towards normal ranges. Peripheral blood mononuclear cells (PBMC) from infliximab-treatedpatients showed undiminished proliferative responsiveness to stimuli compared with untreatedpatients, and no substantial changes in cytokine production by stimulated PBMC were observedfollowing treatment with infliximab. Analysis of lamina propria mononuclear cells obtained by biopsyof the intestinal mucosa showed that infliximab treatment caused a reduction in the number of cellscapable of expressing TNFα and interferon . Additional histological studies provided evidence thattreatment with infliximab reduces the infiltration of inflammatory cells into affected areas of theintestine and the presence of inflammation markers at these sites. Endoscopic studies of intestinalmucosa have shown evidence of mucosal healing in infliximab-treated patients.

Adult rheumatoid arthritis

The efficacy of infliximab was assessed in two multicenter, 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), theprevention of structural joint damage, and the improvement in physical function. A reduction in signsand symptoms was defined to be at least a 20% improvement (ACR20) in both tender and swollenjoint counts, and in 3 of the following 5 criteria: (1) evaluator’s global assessment, (2) patient’s globalassessment, (3) functional/disability measure, (4) visual analogue pain scale and (5) erythrocytesedimentation rate or C-reactive protein. ACR-N uses the same criteria as the ACR20, calculated bytaking the lowest percent improvement in swollen joint count, tender joint count, and the median ofthe remaining 5 components of the ACR response. Structural joint damage (erosions and joint spacenarrowing) in both hands and feet was measured by the change from baseline in the total van der

Heijde-modified Sharp score (0-440). The Health Assessment Questionnaire (HAQ; scale 0-3) wasused to measure patients’ average change from baseline scores over time, in physical function.

The ATTRACT study evaluated responses at 30, 54 and 102 weeks in a placebo-controlled study of428 patients with active rheumatoid arthritis despite treatment with methotrexate. Approximately 50%of patients were in functional Class III. Patients received placebo, 3 mg/kg or 10 mg/kg infliximab atweeks 0, 2 and 6, and then every 4 or 8 weeks thereafter. All patients were on stable methotrexatedoses (median 15 mg/wk) for 6 months prior to enrolment and were to remain on stable dosesthroughout 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 infliximabgroups at 30 and 54 weeks compared with methotrexate alone.

A reduction in the rate of the progression of structural joint damage (erosions and joint spacenarrowing) was observed in all infliximab groups at 54 weeks (Table 3).

The effects observed at 54 weeks were maintained through 102 weeks. Due to a number of treatmentwithdrawals, the magnitude of the effect difference between infliximab and the methotrexate alonegroup cannot be defined.

Table 3

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

Infliximabba 3 mg/kg 3 mg/kg 10 mg/kg 10 mg/kg All

Controlq 8 wks q 4 wks q 8 wks q 4 wks infliximabb

Patients with ACR20 15/88 36/86 41/86 51/87 48/81 176/340response/Patients (17%) (42%) (48%) (59%) (59%) (52%)evaluated (%)

Total scored (van der Heijde-modified Sharp score)

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

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 13/64 34/71 35/71 37/77 44/66 150/285deterioration/patients (20%) (48%) (49%) (48%) (67%) (53%)evaluated (%)c

HAQ change from 87 86 85 87 81 339baseline over timee(patients evaluated)

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 toenrolment and were to remain on stable doses throughout the study. Concurrent use of stable doses of oralcorticosteroids (≤10 mg/day) and/or NSAIDs was permitted, and folate supplementation was given.

b all infliximab doses given in combination with methotrexate and folate with some on corticosteroidsand/or NSAIDs.

c p <0.001, for each infliximab treatment group vs. control.

d greater values indicate more joint damage.

e HAQ = Health Assessment Questionnaire; greater values indicate less disability.

The ASPIRE study evaluated responses at 54 weeks in 1,004 methotrexate naive patients with early(≤ 3 years disease duration, median 0.6 years) active rheumatoid arthritis (median swollen and tenderjoint count of 19 and 31, respectively). All patients received methotrexate (optimised to 20 mg/wk byweek 8) and either placebo, 3 mg/kg or 6 mg/kg infliximab at weeks 0, 2, and 6 and every 8 weeksthereafter. Results from week 54 are shown in Table 4.

After 54 weeks of treatment, both doses of infliximab + methotrexate resulted in statisticallysignificantly greater improvement in signs and symptoms compared to methotrexate alone asmeasured by the proportion of patients achieving ACR20, 50 and 70 responses.

In ASPIRE, more than 90% of patients had at least two evaluable X-rays. Reduction in the rate ofprogression of structural damage was observed at weeks 30 and 54 in the infliximab + methotrexategroups compared to methotrexate alone.

Table 4

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

Infliximab + MTX

Placebo3 mg/kg 6 mg/kg Combined+ MTX

Subjects randomised 282 359 363 722

Percentage ACR improvement

Mean ± SDa 24.8 ± 59.7 37.3 ± 52.8 42.0 ± 47.3 39.6 ± 50.1

Change from baseline in total van der Heijde-modified Sharp scoreb

Mean ± SDa 3.70 ± 9.61 0.42 ± 5.82 0.51 ± 5.55 0.46 ± 5.68

Median 0.43 0.00 0.00 0.00

Improvement from baseline in HAQ averaged over time from week 30 to week 54c

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. control.

b greater values indicate more joint damage.

c HAQ = Health Assessment Questionnaire; greater values indicate less disability.

d p = 0.030 and <0.001 for the 3 mg/kg and 6 mg/kg treatment groups respectively vs.

placebo + MTX.

Data to support dose titration in rheumatoid arthritis come from ATTRACT, ASPIRE and the STARTstudy. START was a randomised, multicenter, double-blind, 3-arm, parallel-group safety study. In oneof the study arms (group 2, n=329), patients with an inadequate response were allowed to dose titratewith 1.5 mg/kg increments from 3 up to 9 mg/kg. The majority (67%) of these patients did not requireany dose titration. Of the patients who required a dose titration, 80% achieved clinical response andthe majority (64%) of these required 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’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 ≤ 400) in a randomised,double-blinded, placebo-controlled, dose-response study. Of these 108 patients, 27 were treated withthe recommended dosage of infliximab 5 mg/kg. All patients had experienced an inadequate responseto prior conventional therapies. Concurrent use of stable doses of conventional therapies waspermitted, and 92% of patients continued to receive 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 theuse of medicinal products or surgery for Crohn’s disease. Patients who responded at week 4 werefollowed to week 12. Secondary endpoints included the proportion of patients in clinical remission atweek 4 (CDAI < 150) and clinical response over time.

At week 4, following administration of a single dose, 22/27 (81%) of infliximab-treated patientsreceiving a 5 mg/kg dose achieved a clinical response vs. 4/25 (16%) of the placebo-treated patients(p <0.001). Also at week 4, 13/27 (48%) of infliximab-treated patients achieved a clinical remission(CDAI < 150) vs. 1/25 (4%) of placebo-treated patients. A response was observed within 2 weeks,with a maximum response at 4 weeks. At the last observation at 12 weeks, 13/27 (48%) ofinfliximab-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 a single infusion of 5 mg/kg at week 0. 178 of the 580 enrolled patients (30.7%) were definedas having severe disease (CDAI score > 300 and concomitant corticosteroid and/orimmunosuppressants) corresponding to the population defined in the indication (see section 4.1). Atweek 2, all patients were assessed for clinical response and randomised to one of 3 treatment groups; aplacebo maintenance group, 5 mg/kg maintenance group and 10 mg/kg maintenance group. All3 groups received repeated infusions at week 2, 6 and every 8 weeks thereafter.

Of the 573 patients randomised, 335 (58%) achieved clinical response by week 2. These patients wereclassified as week-2 responders and were included in the primary analysis (see Table 5). Amongpatients classified as non-responders at week 2, 32% (26/81) in the placebo maintenance group and42% (68/163) in the infliximab group achieved clinical response by week 6. There was no differencebetween groups in the number of late responders thereafter.

The co-primary endpoints were the proportion of patients in clinical remission (CDAI < 150) atweek 30 and time to loss of response through week 54. Corticosteroid tapering was permitted afterweek 6.

Table 5

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

ACCENT I (Week-2 responders)% of Patients

Placebo Infliximab Infliximab

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

Median time to loss of response 19 weeks 38 weeks >54 weeksthrough week 54 (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 5.7 (3/53) 17.9 (10/56) 28.6 (16/56)

Remissionb (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 54among patients who were receiving corticosteroids at baseline.

Beginning at week 14, patients who had responded to treatment, but subsequently lost their clinicalbenefit, were allowed to cross over to a dose of infliximab 5 mg/kg higher than the dose to which theywere originally randomised. Eighty-nine percent (50/56) of patients who lost clinical response oninfliximab 5 mg/kg maintenance therapy after week 14 responded to treatment with infliximab10 mg/kg.

Improvements in quality of life measures, a reduction in disease-related hospitalisations andcorticosteroid use were seen in the infliximab maintenance groups compared with the placebomaintenance group at weeks 30 and 54.

Infliximab with or without AZA was assessed in a randomised, double-blind, active comparator study(SONIC) of 508 adult patients with moderate to severe Crohn’s disease (CDAI ≥ 220 ≤ 450) who werenaive to biologics and immunosuppressants and had a median disease duration of 2.3 years. Atbaseline 27.4% of patients were receiving systemic corticosteroids, 14.2% of patients were receivingbudesonide, and 54.3% of patients were receiving 5-ASA compounds. Patients were randomised toreceive AZA monotherapy, infliximab monotherapy, or infliximab plus AZA combination therapy.

Infliximab was administered at a dose of 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks. AZA wasgiven at a dose of 2.5 mg/kg daily.

The primary endpoint of the study was corticosteroid-free clinical remission at week 26, defined aspatients in clinical remission (CDAI of < 150) who, for at least 3 weeks, had not taken oral systemiccorticosteroids (prednisone or equivalent) or budesonide at a dose > 6 mg/day. For results see Table 6.

The proportions of patients with mucosal healing at week 26 were significantly greater in theinfliximab plus AZA combination (43.9%, p<0.001) and infliximab monotherapy groups (30.1%,p=0.023) compared to the AZA monotherapy group (16.5%).

Table 6

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

AZA Infliximab Infliximab + AZA

Monotherapy Monotherapy Combination therapy

Week 26

All randomised patients 30.0% 44.4% (75/169) 56.8% (96/169)(51/170) (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 patientswith fistulising Crohn’s disease who had fistulae that were of at least 3 months’ duration. Thirty one ofthese patients were treated with infliximab 5 mg/kg. Approximately 93% of the patients hadpreviously received antibiotic or immunosuppressive therapy.

Concurrent use of stable doses of conventional therapies was permitted, and 83% of patients continuedto receive at least one of these therapies. Patients received three doses of either placebo or infliximabat weeks 0, 2 and 6. Patients were followed up to 26 weeks. The primary endpoint was the proportionof patients who experienced a clinical response, defined as ≥ 50% reduction from baseline in thenumber of fistulae draining upon gentle compression on at least two consecutive visits (4 weeks apart),without an increase in the use of medicinal products or surgery for Crohn’s disease.

Sixty-eight percent (21/31) of infliximab-treated patients receiving a 5 mg/kg dose regimen achieved aclinical response vs. 26% (8/31) placebo-treated patients (p=0.002). The median time to onset ofresponse in the infliximab-treated group was 2 weeks. The median duration of response was 12 weeks.

Additionally, closure of all fistulae was achieved in 55% of infliximab-treated patients compared with13% of placebo-treated patients (p=0.001).

The efficacy of repeated infusions with infliximab in patients with fistulising Crohn’s disease wasstudied in a 1-year clinical study (ACCENT II). A total of 306 patients received 3 doses of infliximab5 mg/kg at week 0, 2 and 6. At baseline, 87% of the patients had perianal fistulae, 14% had abdominalfistulae, 9% had rectovaginal fistulae. The median CDAI score was 180. At week 14, 282 patientswere assessed for clinical response and randomised to receive either placebo or 5 mg/kg infliximabevery 8 weeks through week 46.

Week-14 responders (195/282) were analysed for the primary endpoint, which was time fromrandomisation to loss of response (see Table 7). Corticosteroid tapering was permitted after week 6.

Table 7

Effects on response rate, data from ACCENT II (Week-14 responders)

ACCENT II (Week-14 responders)

Placebo Infliximab p-value

Maintenance Maintenance(n=99) (5 mg/kg)(n=96)

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

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 weeks.

b Absence of any draining fistulas.

Beginning at week 22, patients who initially responded to treatment and subsequently lost theirresponse were eligible to cross over to active re-treatment every 8 weeks at a dose of infliximab5 mg/kg higher than the dose to which they were originally randomised. Among patients in theinfliximab 5 mg/kg group who crossed over because of loss of fistula response after week 22,57% (12/21) responded to re-treatment with infliximab 10 mg/kg every 8 weeks.

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 andurinary tract infection or for number of newly developed fistulas during treatment.

Maintenance therapy with infliximab every 8 weeks significantly reduced disease-relatedhospitalisations and surgeries compared with placebo. Furthermore, a reduction in corticosteroid useand improvements in quality 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 activeulcerative colitis (Mayo score 6 to 12; Endoscopy subscore ≥ 2) with an inadequate response toconventional therapies [oral corticosteroids, aminosalicylates and/or immunomodulators (6-MP,

AZA)]. Concomitant stable doses of oral aminosalicylates, corticosteroids, and/or immunomodulatoryagents were permitted. In both studies, patients were randomised to receive either placebo, 5 mg/kginfliximab, or 10 mg/kg infliximab at weeks 0, 2, 6, 14 and 22, and in ACT 1 at weeks 30, 38 and 46.

Corticosteroid taper was permitted after week 8.

Table 8

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

Combined data from ACT 1 & 2

Infliximab

Placebo 5 mg/kg 10 mg/kg Combined

Subjects randomised 244 242 242 484

Percentage of subjects in clinical response and in sustained clinical response

Clinical response at week 8a 33.2% 66.9% 65.3% 66.1%

Clinical response at week 30a 27.9% 49.6% 55.4% 52.5%

Sustained response (clinicalresponse at both week 8 and 19.3% 45.0% 49.6% 47.3%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 remissionat both week 8 and week 30)a 5.3% 19.0% 24.4% 21.7%

Infliximab

Placebo 5 mg/kg 10 mg/kg Combined

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 tothe placebo treatment group at week 54 (34.6% vs. 16.5%, p<0.001 and 46.1% vs. 18.2%, p<0.001,respectively). The proportions of patients in sustained response and sustained remission at week 54were greater in the combined infliximab treatment group than in the placebo treatment group (37.9%vs. 14.0%, p<0.001; and 20.2% vs. 6.6%, p<0.001, respectively).

A greater proportion of patients in the combined infliximab treatment group were able to discontinuecorticosteroids while remaining in clinical remission compared to the placebo treatment group at bothweek 30 (22.3% vs. 7.2%, p <0.001, pooled ACT 1 & ACT 2 data) and week 54 (21.0% vs. 8.9%,p=0.022, ACT 1 data).

The pooled data analysis from the ACT 1 and ACT 2 studies and their extensions, analysed frombaseline through 54 weeks, demonstrated a reduction of ulcerative colitis-related hospitalisations andsurgical procedures with infliximab treatment. The number of ulcerative colitis-related hospitalisationswas significantly lower in the 5 and 10 mg/kg infliximab treatment groups than in the placebo group(mean number of hospitalisations per 100 subject-years: 21 and 19 vs. 40 in the placebo group;p=0.019 and p=0.007, respectively). The number of ulcerative colitis-related surgical procedures wasalso lower in the 5 and 10 mg/kg infliximab treatment groups than in the placebo group (mean numberof surgical procedures per 100 subject-years: 22 and 19 vs. 34; p=0.145 and p=0.022, respectively).

The proportion of subjects who underwent colectomy at any time within 54 weeks following the firstinfusion of study agent were collected and pooled from the ACT 1 and ACT 2 studies and theirextensions. Fewer subjects underwent colectomy in the 5 mg/kg infliximab group (28/242 or 11.6%[N.S.]) and the 10 mg/kg infliximab group (18/242 or 7.4% [p=0.011]) than in the placebo group(36/244; 14.8%).

The reduction in incidence of colectomy was also examined in another randomised, double-blind study(C0168Y06) in hospitalised patients (n=45) with moderately to severely active ulcerative colitis whofailed to respond to intravenous corticosteroids and who were therefore at higher risk for colectomy.

Significantly fewer colectomies occurred within 3 months of study infusion in patients who received asingle dose of 5 mg/kg infliximab compared to patients who received placebo (29.2% vs. 66.7%respectively, p=0.017).

In ACT 1 and ACT 2, infliximab improved quality of life, confirmed by statistically significantimprovement in both a disease specific measure, IBDQ, and by improvement in the generic 36-itemshort form survey SF-36.

Efficacy and safety of infliximab were assessed in two multicenter, double-blind, placebo-controlledstudies in patients with active ankylosing spondylitis (Bath Ankylosing Spondylitis Disease Activity

Index [BASDAI] score ≥ 4 and spinal pain ≥ 4 on a scale of 1-10).

In the first study (P01522), which had a 3 month double-blind phase, 70 patients received either5 mg/kg infliximab or placebo at weeks 0, 2, 6 (35 patients in each group). At week 12, placebopatients were switched to infliximab 5 mg/kg every 6 weeks up to week 54. After the first year of thestudy, 53 patients continued into an open-label extension to week 102.

In the second clinical study (ASSERT), 279 patients were randomised to receive either placebo(Group 1, n=78) or 5 mg/kg infliximab (Group 2, n=201) at 0, 2 and 6 weeks and every 6 weeks toweek 24. Thereafter, all subjects continued on infliximab every 6 weeks to week 96. Group 1 received5 mg/kg infliximab. In Group 2, starting with the week 36 infusion, patients who had a BASDAI ≥ 3 at2 consecutive visits, received 7.5 mg/kg infliximab every 6 weeks thereafter through week 96.

In ASSERT, improvement in signs and symptoms was observed as early as week 2. At week 24, thenumber of ASAS 20 responders was 15/78 (19%) in the placebo group, and 123/201 (61%) in the5 mg/kg infliximab group (p<0.001). There were 95 subjects from group 2 who continued on 5 mg/kgevery 6 weeks. At 102 weeks there were 80 subjects still on infliximab treatment and among those,71 (89%) were ASAS 20 responders.

In P01522, improvement in signs and symptoms was also observed as early as week 2. At week 12,the number of BASDAI 50 responders were 3/35 (9%) in the placebo group, and 20/35 (57%) in the5 mg/kg group (p<0.01). There were 53 subjects who continued on 5 mg/kg every 6 weeks. At102 weeks there were 49 subjects still on infliximab treatment and among those, 30 (61%) were

BASDAI 50 responders.

In both studies, physical function and quality of life as measured by the BASFI and the physicalcomponent score of the SF-36 were also improved significantly.

Efficacy and safety were assessed in two multicenter, double-blind, placebo-controlled studies inpatients with active psoriatic arthritis.

In the first clinical study (IMPACT), efficacy and safety of infliximab were studied in 104 patientswith active polyarticular psoriatic arthritis. During the 16-week double-blind phase, patients receivedeither 5 mg/kg infliximab or placebo at weeks 0, 2, 6, and 14 (52 patients in each group). Starting atweek 16, placebo patients were switched to infliximab and all patients subsequently received 5 mg/kginfliximab every 8 weeks up to week 46. After the first year of the study, 78 patients continued into anopen-label extension to week 98.

In the second clinical study (IMPACT 2), efficacy and safety of infliximab were studied in200 patients with active psoriatic arthritis (≥ 5 swollen joints and ≥ 5 tender joints). Forty-six percentof patients continued on stable doses of methotrexate (≤ 25 mg/week). During the 24-weekdouble-blind phase, patients received either 5 mg/kg infliximab or placebo at weeks 0, 2, 6, 14, and 22(100 patients in each group). At week 16, 47 placebo patients with < 10% improvement from baselinein both swollen and tender joint counts were switched to infliximab induction (early escape). Atweek 24, all placebo-treated patients crossed over to infliximab induction. Dosing continued for allpatients 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 52 52 N/Aa 100 100 100randomised

ACR response(% of patients)

N 52 52 78 100 100 100

ACR 20 5(10%) 34 (65%) 48 (62%) 16 (16%) 54 (54%) 53 (53%)response*

IMPACT IMPACT 2*

Placebo Infliximab Infliximab Placebo Infliximab Infliximab(Week 16) (Week 16) (Week 98) (Week 24) (Week 24) (Week 54)

Patients 52 52 N/Aa 100 100 100randomised

ACR 50 0(0%) 24 (46%) 35 (45%) 4 (4%) 41(41%) 33 (33%)response*

ACR 70 0(0%) 15 (29%) 27 (35%) 2 (2%) 27 (27%) 20 (20%)response*

PASI response(% ofpatients)b 87 83 82

N

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

* ITT-analysis where subjects with missing data were included as non-responders.

a Week 98 data for IMPACT includes combined placebo crossover and infliximab patients who enteredthe open-label extension.

b Based on patients with PASI > 2.5 at baseline for IMPACT, and patients with > 3% BSA psoriasis skininvolvement at baseline in IMPACT 2.

** PASI 75 response for IMPACT not included due to low N; p<0.001 for infliximab vs. placebo at week24 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 withoutconcomitant use of methotrexate. Decreases in parameters of peripheral activity characteristic ofpsoriatic arthritis (such as number of swollen joints, number of painful/tender joints, dactylitis andpresence of enthesopathy) were seen in 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 jointdamage compared with placebo treatment at the week 24 primary endpoint as measured by changefrom baseline in total modified vdH-S score (mean ± SD score was 0.82 ± 2.62 in the placebo groupcompared with -0.70 ± 2.53 in the infliximab group; p<0.001). In the infliximab group, the meanchange in total modified vdH-S score remained below 0 at the week 54 timepoint.

Infliximab-treated patients demonstrated significant improvement in physical function as assessed by

HAQ. Significant improvements in health-related quality of life were also demonstrated as measuredby the physical and mental component summary scores of the SF-36 in IMPACT 2.

The efficacy of infliximab was assessed in two multicenter, randomised, double-blind studies: SPIRITand 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 thepercent of patients who achieved ≥ 75% improvement in PASI from baseline at week 10.

SPIRIT evaluated the efficacy of infliximab induction therapy in 249 patients with plaque psoriasisthat had previously received PUVA or systemic therapy. Patients received either 3 or 5 mg/kginfliximab or placebo infusions at weeks 0, 2 and 6. Patients with a PGA score ≥ 3 were eligible toreceive an additional infusion of the same treatment at week 26.

In SPIRIT, the proportion of patients achieving PASI 75 at week 10 was 71.7% in the 3 mg/kginfliximab group, 87.9% in the 5 mg/kg infliximab group, and 5.9% in the placebo group (p<0.001).

By week 26, twenty weeks after the last induction dose, 30% of patients in the 5 mg/kg group and13.8% of patients in the 3 mg/kg group were PASI 75 responders. Between weeks 6 and 26, symptomsof psoriasis gradually returned with a median time to disease relapse of > 20 weeks. No rebound wasobserved.

EXPRESS evaluated the efficacy of infliximab induction and maintenance therapy in 378 patientswith plaque psoriasis. Patients received 5 mg/kg infliximab- or placebo-infusions at weeks 0, 2 and 6followed by maintenance therapy every 8 weeks through week 22 in the placebo group and throughweek 46 in the infliximab group. At week 24, the placebo group crossed over to infliximab inductiontherapy (5 mg/kg) followed by infliximab maintenance therapy (5 mg/kg). Nail psoriasis was assessedusing the Nail Psoriasis Severity Index (NAPSI). Prior therapy with PUVA, methotrexate, ciclosporin,or acitretin had been received by 71.4% of patients, although they were not necessarily therapyresistant. Key results are presented in Table 10. In infliximab treated subjects, significant PASI 50responses were apparent at the first visit (week 2) and PASI 75 responses by the second visit (week 6).

Efficacy was similar in the subgroup of patients that were exposed to previous systemic therapiescompared 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 5 mg/kg(at week 24)

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 14 (18.2%) 275 (94.2%) ab(2)

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 15 (19.5%) 246 (89.1%) a(2)

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 59 (86.8%) 189 (67.3%)(2)

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. control.

b n = 292.

c Analysis was based on subjects with nail psoriasis at baseline (81.8% of subjects). Mean baseline NAPSIscores were 4.6 and 4.3 in infliximab and placebo group.

Significant improvements from baseline were demonstrated in DLQI (p<0.001) and the physical andmental component 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 conventionaltherapies were to receive 5 mg/kg infliximab at weeks 0, 2, and 6. All patients were required to be on astable dose of 6-MP, AZA or MTX (35% were also receiving corticosteroids at baseline). Patientsassessed by the investigator to be in clinical response at week 10 were randomised and received5 mg/kg infliximab at either q8 weeks or q12 weeks as a maintenance treatment regimen. If responsewas lost during maintenance treatment, crossing over to a higher dose (10 mg/kg) and/or shorterdosing interval (q8 weeks) was allowed. Thirty two (32) evaluable paediatric patients crossed over(9 subjects in the q8 weeks and 23 subjects in the q12 weeks maintenance groups). Twenty four ofthese 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 ofsubjects achieving clinical remission at week 10 was 58.9% (66/112).

At week 30, the proportion of subjects in clinical remission was higher in the q8 week (59.6%, 31/52)than the q12 week maintenance treatment group (35.3%, 18/51; p=0.013). At week 54, the figureswere 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 and54, 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 asa significant reduction in corticosteroid use, were observed versus baseline.

The safety and efficacy of infliximab were assessed in a multicenter, randomised, open-label,parallel-group clinical study (C0168T72) in 60 paediatric patients aged 6 through 17 years (medianage 14.5 years) with moderately to severely active ulcerative colitis (Mayo score of 6 to 12;endoscopic subscore ≥ 2) with an inadequate response to conventional therapies. At baseline 53% ofpatients were receiving immunomodulator therapy (6-MP, AZA and/or MTX) and 62% of patientswere receiving corticosteroids. Discontinuation of immunomodulators and corticosteroid taper werepermitted after week 0.

All patients received an induction regimen of 5 mg/kg infliximab at weeks 0, 2, and 6. Patients whodid not respond to infliximab at week 8 (n=15) received no further medicinal product and returned forsafety follow-up. At week 8, 45 patients were randomised and received 5 mg/kg infliximab at eitherq8 weeks or q12 weeks as a maintenance treatment regimen.

The proportion of patients in clinical response at week 8 was 73.3% (44/60). Clinical response at week8 was similar between those with or without concomitant immunomodulator use at baseline. Clinicalremission at week 8 was 33.3% (17/51) as measured by the Paediatric Ulcerative Colitis Activity

Index (PUCAI) score.

At week 54, the proportion of patients in clinical remission as measured by the PUCAI score was 38%(8/21) in the q8 week maintenance group and 18% (4/22) in the q12 week maintenance treatmentgroup. For patients receiving corticosteroids at baseline, the proportion of patients in remission and notreceiving corticosteroids at week 54 was 38.5% (5/13) for the q8 week and 0% (0/13) for theq12 week maintenance treatment group.

In this study, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group(45/60 vs.15/60). While the numbers of patients in each subgroup are too small to draw definitiveconclusions about the effect of age, there was a higher number of patients in the younger age groupwho stepped 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 inrheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasisand 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 proportionalincreases in the maximum serum concentration (Cmax) and area under the concentration-time curve(AUC). The volume of distribution at steady state (median Vd of 3.0 to 4.1 litres) was not dependenton the administered dose and indicated that infliximab is predominantly distributed within the vascularcompartment. No time-dependency of the Pharmacokinetics was observed. The elimination pathwaysfor infliximab have not been characterised. Unchanged infliximab was not detected in urine. No majorage- or weight-related differences in clearance or volume of distribution were observed in rheumatoidarthritis patients. The pharmacokinetics of infliximab in elderly patients has not been studied. Studieshave 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 of5 mg/kg for Crohn’s disease and the rheumatoid arthritis maintenance dose of 3 mg/kg every 8 weeks.

Repeated administration of infliximab (5 mg/kg at 0, 2 and 6 weeks in fistulising Crohn’s disease, 3 or10 mg/kg every 4 or 8 weeks in rheumatoid arthritis) resulted in a slight accumulation of infliximab inserum after the second dose. No further clinically relevant accumulation was observed. In mostfistulising Crohn’s disease patients, infliximab was detected in serum for 12 weeks (range 4-28 weeks)after administration of the 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 an overall age range from 2 months to 17 years indicated that exposure to infliximab wasdependent on body weight in a non-linear way. Following administration of 5 mg/kg infliximab every8 weeks, the predicted median steady-state infliximab exposure (area under concentration-time curveat steady state, AUCss) in paediatric patients aged 6 years to 17 years was approximately 20% lowerthan the predicted median steady-state medicinal product exposure in adults. The median AUCss inpaediatric patients aged 2 years to less than 6 years was predicted to be approximately 40% lower thanthat in adults, although the number of patients supporting this estimate 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 studyconducted in mice using an analogous antibody that selectively inhibits the functional activity ofmouse TNFα, there was no indication of maternal toxicity, embryotoxicity or teratogenicity. In afertility and general reproductive function study, the number of pregnant mice was reduced followingadministration of the same analogous antibody. It is not known whether this finding was due to effectson the males and/or the females. In a 6-month repeated dose toxicity study in mice, using the sameanalogous antibody against mouse TNFα, crystalline deposits were observed on the lens capsule ofsome of the treated male mice. No specific ophthalmologic examinations have been performed inpatients to investigate the relevance of this finding for humans.

Long-term studies have not been performed to evaluate the carcinogenic potential of infliximab.

Studies in mice deficient in TNFα demonstrated no increase in tumours when challenged with knowntumour initiators and/or promoters.

Sucrose

Polysorbate 80

Sodium dihydrogen phosphate monohydrate

Disodium phosphate dihydrate

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

Before reconstitution5 years at 2 °C - 8 °C.

Inflectra may be stored at temperatures up to a maximum of 25 °C for a single period of up to6 months, but not exceeding the original expiry date. The new expiry date must be written on thecarton. Upon removal from refrigerated storage, Inflectra must not be returned to refrigerated storage.

Chemical and physical in use stability of the diluted solution has been demonstrated for up to 60 daysat 2 °C - 8 °C and for an additional 24 hours at 25 °C after removal from refrigeration. From amicrobiological point of view, the infusion solution should be administered immediately, in usestorage times and conditions prior to use are the responsibility of the user and would normally not belonger than 24 hours at 2 °C - 8 °C, unless reconstitution/dilution has been taken place in controlledand 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 (butyl) rubber stopper and an aluminium seal with a flip-off button.

Pack sizes of 1, 2, 3, 4, 5 vials.

Not all pack sizes may be marketed.

1. The dose and the number of Inflectra vials have to be calculated. Each Inflectra vial contains100 mg infliximab. The required total volume of reconstituted Inflectra solution has to becalculated.

2. Under aseptic conditions, each Inflectra vial should be reconstituted with 10 mL of water forinjections, using a syringe equipped with a 21-gauge (0.8 mm) or smaller needle. The flip-topfrom the vial has to be removed and the top has to be wiped with a 70% alcohol swab. Thesyringe needle should be inserted into the vial through the centre of the rubber stopper and thestream of water for injections directed to the glass wall of the vial. The solution has to be gentlyswirled by rotating the vial to dissolve the powder. Prolonged or vigorous agitation must beavoided. THE VIAL MUST NOT BE SHAKEN. Foaming of the solution on reconstitution mayoccur. The reconstituted solution should stand for 5 minutes. The solution should be colourlessto light yellow and opalescent. The solution may develop a few fine translucent particles, asinfliximab is a protein. The solution must not be used if opaque particles, discolouration, orother foreign particles are present.

3. The required volume of the reconstituted Inflectra solution should be diluted to 250 mL withsodium chloride 9 mg/mL (0.9%) solution for infusion. Do not dilute the reconstituted Inflectrasolution with any other diluent. The dilution can be accomplished by withdrawing a volume ofthe sodium chloride 9 mg/mL (0.9%) solution for infusion from the 250-mL glass bottle orinfusion bag equal to the volume of reconstituted Inflectra. The required volume of reconstituted

Inflectra solution should slowly be added to the 250-mL infusion bottle or bag and gently bemixed. For volumes greater than 250 mL, either use a larger infusion bag (e.g. 500 mL,1000 mL) or use multiple 250 mL infusion bags to ensure that the concentration of the infusionsolution 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 priorto Step 4 (infusion). Storage beyond 24 hours at 2 °C - 8 °C applies to preparation of Inflectra inthe infusion bag only.

4. The infusion solution has to be administered over a period of not less than the infusion timerecommended (see section 4.2). Only an infusion set with an in-line, sterile, non-pyrogenic, lowprotein-binding filter (pore size 1.2 micrometre or less) should be used. Since no preservative ispresent, it is recommended that the administration of the solution for infusion is to be started assoon as possible and within 3 hours of reconstitution and dilution. If not used immediately, inuse storage times and conditions prior to use are the responsibility of the user and wouldnormally not be longer than 24 hours at 2 °C to 8 °C, unless reconstitution/dilution has beentaken place in controlled and validated aseptic conditions (see section 6.3 above). Any unusedportion of the infusion solution should not be stored for reuse.

5. Inflectra should be visually inspected for particulate matter or discolouration prior toadministration. If visibly opaque particles, discolouration or foreign particles are observed itshould not be used.

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

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/13/854/001

EU/1/13/854/002

EU/1/13/854/003

EU/1/13/854/004

EU/1/13/854/005

Date of first authorisation: 10 September 2013

Date of latest renewal: 21 June 2018

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

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