Leaflet ZESSLY 100mg powder for concentrate infusion solution

Zessly 100 mg powder for concentrate for solution for infusion

Each vial contains 100 mg of infliximab. Infliximab is a chimeric human-murine IgG1 monoclonalantibody produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. Afterreconstitution each ml contains 10 mg of infliximab.

Each vial contains 0.5 mg of polysorbate 80 (E 433), see section 4.4 for further information.

For the full list of excipients, see section 6.1.

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

The powder is a freeze-dried white pellet.

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

Zessly 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 respondeddespite a full and adequate course of therapy with conventional treatment (includingantibiotics, drainage and immunosuppressive therapy).

Zessly is indicated for treatment of severe, active Crohn’s disease, in children and adolescents aged6 to 17 years, who have not responded to conventional therapy including a corticosteroid, animmunomodulator and primary nutrition therapy; or who are intolerant to or have contraindicationsfor such therapies. Infliximab has been studied only in combination with conventionalimmunosuppressive therapy.

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

Zessly is indicated for treatment of severely active ulcerative colitis, in children and adolescentsaged 6 to 17 years, who have had an inadequate response to conventional therapy includingcorticosteroids and 6-MP or AZA, or who are intolerant to or have medical contraindications forsuch therapies.

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

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

Zessly 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).

Zessly 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 therapyincluding ciclosporin, methotrexate or PUVA (see section 5.1).

Zessly treatment is to be initiated and supervised by qualified physicians experienced in thediagnosis and treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosingspondylitis, psoriatic arthritis or psoriasis. Zessly should be administered intravenously. Zesslyinfusions should be administered by qualified healthcare professionals trained to detect anyinfusion-related issues. Patients treated with Zessly should be given the package leaflet and thepatient reminder card.

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

Adults (≥ 18 years)

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.

Zessly must be given concomitantly with methotrexate.

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

If a patient has an inadequate response or loses response after this period, consideration may begiven to increase the dose step-wise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kgevery 8 weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may beconsidered. If adequate response is achieved, patients should be continued on the selected dose ordose frequency. Continued therapy should be carefully reconsidered in patients who show noevidence of therapeutic benefit 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 afterthe first 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 notresponding within 6 weeks of the initial infusion.

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

* Maintenance: Additional infusion of 5 mg/kg at 6 weeks after the initial dose, followed 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/kgbut who 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 evidenceof therapeutic 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 and6 weeks after the first infusion. If a patient does not respond after 3 doses, no additional treatmentwith infliximab 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 followedby infusions of 5 mg/kg every 8 weeks (see ‘Re-administration’ below and section 4.4).

Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kgbut who 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 evidenceof therapeutic benefit after dose adjustment.

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

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 noevidence of therapeutic 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, Zessly can be re-administered within 16 weeksfollowing the last infusion. In clinical studies, delayed hypersensitivity reactions have beenuncommon and have occurred after infliximab-free intervals of less than 1 year (see sections 4.4and 4.8). The safety and efficacy of re-administration after an infliximab-free interval of more than16 weeks has not been established. This applies to both Crohn’s disease patients and rheumatoidarthritis patients.

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

Limited experience from re-treatment with one single infliximab dose in psoriasis after an intervalof 20 weeks suggests reduced efficacy and a higher incidence of mild to moderate infusionreactions when compared to the initial induction regimen (see section 5.1).

Limited experience from re-treatment following disease flare by a re-induction regimen suggests 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 a re-induction regimen is not recommended (see section 4.8). In this situation, Zessly should be re-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 inelderly patients (see sections 4.4 and 4.8).

Infliximab has not been studied in these patient populations. No dose recommendations can bemade (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 oftreatment (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 shortenedinterval should be carefully considered in those patients who show no evidence of additionaltherapeutic benefit after a change in dosing interval.

The safety and efficacy of infliximab have not been studied in children with Crohn’s disease 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.

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(see section 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 insection 5.2 but no recommendation on a posology can be made.

The safety and efficacy of infliximab in children and adolescents younger than 18 years for theindications of juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis have notbeen established. 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.

Zessly should be administered intravenously over a 2 hour period. All patients administered Zesslyare 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 airwaymust be available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/orparacetamol and infusion rate may be slowed in order to decrease the risk of infusion-relatedreactions especially if infusion-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 Zessly(induction phase) and are receiving maintenance therapy, consideration may be given toadministering subsequent infusions over a period of not less than 1 hour. If an infusion reactionoccurs in association with a shortened infusion, a slower infusion rate may be considered for futureinfusions if treatment is to be continued. Shortened infusions at doses > 6 mg/kg have not beenstudied (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 listedin section 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 batchnumber of 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 withlower incidence of antibodies to infliximab and a reduction in the frequency of infusion reactions.

The effect of concomitant immunomodulator therapy was more profound in episodically-treatedpatients than in patients given maintenance therapy. Patients who discontinue immunosuppressantsprior to or during infliximab treatment are at greater risk of developing these antibodies. Antibodiesto infliximab cannot always be detected in serum samples. If serious reactions occur, symptomatictreatment must be given and further Zessly 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 shouldbe advised to seek immediate medical advice if they experience any delayed adverse reaction (seesection 4.8). If patients are re-treated after a prolonged period, they must be closely monitored forsigns and symptoms of delayed hypersensitivity.

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

Caution should be exercised when considering the use of Zessly 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 patientstreated with infliximab.

It should be noted that suppression of TNFα may mask symptoms of infection such as fever. Earlyrecognition of atypical clinical presentations of serious infections and of typical clinicalpresentation of rare and unusual infections is critical in order to minimise delays in diagnosis andtreatment.

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 mortalityrate of > 5% include pneumocystosis, candidiasis, listeriosis and aspergillosis.

Patients who develop a new infection while undergoing treatment with Zessly, should be monitoredclosely and undergo a complete diagnostic evaluation. Administration of Zessly should bediscontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial orantifungal therapy should be initiated until the infection is controlled.

There have been reports of active tuberculosis in patients receiving infliximab. It should be notedthat in the majority of these reports tuberculosis was extrapulmonary, presenting as either local ordisseminated disease.

Before starting treatment with Zessly, all patients must be evaluated for both active and inactive(‘latent’) tuberculosis. This evaluation should include a detailed medical history with personalhistory of 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 (localrecommendations may apply). It is recommended that the conduct of these tests should be recordedin the patient’s reminder card. Prescribers are reminded of the risk of false negative tuberculin skintest results, especially in patients who are severely ill or immunocompromised.

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

If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis shouldbe consulted. In all situations described below, the benefit/risk balance of Zessly therapy should bevery carefully considered.

If inactive (‘latent’) tuberculosis is diagnosed, treatment for latent tuberculosis must be started withantituberculosis therapy before the initiation of Zessly, 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 Zessly.

Use of antituberculosis therapy should also be considered before the initiation of Zessly in patientswith a past history of latent or active tuberculosis in whom an adequate course of treatment cannotbe confirmed.

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 oftuberculosis (e.g. persistent cough, wasting/weight loss, low-grade fever) appear during or after

Zessly treatment.

In patients treated with Zessly, 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 antigenand antibody 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 Zesslytreatment should be carefully considered before initiation of Zessly therapy.

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

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

Patients should be tested for HBV infection before initiating treatment with Zessly. 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 Zessly should be closelymonitored for signs and symptoms of active HBV infection throughout therapy and for severalmonths following termination of therapy. Adequate data of treating patients who are carriers of

HBV with antiviral therapy in conjunction with TNF-antagonist therapy to prevent HBVreactivation are not available. In patients who develop HBV reactivation, Zessly should be stoppedand effective antiviral therapy with appropriate supportive treatment should be initiated.

Cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, havebeen observed in the post-marketing experience of infliximab. Isolated cases of liver failureresulting in liver transplantation or death have occurred. Patients with symptoms or signs of liverdysfunction should be evaluated for evidence of liver injury. If jaundice and/or ALTelevations ≥ 5 times the upper limit of normal develop(s), Zessly should be discontinued, and athorough investigation of the abnormality 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 etanerceptalone. Because of the nature of the adverse reactions seen with combination of etanercept andanakinra therapy, similar toxicities may also result from the combination of anakinra and other

TNFα-blocking agents. Therefore, the combination of Zessly 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-antagonistsalone, without increased clinical benefit. The combination of Zessly and abatacept is notrecommended.

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 onebiologic to another, since overlapping biological activity may further increase the risk for adversereactions, including infection.

It is recommended that patients, if possible, be brought up to date with all vaccinations inagreement with current vaccination guidelines prior to initiating infliximab therapy. Patients oninfliximab may receive 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 study 2 a similar proportion ofpatients in each treatment group (methotrexate plus: placebo [n=17], 3 mg/kg [n=27] or 6 mg/kginfliximab [n=46]) mounted an effective two-fold increase in titers to a polyvalent 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 treatmentwith anti-TNF therapies, including infliximab, may elicit a lower immune response than in patientsnot receiving anti-TNF therapy.

In patients receiving anti-TNF therapy, limited data are available on the response to vaccinationwith live vaccines or on the secondary transmission of infection by live vaccines. Use of livevaccines can result in clinical infections, including disseminated infections. The concurrentadministration of live vaccines with Zessly 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. Atwelve month waiting period following birth is recommended before the administration of livevaccines to infants exposed in utero to infliximab. If infant infliximab serum levels are undetectableor infliximab administration was limited to the first trimester of pregnancy, administration of a livevaccine might be considered at an earlier timepoint if there is a clear clinical benefit for theindividual infant (see section 4.6).

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

Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladderinstillation for the treatment of cancer) could result in clinical infections, including disseminatedinfections. It is recommended that therapeutic infectious agents not be given concurrently with

Zessly.

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 Zessly and is positive for antibodies against double-stranded DNA, further treatmentwith Zessly 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 beforeinitiation of Zessly therapy. Discontinuation of Zessly should be considered if these disordersdevelop.

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 incidenceof lymphoma in infliximab-treated patients was higher than expected in the general population, butthe occurrence 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 in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking.

Caution should be exercised in considering treatment of patients with increased risk for malignancydue 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 orwhen considering 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),including infliximab in the post-marketing setting. Approximately half the cases were lymphomas.

The other cases represented a variety of different malignancies and included rare malignanciesusually associated with immunosuppression. A risk for the development of malignancies in patientstreated 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 avery aggressive disease course and is usually fatal. Almost all patients had received treatment with

AZA or 6-MP concomitantly with or immediately prior to a TNF-blocker. The vast majority ofinfliximab cases have occurred in patients with Crohn’s disease or ulcerative colitis and most werereported in adolescent or young adult males. The potential risk with the combination of AZA or 6-

MP and Zessly 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 Zessly, 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 whohad a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regularintervals before therapy and throughout their disease course. This evaluation should includecolonoscopy and biopsies per local recommendations. Current data do not indicate that infliximabtreatment influences the 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.

Zessly should be used with caution in patients with mild heart failure (NYHA class I/II). Patientsshould be closely monitored and Zessly 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, leukopenia, neutropenia, and thrombocytopenia inpatients receiving TNF-blockers, including infliximab. All patients should be advised to seekimmediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias(e.g. persistent fever, bruising, bleeding, pallor). Discontinuation of Zessly therapy should beconsidered in patients with confirmed significant haematologic abnormalities.

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

Failure to respond to treatment for Crohn’s disease may indicate the presence of a fixed fibroticstricture that may require surgical treatment. There is no evidence to suggest that infliximabworsens or causes fibrotic strictures.

The incidence of serious infections in infliximab-treated patients 65 years and older was greaterthan in those under 65 years of age. Some of those had a fatal outcome. Particular attentionregarding the risk 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 patientscompared to 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 Zessly therapy. Paediatric patientson infliximab may receive concurrent vaccinations, except for live vaccines (see sections 4.5and 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),including infliximab in the post-marketing setting. Approximately half the cases were lymphomas.

The other cases represented a variety of different malignancies and included rare malignanciesusually associated with immunosuppression. A risk for the development of malignancies in childrenand adolescents treated with TNF-blockers cannot be excluded.

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

TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a very 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 caseshave 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 and

Zessly 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).

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

Zessly is however, diluted in sodium chloride 9 mg/ml (0.9%) solution for injection. This should betaken into consideration for patients on a controlled sodium diet (see section 6.6).

Polysorbate content

Zessly contains 0.5 mg of polysorbate 80 (E 433) in each vial, which is equivalent to 0.05 mg/ml inthe reconstituted solution. Polysorbates may cause allergic reactions.

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 Zessly with other biological therapeutics used to treat the same conditions as

Zessly, including anakinra and abatacept, is not recommended (see section 4.4).

It is recommended that live vaccines not be given concurrently with Zessly. It is also recommendedthat live vaccines not be given to infants after in utero exposure to infliximab for 12 monthsfollowing birth. If infant infliximab serum levels are undetectable or infliximab administration waslimited to the first trimester of pregnancy, administration of a live vaccine might be considered atan earlier timepoint if there is a clear clinical benefit for the individual infant (see section 4.4).

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

It is recommended that therapeutic infectious agents not be given concurrently with Zessly (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 Zessly 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, doesnot indicate an increase in the rate of malformation in the newborn.

Based on an observational study from Northern Europe, an increased risk (OR, 95% CI; p-value)for C-section (1.50, 1.14-1.96; p = 0.0032), preterm birth (1.48, 1.05-2.09; p = 0.024), small forgestational age (2.79, 1.54-5.04; p = 0.0007), and low birth weight (2.03, 1.41-2.94; p = 0.0002)was observed in women exposed during pregnancy to infliximab (with or 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 normalimmune responses in the newborn. In a developmental toxicity study conducted in mice using ananalogous antibody that selectively inhibits the functional activity of mouse TNFα, there was noindication of maternal 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 mightbe considered at an earlier timepoint if there is a clear clinical benefit for the individual infant.

Cases of agranulocytosis have also been reported (see section 4.8).

Limited data from published literature indicate infliximab has been detected at low levels in 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 beconsidered for use during breast-feeding.

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

Zessly 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 studies, 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 reportedfor infliximab include HBV reactivation, CHF (congestive heart failure), serious infections(including sepsis, opportunistic infections and TB), serum sickness (delayed hypersensitivityreactions), haematologic reactions, systemic lupus erythematosus/lupus-like syndrome,demyelinating disorders, hepatobiliary events, lymphoma, HSTCL, leukaemia, Merkel cellcarcinoma, melanoma, paediatric malignancy, sarcoidosis/sarcoid-like reaction, intestinal orperianal abscess (in Crohn’s disease), and serious infusion reactions (see section 4.4).

Table 1 lists 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: verycommon (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000to < 1/1 000); very rare (< 1/10 000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1

Undesirable effects 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 fungalinfections [pneumocystosis, histoplasmosis, aspergillosis,coccidioidomycosis, cryptococcosis, blastomycosis],bacterial infections [atypical mycobacterial, listeriosis,salmonellosis], and viral infections [cytomegalovirus]),parasitic infections, hepatitis B reactivation.

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

Neoplasms benign, malignantand unspecified (includingcysts and polyps)

Rare: Lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s disease,leukaemia, melanoma, cervical cancer.

Not known: Hepatosplenic T-cell lymphoma (primarily in adolescents andyoung adult males with Crohn’s disease or ulcerative colitis),

Merkel cell carcinoma, Kaposi’s sarcoma.

Blood and lymphaticsystem disorders

Common: Neutropenia, leukopenia, anaemia, lymphadenopathy.

Uncommon: Thrombocytopenia, lymphopenia, lymphocytosis.

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

Common: Allergic respiratory symptom.

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

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

Uncommon: Dyslipidaemia.

P. sychiatric disorders

Common: Depression, insomnia.

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

Rare: Apathy.

Very common: Headache.

Common: Vertigo, dizziness, hypoesthesia, paraesthesia.

Uncommon: Seizure, neuropathy.

Rare: Transverse myelitis, central nervous systemdemyelinating disorders (multiple sclerosis-likedisease and optic neuritis), peripheral demyelinatingdisorders (such as Guillain-Barré syndrome, chronicinflammatory demyelinating polyneuropathy andmultifocal motor neuropathy).

Not known: Cerebrovascular accidents in close temporalassociation with infusion.

Common: Conjunctivitis.

Uncommon: Keratitis, periorbital oedema, hordeolum.

Rare: Endophthalmitis.

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

Common: Tachycardia, palpitation.

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

Rare: Cyanosis, pericardial effusion.

Not known: Myocardial ischaemia/myocardial infarction.

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

Uncommon: Peripheral ischaemia, thrombophlebitis, haematoma.

Rare: Circulatory failure, petechia, vasospasm.

Respiratory, thoracicand mediastinaldisorders

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,lung fibrosis and pneumonitis).

Very common: Abdominal pain, nausea.

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

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

Common: Hepatic function abnormal, transaminases increased.

Uncommon: Hepatitis, hepatocellular damage, cholecystitis.

Rare: Autoimmune hepatitis, jaundice.

Not known: Liver failure.

Skin and subcutaneoustissue disorders

Common: New onset or worsening psoriasis including pustular psoriasis(primarily palm & soles), urticaria, rash, pruritus,hyperhidrosis, dry skin, fungal dermatitis, eczema, alopecia.

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

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

Not known: Worsening of symptoms of dermatomyositis.

Musculoskeletal andconnective tissue disorders

Common: Arthralgia, myalgia, back pain.

Common: Urinary tract infection.

Uncommon: Pyelonephritis.

Reproductive system andbreast disorders

Uncommon: Vaginitis.

General disorders andadministration siteconditions

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, andprocedural complications

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

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

Description of selected adverse drug reactions

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

In a clinical study of patients with rheumatoid arthritis, infusions were to be administered over2 hours for the first 3 infusions. The duration of subsequent infusions could be shortened to not lessthan 40 minutes in patients who did not experience serious infusion reactions. In this trial, sixty sixpercent of the patients (686 out of 1 040) received at least one shortened infusion of 90 minutes orless and 44% of the patients (454 out of 1 040) received at least one shortened infusion of60 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 occurredin 0.4% of patients.

In a clinical study of patients with Crohn’s disease, infusion-related reactions occurredin 16.6% (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.

One serious 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 beenreported, some in close temporal association with infusion of infliximab; cerebrovascular accidentshave also been reported in close temporal association with infusion of infliximab.

A clinical study in patients with moderate to severe psoriasis was designed to assess the efficacyand safety of long-term maintenance therapy versus re-treatment with an induction regimen ofinfliximab (maximum of four infusions at 0, 2, 6, and 14 weeks) following disease flare. Patientsdid not receive any concomitant immunosuppressant therapy. In the re-treatment arm,4% (8/219) of patients experienced a serious infusion reaction versus < 1% (1/222) on maintenancetherapy. The majority of serious infusion reactions occurred during the second infusion at week 2.

The interval between the last maintenance dose and the first re-induction dose ranged from 35-231 days. Symptoms included, but were not limited to, dyspnoea, urticaria, facial oedema, andhypotension. In all cases, infliximab treatment was discontinued and/or other treatment institutedwith complete resolution of signs and symptoms.

In clinical studies delayed hypersensitivity reactions have been uncommon and have occurred afterinfliximab-free intervals of less than 1 year. In the psoriasis studies, delayed hypersensitivityreactions occurred early in the treatment course. Signs and symptoms included myalgia and/orarthralgia with fever and/or rash, with some patients experiencing pruritus, facial, hand or lipoedema, dysphagia, urticaria, sore throat and headache.

There are insufficient data on the incidence of delayed hypersensitivity reactions after infliximab-free intervals of more than 1 year but limited data from clinical studies suggest an increased risk 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, the incidence ofserum sickness-like reactions was 2.4%.

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

In clinical studies using single and multiple infliximab doses ranging from 1 to 20 mg/kg,antibodies to infliximab were detected in 14% of patients with any immunosuppressant therapy, andin 24% of patients without immunosuppressant therapy. In rheumatoid arthritis patients whoreceived the recommended repeated treatment dose regimens with methotrexate, 8% of patientsdeveloped antibodies to infliximab. In psoriatic arthritis patients who received 5 mg/kg with andwithout methotrexate, antibodies occurred overall in 15% of patients (antibodies occurred in 4% ofpatients receiving methotrexate and in 26% of patients not receiving methotrexate at baseline). In

Crohn's disease patients who received maintenance treatment, antibodies to infliximab occurredoverall in 3.3% 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 theabsence of concomitant immunomodulators, approximately 28% developed antibodies to infliximab(see section 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 theseinfections have been fatal; the most frequently reported opportunistic infections with a mortalityrate of > 5% include pneumocystosis, candidiasis, listeriosis and aspergillosis (see section 4.4).

In clinical studies 36% of infliximab-treated patients were treated for infections comparedwith 25% of placebo-treated patients.

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

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

Some of the cases have resulted in a fatal outcome. Nearly 50% of reported deaths have 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 withno lymphomas 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 developedmalignancies, including 1 lymphoma. The median duration of follow-up was 0.8 years (incidence5.7% [95% CI 2.65%-10.6%]. There was one reported malignancy amongst 77 control patients(median duration of follow-up 0.8 years; incidence 1.3% [95% CI 0.03%-7.0%]). The majority ofthe malignancies developed 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 orthe general population, including those over 60 years of age (see section 4.4).

In addition, post-marketing cases of hepatosplenic T-cell lymphoma have been reported in 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 treatedwith the higher dose of 10 mg/kg (i.e. twice the maximum approved dose). In this study150 patients with NYHA Class III-IV CHF (left ventricular ejection fraction ≤ 35%) were treatedwith 3 infusions of infliximab 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 38 weeks, 9 of101 patients treated with infliximab (2 at 5 mg/kg and 7 at 10 mg/kg) died compared to one deathamong the 49 patients on placebo.

There have been post-marketing reports of worsening heart failure, with and without identifiableprecipitating factors, in patients taking infliximab. There have also been post-marketing reports ofnew onset heart failure, including heart failure in patients without known pre-existingcardiovascular disease. 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 infliximabthan in controls, both when infliximab was given as monotherapy and when it was used incombination with other immunosuppressive agents. Most aminotransferase abnormalities weretransient; however, a small number of patients experienced more prolonged elevations. In general,patients who developed ALT and AST elevations were asymptomatic, and the abnormalitiesdecreased or resolved with either continuation or discontinuation of infliximab, or modification ofconcomitant therapy. In post-marketing surveillance, cases of jaundice and hepatitis, some withfeatures of autoimmune hepatitis, have been reported in patients receiving infliximab (seesection 4.4).

Table 2

Proportion of patients with increased ALT activity in clinical studies

Number of patients Median follow-up

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

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

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

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

Crohn’sdisease

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

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

Ulcerativecolitis

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

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

Plaque 281 1,175 16.1 50.1 0.4% 7.7% 0.0% 3.4%psoriasis1 Placebo patients received methotrexate while infliximab patients received both infliximaband methotrexate.

2 Placebo patients in the two Phase III studies in Crohn’s disease, received an initial dose of5 mg/kg infliximab at study start and were on placebo in the maintenance phase. Patientswho were randomised to the placebo maintenance group and then later crossed over toinfliximab are included in the infliximab group in the ALT analysis. In the Phase IIIb trial in

Crohn’s disease, placebo patients received AZA 2.5 mg/kg/day as active control in additionto 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 a 3-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(2 of which were among the serious infusion reactions). In the 6 mg/kg group, 2 out of 57 patientshad a serious 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 receivingplacebo over 14 weeks (see section 4.4).

The following adverse reactions were reported more commonly in paediatric Crohn’s diseasepatients (see section 5.1) than in adult Crohn’s disease patients: anaemia (10.7%), blood instool (9.7%), leukopenia (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, bonefracture (6.8%) was reported, however, a causal association has not been established. Other specialconsiderations are discussed below.

In the paediatric Crohn’s disease study, 17.5% of randomised patients experienced 1 or moreinfusion reactions. There were no serious infusion reactions, and 2 subjects in the paediatric

Crohn’s disease study had non-serious anaphylactic reactions.

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

In the paediatric Crohn’s disease study, infections were reported in 56.3% of randomised subjectstreated with infliximab. Infections were reported more frequently for subjects whoreceived q8 week as opposed to q12 week infusions (73.6% and 38.0%, respectively), while seriousinfections were reported for 3 subjects in the q8 week and 4 subjects in the q12 week maintenancetreatment group. The most commonly reported infections were upper respiratory tract infection andpharyngitis, and the most commonly reported serious infection was abscess. Three cases ofpneumonia (1 serious) and 2 cases of herpes zoster (both non-serious) were reported.

Overall, the adverse reactions reported in the paediatric ulcerative colitis trial and adult ulcerativecolitis studies were generally consistent. In the paediatric ulcerative colitis trial, the most commonadverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, andheadache. 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 of22 (18.2%) in the q8 week and 3 of 23 (13.0%) in the q12 week treatment maintenance group. Noserious infusion 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 the paediatric ulcerative colitis trialand 22 (36.7%) required oral or parenteral antimicrobial treatment. The proportion of patients withinfections in the paediatric ulcerative colitis trial was similar to that in the paediatric Crohn’sdisease study but higher than the proportion in the adults’ ulcerative colitis studies. The overallincidence of infections in the paediatric ulcerative colitis trial was 13/22 (59%) in the every 8 weekmaintenance treatment group and 14/23 (60.9%) in the every 12 week maintenance treatmentgroup. Upper respiratory tract infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the mostfrequently reported respiratory system infections. Serious infections were reported in 12% (7/60) ofall treated patients.

In this study, there were more patients in the 12 to 17 year age group than in the 6 to 11 year agegroup (45/60 [75.0%]) vs.15/60 [25.0%]). While the numbers of patients in each subgroup are toosmall to make any definitive conclusions about the effect of age on safety events, there were higherproportions of patients with serious adverse events and discontinuation due to adverse events in theyounger age group than in the older age group. While the proportion of patients with infections wasalso higher in the younger age group, for serious infections, the proportions were similar in the twoage groups. Overall proportions of adverse events and infusion reactions were similar between the6 to 11 and 12 to 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).

Additional information on special populations

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 ofage (4.6%). In patients treated with methotrexate alone, the incidence of serious infections was5.2% in patients 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 administeredwithout toxic effects.

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

ATC code: L04AB02.

Zessly 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 (TNFß).

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

TNFα bioactivity.

Elevated concentrations of TNFα have been found in the joints of rheumatoid arthritis patients 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 withuntreated patients’ cells. In psoriasis patients, treatment with infliximab resulted in decreases inepidermal inflammation and normalisation of keratinocyte differentiation in psoriatic plaques. Inpsoriatic arthritis, short-term treatment with infliximab reduced the number of T-cells and bloodvessels in the synovium 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 bybiopsy of the intestinal mucosa showed that infliximab treatment caused a reduction in the numberof cells capable of expressing TNFα and interferon γ. Additional histological studies providedevidence that treatment with infliximab reduces the infiltration of inflammatory cells into affectedareas of the intestine and the presence of inflammation markers at these sites. Endoscopic studies ofintestinal mucosa have shown evidence of mucosal healing in infliximab-treated patients.

Adult rheumatoid arthritis

The efficacy of infliximab was assessed in two multicentre, randomised, double-blind, pivotalclinical studies. In both studies concurrent use of stable doses of folic acid, oral corticosteroids(≤ 10 mg/day) and/or non-steroidal anti-inflammatory drugs (NSAIDs) was permitted.

The primary endpoints were the reduction of signs and symptoms as assessed by the American

College of Rheumatology criteria (ACR20 for study 1 (described below), landmark ACR-N forstudy 2 (described below)), the prevention of structural joint damage, and the improvement inphysical function. A reduction in signs and symptoms was defined to be at leasta 20% improvement (ACR20) in both tender and swollen joint counts, and in 3 of the following5 criteria: (1) evaluator’s global assessment, (2) patient’s global assessment, (3)functional/disability measure, (4) visual analogue pain scale and (5) erythrocyte sedimentation rateor C-reactive protein. ACR-N uses the same criteria as the ACR20, calculated by taking the lowestpercent improvement in swollen joint count, tender joint count, and the median of the remaining5 components of the ACR response. Structural joint damage (erosions and joint space narrowing) inboth hands and feet was measured by the change from baseline in the total van der Heijde-modified

Sharp score (0-440). The Health Assessment Questionnaire (HAQ; scale 0-3) was used to measurepatients’ average change from baseline scores over time, in physical function.

Study 1 evaluated responses at 30, 54 and 102 weeks in a placebo-controlled study of 428 patientswith active rheumatoid arthritis despite treatment with methotrexate. Approximately 50% ofpatients were in functional Class III. Patients received placebo, 3 mg/kg or 10 mg/kg infliximabat weeks 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 oftreatment withdrawals, the magnitude of the effect difference between infliximab and themethotrexate alone group cannot be defined.

Table 3

Effects on ACR20, structural joint damage and physical function at week 54, study 1infliximabb

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

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

Patients evaluated (%)

Total scored (van der

Heijde-modified Sharpscore)

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

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 for6 months prior to enrolment and were to remain on stable doses throughout the study.

Concurrent use of stable doses of oral corticosteroids (≤ 10 mg/day) and/or NSAIDs waspermitted, and folate supplementation was given.

b all infliximab doses given in combination with methotrexate and folate with some oncorticosteroids and/or NSAIDsc p < 0.001, for each infliximab treatment group vs. controld greater values indicate more joint damage.e HAQ = Health Assessment Questionnaire; greater values indicate less disability.

Study 2 evaluated responses at 54 weeks in 1 004 methotrexate naive patients with early (≤ 3 yearsdisease duration, median 0.6 years) active rheumatoid arthritis (median swollen and tender jointcount of 19 and 31, respectively). All patients received methotrexate (optimised to 20 mg/wk 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 study 2, 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, study 2infliximab + MTX

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

Subjects randomised 282 359 363 722

Percentage ACR improvement

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

Change from baseline in total van der

Heijde-modified Sharp scoreb

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

Median 0.43 0.00 0.00 0.00

Improvement from baseline in HAQaveraged over time from week 30 toweek 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 study 1, study 2 and study 3.

Study 3 was a randomised, multicenter, double-blind, 3-arm, parallel-group safety study. In one ofthe 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 notrequire any dose titration. Of the patients who required a dose titration, 80% achieved clinicalresponse and the 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 with therecommended dose of infliximab 5 mg/kg. All patients had experienced an inadequate response toprior 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, definedas a decrease in CDAI by ≥ 70 points from baseline at the 4-week evaluation and without anincrease in the use of medicinal products or surgery for Crohn’s disease. Patients who responded atweek 4 were followed to week 12. Secondary endpoints included the proportion of patients inclinical remission at week 4 (CDAI < 150) and clinical response over time.

At week 4, following administration of a single dose, 22/27 (81%) of infliximab-treated 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 clinicalremission (CDAI < 150) vs. 1/25 (4%) of placebo-treated patients. A response was observed within2 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 (study 4).

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%) weredefined as 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 treatmentgroups; a placebo maintenance group, 5 mg/kg maintenance group and 10 mg/kg maintenancegroup. All 3 groups received repeated infusions at week 2, 6 and every 8 weeks thereafter.

Of the 573 patients randomised, 335 (58%) achieved clinical response by week 2. These patientswere classified as week-2 responders and were included in the primary analysis (see Table 5).

Among patients classified as non-responders at week 2, 32% (26/81) in the placebo maintenancegroup and 42% (68/163) in the infliximab group achieved clinical response by week 6. There wasno difference between 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 in patients with moderately to severely active Crohn’sdisease, data from study 4 (week-2 responders)

Study 4 (week-2 responders)% of Patients

Placebo infliximab infliximab

Maintenance Maintenance Maintenance(n = 110) 5 mg/kg 10 mg/kg(n = 113) (n = 112)(p value) (p value)

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

Week 30 27.3 51.3 59.1

Clinical Responsea (< 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 15.5 38.1 47.7

Clinical Responsea (< 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 priorto week 54 among 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 whichthey were originally randomised. Eighty nine percent (50/56) of patients who lost clinical responseon infliximab 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 comparatorstudy 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 werereceiving budesonide, and 54.3% of patients were receiving 5-ASA compounds. Patients wererandomised to receive AZA monotherapy, infliximab monotherapy, or infliximab plus AZAcombination therapy. Infliximab was administered at a dose of 5 mg/kg at weeks 0, 2, 6, and thenevery 8 weeks. AZA was given at a dose of 2.5 mg/kg daily.

The primary endpoint of the study was corticosteroid-free clinical remission at week 26, defined aspatients in clinical remission (CDAI of < 150) who, for at least 3 weeks, had not taken oralsystemic corticosteroids (prednisone or equivalent) or budesonide at a dose > 6 mg/day. For resultssee Table 6. The proportions of patients with mucosal healing at week 26 were significantly greaterin the infliximab plus AZA combination (43.9%, p < 0.001) and infliximab monotherapy groups(30.1%, p = 0.023) compared to the AZA monotherapy group (16.5%).

Table 6

Percent of patients with Crohn’s disease achieving corticosteroid-free clinical remission atweek 26

AZA Monotherapy infliximab infliximab + AZA

Monotherapy Combination Therapy

Week 26

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

* P-values represent each infliximab treatment group vs. AZA monotherapy.

Similar trends in the achievement of corticosteroid-free clinical remission were observed atweek 50. Furthermore, improved quality of life as measured by IBDQ was observed withinfliximab.

The efficacy was assessed in a randomised, double-blinded, placebo-controlled study in 94 patientswith fistulising Crohn’s disease who had fistulas that were of at least 3 months’ duration. Thirty oneof these 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 patientscontinued to receive at least one of these therapies. Patients received three doses of either placeboor infliximab at weeks 0, 2, and 6. Patients were followed up to 26 weeks. The primary endpointwas the proportion of patients who experienced a clinical response, defined as ≥ 50% reductionfrom baseline in the number of fistulae draining upon gentle compression on at least twoconsecutive visits (4 weeks apart), without an increase in the use of medicinal products or surgeryfor Crohn’s disease.

Sixty eight percent (21/31) of infliximab-treated patients receiving a 5 mg/kg dose regimenachieved a clinical response vs. 26% (8/31) placebo-treated patients (p = 0.002). The median timeto onset of response in the infliximab-treated group was 2 weeks. The median duration of responsewas 12 weeks. Additionally, closure of all fistulae was achieved in 55% of infliximab-treatedpatients compared with 13% 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 (clinical Study 5). A total of 306 patients received 3 doses ofinfliximab 5 mg/kg at week 0, 2, and 6. At baseline, 87% of the patients had perianal fistulae,14% had abdominal fistulae, 9% had rectovaginal fistulae. The median CDAI score was 180. Atweek 14, 282 patients were assessed for clinical response and randomised to receive either placeboor 5 mg/kg infliximab every 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 in patients with fistulising Crohn’s disease, data from study 5 (week-14 responders)

Study 5 (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 patientswith sustained closure of all fistulas through week 54, for symptoms such as proctalgia, abscessesand urinary 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 corticosteroiduse and improvements in quality of life were observed.

The safety and efficacy of infliximab were assessed in two (studies 6 and 7) 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/orimmunomodulatory agents were permitted. In both studies, patients were randomised to receiveeither placebo, 5 mg/kg infliximab, or 10 mg/kg infliximab at weeks 0, 2, 6, 14, and 22, and instudy 6 at weeks 30, 38, and 46. Corticosteroid taper was permitted after week 8.

Table 8

Effects on clinical response in adult patients with moderately to severely active ulcerativecolitis, clinical remission and mucosal healing at weeks 8 and 30. Combined data from studies6 & 7infliximab

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 19.3% 45.0% 49.6% 47.3%(clinical response at bothweek 8 and week 30)a

Percentage of subjects in clinical remission and sustained remission

Clinical remission at week 8a 10.2% 36.4% 29.8% 33.1%

Clinical remission at week 30a 13.1% 29.8% 36.4% 33.1%

Sustained remission 5.3% 19.0% 24.4% 21.7%(in remission at both week 8and week 30)a

Percentage of subjects with mucosal healing

Mucosal healing at week 8a 32.4% 61.2% 60.3% 60.7%

Mucosal healing at week 30a 27.5% 48.3% 52.9% 50.6%a p < 0.001, for each infliximab treatment group vs. placebo.

The efficacy of infliximab through week 54 was assessed in study 6. At 54 weeks, 44.9% ofpatients in the combined infliximab treatment group were in clinical response compared to 19.8% inthe placebo treatment group (p < 0.001). Clinical remission and mucosal healing occurred in agreater proportion of patients in the combined infliximab treatment group compared to the placebotreatment 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 todiscontinue corticosteroids while remaining in clinical remission compared to the placebo treatmentgroup at both week 30 (22.3% vs. 7.2%, p < 0.001, pooled study 6 & study 7 data) andweek 54 (21.0% vs. 8.9%, p = 0.022, study 6 data).

The pooled data analysis from study 6 and study 7 and their extensions, analysed from baselinethrough 54 weeks, demonstrated a reduction of ulcerative colitis-related hospitalisations andsurgical procedures with infliximab treatment. The number of ulcerative colitis-relatedhospitalisations was significantly lower in the 5 and 10 mg/kg infliximab treatment groups than inthe placebo group (mean number of hospitalisations per 100 subject-years: 21 and 19 vs. 40 in theplacebo group; p = 0.019 and p = 0.007, respectively). The number of ulcerative colitis-relatedsurgical procedures was also lower in the 5 and 10 mg/kg infliximab treatment groups than in theplacebo group (mean number of surgical procedures per 100 subject-years: 22 and 19 vs. 34;p = 0.145 and p = 0.022, respectively).

The proportion of subjects who underwent colectomy at any time within 54 weeks following thefirst infusion of study agent were collected and pooled from study 6 and study 7 and theirextensions. Fewer subjects underwent colectomy in the 5 mg/kg infliximab group (28/242 or11.6% [N.S.]) and the 10 mg/kg infliximab group (18/242 or 7.4% [p = 0.011]) than in the placebogroup (36/244; 14.8%).

The reduction in incidence of colectomy was also examined in another randomised, double-blindstudy 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 forcolectomy. Significantly fewer colectomies occurred within 3 months of study infusion in patientswho received a single dose of 5 mg/kg infliximab compared to patients who received placebo(29.2% vs. 66.7% respectively, p = 0.017).

In study 6 and study 7, 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-controlled studies 8 and 9 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, (study 8), 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 ofthe study, 53 patients continued into an open-label extension to week 102.

In the second clinical study, (study 9), 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 weeksto week 24. Thereafter, all subjects continued on infliximab every 6 weeks to week 96. Group 1received 5 mg/kg infliximab. In group 2, starting with the week 36 infusion, patients who had a

BASDAI ≥ 3 at 2 consecutive visits, received 7.5 mg/kg infliximab every 6 weeks thereafterthrough week 96.

In the second clinical study (study 9), improvement in signs and symptoms was observed as early asweek 2. At week 24, the number of ASAS 20 responders was 15/78 (19%) in the placebo group,and 123/201 (61%) in the 5 mg/kg infliximab group (p < 0.001). There were 95 subjects fromgroup 2 who continued on 5 mg/kg every 6 weeks. At 102 weeks there were 80 subjects still oninfliximab treatment and among those, 71 (89%) were ASAS 20 responders.

In the first study, (study 8), improvement in signs and symptoms was also observed as early asweek 2. At week 12, the number of BASDAI 50 responders were 3/35 (9%) in the placebo group,and 20/35 (57%) in the 5 mg/kg group (p < 0.01). There were 53 subjects who continued on5 mg/kg every 6 weeks. At 102 weeks there were 49 subjects still on infliximab treatment andamong 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 (studies 10 and 11).

In the first clinical study, (study 10), efficacy and safety of infliximab were studied in 104 patientswith active polyarticular psoriatic arthritis. During the 16-week double-blind phase, patientsreceived either 5 mg/kg infliximab or placebo at weeks 0, 2, 6, and 14 (52 patients in each group).

Starting at week 16, placebo patients were switched to infliximab and all patients subsequentlyreceived 5 mg/kg infliximab every 8 weeks up to week 46. After the first year of the study,78 patients continued into an open-label extension to week 98.

In the second clinical study, (study 11), efficacy and safety of infliximab were studied in200 patients with active psoriatic arthritis (≥ 5 swollen joints and ≥ 5 tender joints).

Forty six percent of patients continued on stable doses of methotrexate (≤ 25 mg/week). During the24-week double-blind phase, patients received either 5 mg/kg infliximab or placebo at weeks 0, 2,6, 14, and 22 (100 patients in each group). At week 16, 47 placebo patients with < 10%improvement from baseline in both swollen and tender joint counts were switched to infliximabinduction (early escape). At week 24, all placebo-treated patients crossed over to infliximabinduction. Dosing continued for all patients through week 46.

Key efficacy results for study 10 and study 11 in patients with active psoriatic arthritis are shown in

Table 9 below:

Table 9

Effects on ACR and PASI in patients with active psoriatic arthritis, data from study 10 andstudy 11

Study 10 Study 11*

Placebo infliximab infliximab Placebo infliximab infliximab(week 16) (week 16) (week 98) (week 24) (week 24) (week 54)

Patients randomised 52 52 N/Aa 100 100 100

ACR response(% of patients)

N 52 52 78 100 100 100

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

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

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

PASI response(% of patients)b

N 87 83 82

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

* ITT-analysis where subjects with missing data were included as non-responders.a Week 98 data for study 10 includes combined placebo crossover and infliximab patients whoentered the open-label extension.b Based on patients with PASI ≥ 2.5 at baseline for study 10, and patients with ≥ 3% BSApsoriasis skin involvement at baseline in study 11.

** PASI 75 response for study 10 not included due to low N; p < 0.001 for infliximab vs. placeboat week 24 for study 11.

In study 10 and study 11 in patients with active psoriatic arthritis, clinical responses were observedas early as week 2 and were maintained through week 98 and week 54 respectively. Efficacy hasbeen demonstrated with or without concomitant use of methotrexate. Decreases in parameters ofperipheral activity characteristic of psoriatic arthritis (such as number of swollen joints, number ofpainful/tender joints, dactylitis and presence of enthesopathy) were seen in the infliximab-treatedpatients.

Radiographic changes were assessed in study 11. 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 assessedby HAQ. Significant improvements in health-related quality of life were also demonstrated asmeasured by the physical and mental component summary scores of the SF-36 in study 11.

The efficacy of infliximab was assessed in two multicenter, randomised, double-blind studies 12and 13. 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.

Study 12 evaluated the efficacy of infliximab induction therapy in 249 patients with plaquepsoriasis that had previously received PUVA or systemic therapy. Patients received either 3 or5 mg/kg infliximab or placebo infusions at weeks 0, 2 and 6. Patients with a PGA score ≥ 3 wereeligible to receive an additional infusion of the same treatment at week 26.

In study 12 in patients with plaque psoriasis, the proportion of patients achieving PASI 75 atweek 10 was 71.7% in the 3 mg/kg infliximab group, 87.9% in the 5 mg/kg infliximab group, and5.9% in the placebo group (p < 0.001). By week 26, twenty weeks after the last induction dose,30% of patients in the 5 mg/kg group and 13.8% of patients in the 3 mg/kg group were PASI75 responders. Between weeks 6 and 26, symptoms of psoriasis gradually returned with a mediantime to disease relapse of > 20 weeks. No rebound was observed.

Study 13 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 6 followed by maintenance therapy every 8 weeks through week 22 in the placebo group andthrough week 46 in the infliximab group. At week 24, the placebo group crossed over to infliximabinduction therapy (5 mg/kg) followed by infliximab maintenance therapy (5 mg/kg). Nail psoriasiswas assessed using the Nail Psoriasis Severity Index (NAPSI). Prior therapy with PUVA,methotrexate, ciclosporin, or acitretin had been received by 71.4% of patients, although they werenot necessarily therapy resistant. Key results are presented in Table 10. In infliximab treatedsubjects, significant PASI 50 responses were apparent at the first visit (week 2) and PASI 75responses by the second visit (week 6). Efficacy was similar in the subgroup of patients that wereexposed to previous systemic therapies compared to the overall study population.

Table 10

Summary of PASI response, PGA response and percent of patients with all nails cleared at weeks 10,24, and 50. Study 13

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

Week 24

N 77 276≥ 90% improvement 1 (1.3%) 161 (58.3%)a≥ 75% improvement 3 (3.9%) 227 (82.2%)a≥ 50% improvement 5 (6.5%) 248 (89.9%)

PGA of cleared (0) or minimal (1) 2 (2.6%) 203 (73.6%)a

PGA of cleared (0), minimal (1), or mild (2) 15 (19.5%) 246 (89.1%)a

Week 50

N 68 281≥ 90% improvement 34 (50.0%) 127 (45.2%)≥ 75% improvement 52 (76.5%) 170 (60.5%)≥ 50% improvement 61 (89.7%) 193 (68.7%)

PGA of cleared (0) or minimal (1) 46 (67.6%) 149 (53.0%)

PGA of cleared (0), minimal (1), or mild (2) 59 (86.8%) 189 (67.3%)

All nails clearedc

Week 10 1/65 (1.5%) 16/235 (6.8%)

Week 24 3/65 (4.6%) 58/223 (26.0%)a

Week 50 27/64 (42.2%) 92/226 (40.7%)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). Meanbaseline NAPSI scores were 4.6 and 4.3 in infliximab and placebo group.

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

In the paediatric Crohn’s disease study 14, 112 patients (6 to 17 years, median age 13.0 years) withmoderate to severe, active Crohn’s disease (median paediatric CDAI of 40) and an inadequateresponse to conventional therapies were to receive 5 mg/kg infliximab at weeks 0, 2, and 6. Allpatients were required to be on a stable dose of 6-MP, AZA or MTX (35% were also receivingcorticosteroids at baseline). Patients assessed by the investigator to be in clinical response atweek 10 were randomised and received 5 mg/kg infliximab at either q8 weeks or q12 weeks as amaintenance treatment regimen. If response was lost during maintenance treatment, crossing over toa higher dose (10 mg/kg) and/or shorter dosing interval (q8 weeks) was allowed. Thirty two (32)evaluable paediatric patients crossed over (9 subjects in the q8 weeks and 23 subjects in theq12 weeks maintenance groups). Twenty four of these patients (75.0%) regained clinical responseafter 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, thefigures were 55.8% (29/52) and 23.5% (12/51) in the q8 weeks and q12 weeks maintenance groups,respectively (p < 0.001). Data about fistulas were derived from PCDAI scores. Of the 22 subjectsthat had fistulas at baseline, 63.6% (14/22), 59.1% (13/22) and 68.2% (15/22) were in completefistula response at week 10, 30, and 54, respectively, in the combined q8 weeks and q12 weeksmaintenance groups.

In addition, statistically and clinically significant improvements in quality of life and height, as wellas a 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 15 in 60 paediatric patients aged 6 through 17 years (median age14.5 years) with moderately to severely active ulcerative colitis (Mayo score of 6 to 12; endoscopicsubscore ≥ 2) with an inadequate response to conventional therapies. At baseline 53% of patientswere receiving immunomodulator therapy (6-MP, AZA and/or MTX) and 62% of patients werereceiving 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 returnedfor safety follow-up. At week 8, 45 patients were randomised and received 5 mg/kg infliximab ateither q8 weeks or q12 weeks as a maintenance treatment regimen.

The proportion of patients in clinical response at week 8 was 73.3% (44/60). Clinical response atweek 8 was similar between those with or without concomitant immunomodulator use at baseline.

Clinical remission at week 8 was 33.3% (17/51) as measured by the Paediatric Ulcerative Colitis

Activity Index (PUCAI) score.

At week 54, the proportion of patients in clinical remission as measured by the PUCAI score was38% (8/21) in the q8 week maintenance group and 18% (4/22) in the q12 week maintenancetreatment group. For patients receiving corticosteroids at baseline, the proportion of patients inremission and not receiving corticosteroids at week 54 was 38.5% (5/13) for the q8 week and0% (0/13) for the q12 week maintenance treatment group.

In this study, there were more patients in the 12 to 17 year age group than in the 6 to 11 year agegroup (45/60 vs. 15/60). While the numbers of patients in each subgroup are too small to drawdefinitive conclusions about the effect of age, there was a higher number of patients in the youngerage group who 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 withthe reference 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 thevascular compartment. No time-dependency of the pharmacokinetics was observed. The eliminationpathways for infliximab have not been characterised. Unchanged infliximab was not detected inurine. No major age- or weight-related differences in clearance or volume of distribution wereobserved in rheumatoid arthritis patients. The pharmacokinetics of infliximab in elderly patients hasnot been studied. Studies have not been performed in patients with liver or renal disease.

At single doses of 3, 5, or 10 mg/kg, the median Cmax values were 77, 118, and 277 micrograms/ml,respectively. The median terminal half-life at these doses ranged from 8 to 9.5 days. In mostpatients, infliximab could be detected in the serum for at least 8 weeks after the recommendedsingle dose of 5 mg/kg for Crohn’s disease and the rheumatoid arthritis maintenance dose of3 mg/kg every 8 weeks.

Repeated administration of infliximab (5 mg/kgat 0, 2, and 6 weeks in fistulising Crohn’s disease, 3or 10 mg/kg every 4 or 8 weeks in rheumatoid arthritis) resulted in a slight accumulation ofinfliximab in serum after the second dose. No further clinically relevant accumulation wasobserved. In most fistulising Crohn’s disease patients, infliximab was detected in serum for12 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 infliximabwas dependent on body weight in a non-linear way. Following administration of 5 mg/kg infliximabevery 8 weeks, the predicted median steady-state infliximab exposure (area under concentration-time curve at steady state, AUCss) in paediatric patients aged 6 years to 17 years wasapproximately 20% lower than the predicted median steady-state drug exposure in adults. Themedian AUCss in paediatric patients aged 2 years to less than 6 years was predicted to beapproximately 40% lower than that in adults, although the number of patients supporting thisestimate is limited.

Infliximab does not cross react with TNFα from species other than human and chimpanzee.

Therefore, conventional preclinical safety data with infliximab are limited. In a developmentaltoxicity study conducted in mice using an analogous antibody that selectively inhibits the functionalactivity of mouse TNFα, there was no indication of maternal toxicity, embryotoxicity orteratogenicity. In a fertility and general reproductive function study, the number of pregnant micewas reduced following administration of the same analogous antibody. It is not known whether thisfinding was due to effects on the males and/or the females. In a 6-month repeated dose toxicitystudy in mice, using the same analogous antibody against mouse TNFα, crystalline deposits wereobserved on the lens capsule of some of the treated male mice. No specific ophthalmologicexaminations have been performed in patients to investigate the relevance of this finding forhumans.

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

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

Disodium succinate hexahydrate

Succinic acid

Sucrose

Polysorbate 80 (E 433)

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

Before reconstitution4 years at 2 °C - 8 °C.

Zessly may be stored at temperatures up to a maximum of 30 °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, Zessly must not be returned to refrigerated storage.

Chemical and physical in use stability of the reconstituted solution has been demonstrated for24 hours at 2 °C - 30 °C. From a microbiological point of view, the product should be used as soonas possible but within 3 hours of reconstitution and dilution. If not used immediately, in use storagetimes and conditions prior to use are the responsibility of the user and should not be longer than24 hours at 2 °C - 8 °C.

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

For storage conditions up to 30 °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 rubber stopper and aluminium crimp protected by a plastic cap.

Zessly is available in packs containing 1, 2, 3, 4 or 5 vials.

Not all pack sizes may be marketed.

1. Calculate the dose and the number of Zessly vials needed. Each Zessly vial contains 100 mginfliximab. Calculate the total volume of reconstituted Zessly solution required.

2. Under aseptic conditions, reconstitute each Zessly vial with 10 ml of water for injections,using a syringe equipped with a 21-gauge (0.8 mm) or smaller needle. Remove flip-top fromthe vial and wipe the top with a 70% alcohol swab. Insert the syringe needle into the vialthrough the centre of the rubber stopper and direct the stream of water for injections to theglass wall of the vial. Gently swirl the solution by rotating the vial to dissolve the lyophilisedpowder. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming of the solutionon reconstitution is not unusual. Allow the reconstituted solution to stand for 5 minutes.

Check that the solution is colourless to light brown and opalescent. The solution may developa few fine translucent particles, as infliximab is a protein. Do not use if opaque particles,discolouration, or other foreign particles are present.

3. Dilute the total volume of the reconstituted Zessly solution dose to 250 ml with sodiumchloride 9 mg/ml (0.9%) solution for injection. Do not dilute the reconstituted Zessly solutionwith any other diluent. The dilution can be accomplished by withdrawing a volume of thesodium chloride 9 mg/ml (0.9%) solution for injection from the 250-ml glass bottle orinfusion bag equal to the volume of reconstituted Zessly. Slowly add the total volume ofreconstituted Zessly solution to the 250-ml infusion bottle or bag. Gently mix. If storedrefrigerated after reconstitution and dilution, the infusion solution must be allowed toequilibrate at room temperature to 25°C for 3 hours prior to Step 4 (infusion).

4. Administer the infusion solution over a period of not less than the infusion timerecommended (see section 4.2). Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 1.2 micrometre or less). Since no preservativeis present, it is recommended that the administration of the solution for infusion is to bestarted as soon as possible and within 3 hours of reconstitution and dilution. Whenreconstitution and dilution are performed under aseptic conditions, Zessly infusion solutioncan be used within 24 hours if stored at 2 °C - 8 °C. Do not store any unused portion of theinfusion solution for reuse.

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

6. Visually inspect Zessly for particulate matter or discolouration prior to administration. Donot use if visibly opaque particles, discolouration or foreign particles are observed.

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

Sandoz GmbH

Biochemiestr. 106250 Kundl

Austria

EU/1/18/1280/001

EU/1/18/1280/002

EU/1/18/1280/003

EU/1/18/1280/004

EU/1/18/1280/005

Date of first authorisation: 18 May 2018

Date of latest renewal: 28 November 2022

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

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