REMSIMA 120mg / ml injectible solution medication leaflet

Remsima 120 mg solution for injection in pre-filled syringe

Remsima 120 mg solution for injection in pre-filled pen

Remsima 120 mg solution for injection in pre-filled syringe

Each 1 mL single dose pre-filled syringe contains 120 mg of infliximab*.

Remsima 120 mg solution for injection in pre-filled pen

Each 1 mL single dose pre-filled pen contains 120 mg of infliximab*.

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

Sorbitol 45 mg per 1 mL

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear to opalescent, colourless to pale brown solution.

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

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

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

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

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

Remsima is indicated for:

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

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

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

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

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

Remsima 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).

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

Remsima treatment is to be initiated and supervised by qualified physicians experienced in thediagnosis and treatment of conditions for which Remsima is indicated. Patients treated with Remsimashould be given the package leaflet and the patient reminder card. Instruction for use is provided in thepackage leaflet.

For subsequent injections and after proper training in subcutaneous injection technique, patients mayself-inject with Remsima if their physician determines that it is appropriate and with medical follow-up as necessary. Suitability of the patient for subcutaneous home use should be assessed and patientsshould be advised to inform their healthcare professional if they experience symptoms of an allergicreaction before administering the next dose. Patients should seek immediate medical attention ifdeveloping symptoms of serious allergic reactions (see section 4.4).

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

It is important to check the product labels to ensure that the correct formulation (intravenous orsubcutaneous) is being administered to the patient, as prescribed. Remsima subcutaneous formulationis not intended for intravenous administration and should be administered via a subcutaneous injectiononly.

Treatment with Remsima subcutaneous formulation should be initiated with loading doses ofinfliximab which may be intravenous or subcutaneous. When subcutaneous loading is used, Remsima120 mg should be given as a subcutaneous injection followed by additional subcutaneous injections at1, 2, 3 and 4 weeks after the first injection, then every 2 weeks thereafter. If intravenous loading dosesof infliximab are given to initiate treatment, 2 intravenous infusions of infliximab 3 mg/kg should begiven 2 weeks apart. The first treatment with Remsima administered subcutaneously should beinitiated as maintenance therapy 4 weeks after the second intravenous administration. Therecommended maintenance dose for Remsima subcutaneous formulation is 120 mg once every 2weeks.

Remsima must be given concomitantly with methotrexate.

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

Continued therapy should be carefully reconsidered in patients who show no evidence of therapeuticbenefit within the first 12 weeks of treatment (see section 5.1).

The first treatment with Remsima administered subcutaneously should be initiated as maintenancetherapy 4 weeks after the last administration of intravenous infusions. Before initiating treatment with

Remsima subcutaneous formulation, 2 intravenous infusions of infliximab 5 mg/kg should be given at2 weeks apart, and an additional intravenous infusion of infliximab 5 mg/kg may be given 4 weeksafter the second infusion. The recommended maintenance dose for Remsima subcutaneousformulation is 120 mg once every 2 weeks. If a patient does not respond after loading doses ofintravenous infliximab, no additional treatment with infliximab should be given. Available data do notsupport further infliximab treatment, in patients not responding within 6 weeks of the initial infusion.

Limited data in patients who initially responded to induction regimen with infliximab but who lostresponse indicate that some patients may regain response with dose escalation (see section 5.1).

Continued therapy should be carefully reconsidered in patients who show no evidence of therapeuticbenefit after dose adjustment.

The first treatment with Remsima administered subcutaneously should be initiated as maintenancetherapy 4 weeks after the last administration of intravenous infusions. Before initiating treatment with

Remsima subcutaneous formulation, 2 intravenous infusions of infliximab 5 mg/kg should be given at2 weeks apart, and an additional intravenous infusion of infliximab 5 mg/kg may be given 4 weeksafter the second infusion. The recommended maintenance dose for Remsima subcutaneousformulation is 120 mg once every 2 weeks. If a patient does not respond after loading doses ofintravenous infliximab, no additional treatment with infliximab should be given. Available data do notsupport further infliximab treatment, in patients not responding within 14 weeks of the initial infusion.

Limited data in patients who initially responded to induction regimen with infliximab but who lostresponse indicate that some patients may regain response with dose escalation (see section 5.1).

Continued therapy should be carefully reconsidered in patients who show no evidence of therapeuticbenefit after dose adjustment.

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

The first treatment with Remsima administered subcutaneously should be initiated as maintenancetherapy 4 weeks after the last administration of intravenous infusions. Before initiating treatment with

Remsima subcutaneous formulation, 2 intravenous infusions of infliximab 5 mg/kg should be given at2 weeks apart, and an additional intravenous infusion of infliximab 5 mg/kg may be given 4 weeksafter the second infusion. The recommended maintenance dose for Remsima subcutaneousformulation is 120 mg once every 2 weeks.

Available data suggest that the clinical response is usually achieved within 14 weeks of treatment (seesection 5.1). Continued therapy should be carefully reconsidered in patients who show no evidence oftherapeutic benefit within this time period.

Treatment with Remsima administered subcutaneously should be initiated as maintenance therapy 4weeks after the last administration of two intravenous infusions of infliximab 5 mg/kg given 2 weeksapart. The recommended dose for Remsima subcutaneous formulation is 120 mg once every 2 weeks.

If a patient does not respond by 6 weeks (i.e. after 2 intravenous infusions), no additional treatmentwith infliximab should be given.

Treatment with Remsima administered subcutaneously should be initiated as maintenance therapy 4weeks after the last administration of two intravenous infusions of infliximab 5 mg/kg given 2 weeksapart. The recommended dose for Remsima subcutaneous formulation is 120 mg once every 2 weeks.

Treatment with Remsima administered subcutaneously should be initiated as maintenance therapy 4weeks after the last administration of two intravenous infusions of infliximab 5 mg/kg given 2 weeksapart. The recommended dose for Remsima subcutaneous formulation is 120 mg once every 2 weeks.

If a patient shows no response after 14 weeks (i.e. 2 intravenous infusions and 5 subcutaneousinjections), no additional treatment with infliximab should be given.

From experience with intravenous infliximab, if the signs and symptoms of disease recur, infliximabcan be re-administered within 16 weeks following the last administration. In clinical studies withintravenous infliximab, delayed hypersensitivity reactions have been uncommon and have occurredafter infliximab-free intervals of less than 1 year (see sections 4.4 and 4.8). The safety and efficacy ofre-administration after an infliximab-free interval of more than 16 weeks has not been established.

This applies to both Crohn’s disease patients and rheumatoid arthritis patients.

From experience with intravenous infliximab, the safety and efficacy of re-administration, other thanevery 8 weeks, has not been established (see sections 4.4 and 4.8).

From experience with intravenous infliximab, the safety and efficacy of re-administration, other thanevery 6 to 8 weeks, has not been established (see sections 4.4 and 4.8).

From experience with intravenous infliximab, the safety and efficacy of re-administration, other thanevery 8 weeks, has not been established (see sections 4.4 and 4.8).

Limited experience from re-treatment with one single intravenous infliximab dose in psoriasis after aninterval of 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 of intravenous infliximab following disease flare by are-induction regimen suggests a higher incidence of infusion reactions, including serious ones, whencompared to 8-weekly maintenance treatment of intravenous infliximab (see section 4.8).

In case maintenance therapy is interrupted, and there is a need to restart treatment, use of are-induction regimen of intravenous infliximab is not recommended (see section 4.8). In this situation,infliximab should be re-initiated as a single dose of intravenous infliximab followed by themaintenance dose recommendations of subcutaneous infliximab described above given 4 weeks afterthe last administration of intravenous infliximab.

Switching to and from Remsima subcutaneous formulation across indications

When switching from the maintenance therapy of infliximab intravenous formulation to thesubcutaneous formulation of Remsima, the subcutaneous formulation may be administered at the timeof next planned administration of the intravenous infusions of infliximab.

There is insufficient information regarding the switching of patients who received the intravenousinfusions of infliximab higher than 3 mg/kg for rheumatoid arthritis or 5 mg/kg for Crohn’s diseaseevery 8 weeks to the subcutaneous formulation of Remsima.

Information regarding switching patients from the subcutaneous formulation to the intravenousformulation of Remsima is not available.

If patients miss an injection of Remsima subcutaneous formulation, they should be instructed to takethe missed dose immediately in case this happens within 7 days from the missed dose, and then remainon their original dosing schedule. If the dose is delayed by 8 days or more, the patients should beinstructed to skip the missed dose, wait until their next scheduled dose, and then remain on theiroriginal dosing schedule.

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 with infliximabintravenous formulations and the same is expected for subcutaneous formulation. No dose adjustmentis required (see section 5.2). For more information about the safety of infliximab in elderly patients(see sections 4.4 and 4.8).

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

The safety and efficacy of Remsima subcutaneous therapy in children aged below 18 years of age havenot yet been established. No data are available. Therefore, subcutaneous use of Remsima isrecommended for use only in adults.

Remsima 120 mg solution for injection in pre-filled syringe or in pre-filled pen are administered bysubcutaneous injection only. Full instructions for use are provided in the package leaflet. For the twoinitial intravenous infusions, patients may be pre-treated with, e.g., an antihistamine, hydrocortisoneand/or paracetamol 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). Thephysician should ensure appropriate follow-up of patients for any systemic injection reaction andlocalised injection site reaction after the initial subcutaneous injection is administered.

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

Patients with tuberculosis or other severe infections such as sepsis, abscesses and opportunisticinfections (see section 4.4).

Patients with moderate or severe heart failure (NYHA class III/IV) (see sections 4.4 and 4.8).

In order to improve the traceability of biological medicinal products, the tradename and the batchnumber of the administered product should be clearly recorded.

Systemic injection reaction/ localised injection site reaction/ hypersensitivity

Infliximab has been associated with systemic injection reactions, anaphylactic shock and delayedhypersensitivity reactions (see section 4.8).

Acute reactions including anaphylactic reactions may develop during (within seconds) or within a fewhours following administration of infliximab. If acute reactions occur, medical treatment should besought immediately. For this reason, the initial intravenous administrations should take place whereemergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway isimmediately available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/orparacetamol to prevent mild and transient effects.

Localised injection site reactions predominantly of mild to moderate in nature included the followingreactions limited to injection site: erythema, pain, pruritus, swelling, induration, bruising, haematoma,oedema, coldness, paraesthesia, haemorrhage, irritation, rash, ulcer, urticaria, application site vesiclesand scab were reported to be associated with infliximab subcutaneous treatment. Most of thesereactions may occur immediately or within 24 hours after subcutaneous injection. Most of thesereactions resolved spontaneously without any treatment.

Antibodies to infliximab may develop and have been associated with an increased frequency ofinfusion reactions when administered by intravenous infusion. A low proportion of the infusionreactions was serious allergic reactions. An association between development of antibodies toinfliximab and reduced duration of response has also been observed with intravenously administeredinfliximab. Concomitant administration of immunomodulators has been associated with lowerincidence of antibodies to infliximab and in the case of intravenously administered infliximab, areduction in the frequency of infusion reactions. The effect of concomitant immunomodulator therapywas more profound in episodically-treated patients than in patients given maintenance therapy.

Patients who discontinue immunosuppressants prior to or during infliximab treatment are at greaterrisk of developing these antibodies. Antibodies to infliximab cannot always be detected in serumsamples. If serious reactions occur, symptomatic treatment must be given and further infliximab mustnot be administered (see section 4.8).

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

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

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

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

Clinical experience shows that host defence against infection is compromised in some patients treatedwith infliximab.

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

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

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

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

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

Before starting treatment with infliximab, all patients must be evaluated for both active and inactive(‘latent’) tuberculosis. This evaluation should include a detailed medical history with personal historyof tuberculosis or possible previous contact with tuberculosis and previous and/or currentimmunosuppressive therapy. Appropriate screening tests (e.g. tuberculin skin test, chest X-ray, and/or

Interferon Gamma Release Assay), should be performed in all patients (local recommendations mayapply). It is recommended that the conduct of these tests should be recorded in the patient remindercard. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially inpatients who are severely ill or immunocompromised.

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

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

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

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

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

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

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

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

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

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

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

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

Patients should be tested for HBV infection before initiating treatment with infliximab. For patientswho test positive for HBV infection, consultation with a physician with expertise in the treatment ofhepatitis B is recommended. Carriers of HBV who require treatment with infliximab should be closelymonitored for signs and symptoms of active HBV infection throughout therapy and for several monthsfollowing termination of therapy. Adequate data of treating patients who are carriers of HBV withantiviral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are notavailable. In patients who develop HBV reactivation, infliximab should be stopped and effectiveantiviral therapy with appropriate supportive treatment should be initiated.

Cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have beenobserved in the post-marketing experience of infliximab. Isolated cases of liver failure resulting inliver transplantation or death have occurred. Patients with symptoms or signs of liver dysfunctionshould be evaluated for evidence of liver injury. If jaundice and/or ALT elevations ≥5 times the upperlimit of normal develop(s), infliximab should be discontinued, and a thorough investigation of theabnormality should be undertaken.

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

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

In clinical studies concurrent administration of TNF-antagonists and abatacept has been associatedwith an increased risk of infections including serious infections compared to TNF-antagonists alone,without increased clinical benefit. The combination of infliximab and abatacept is not recommended.

There is insufficient information regarding the concomitant use of infliximab with other biologicaltherapeutics used to treat the same conditions as infliximab. The concomitant use of infliximab withthese biologics is not recommended because of the possibility of an increased risk of infection, andother potential pharmacological interactions.

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

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

In a subset of 90 adult patients with rheumatoid arthritis from the ASPIRE study a similar proportionof patients in each treatment group (methotrexate plus: placebo [n = 17], 3 mg/kg [n = 27] or 6 mg/kginfliximab [n = 46]) mounted an effective two-fold increase in 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 treatment withanti-TNF therapies, including infliximab, may elicit a lower immune response than in patients notreceiving anti-TNF therapy.

In patients receiving anti-TNF therapy, limited data are available on the response to vaccination withlive vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines canresult in clinical infections, including disseminated infections. The concurrent administration of livevaccines with infliximab is not recommended.

In infants exposed in utero to infliximab, fatal outcome due to disseminated Bacillus Calmette-Guérin(BCG) infection has been reported following administration of BCG vaccine after birth. A twelvemonth waiting period following birth is recommended before the administration of live vaccines toinfants exposed in utero to infliximab. If infant infliximab serum levels are undetectable or infliximabadministration was limited to the first trimester of pregnancy, administration of a live vaccine might beconsidered at an earlier timepoint if there is a clear clinical benefit for the individual infant (seesection 4.6).

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

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

The relative deficiency of TNFα caused by anti-TNF therapy may result in the initiation of anautoimmune process. If a patient develops symptoms suggestive of a lupus-like syndrome followingtreatment with infliximab and is positive for antibodies against double-stranded DNA, furthertreatment with infliximab must not be given (see section 4.8).

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

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

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

With the current knowledge, a risk for the development of lymphomas or other malignancies inpatients treated with a TNF-blocking agent cannot be excluded (see section 4.8). Caution should beexercised when considering TNF-blocking therapy for patients with a history of malignancy or whenconsidering continuing treatment in patients who develop a malignancy.

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

Although subcutaneous administration is not indicated for children under age of 18 years, it should benoted that malignancies, some fatal, have been reported among children, adolescents and young adults(up to 22 years of age) treated with TNF-blocking agents (initiation of therapy ≤18 years of age),including infliximab in the post-marketing setting. Approximately half the cases were lymphomas.

The other cases represented a variety of different malignancies and included rare malignancies usuallyassociated with immunosuppression. A risk for the development of malignancies in patients treatedwith TNF-blockers cannot be excluded.

Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patientstreated with TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a veryaggressive disease course and is usually fatal. Almost all patients had received treatment with AZA or6-MP concomitantly with or immediately prior to a TNF-blocker. The vast majority of infliximabcases have occurred in patients with Crohn’s disease or ulcerative colitis and most were reported inadolescent or young adult males. The potential risk with the combination of AZA or 6-MP andinfliximab should be carefully considered. A risk for the development for hepatosplenic T-celllymphoma in patients treated with infliximab cannot be excluded (see section 4.8).

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

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

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

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

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

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

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

A patient who requires surgery while on infliximab should be closely monitored for infectious andnon-infectious complications, and appropriate actions should be taken (see section 4.8).

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

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

Sodium and sorbitol contents

Remsima contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’ and 45 mgsorbitol per 1 mL (in each 120 mg dose).

No interaction studies have been performed.

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

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

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

It is recommended that live vaccines not be given concurrently with Remsima. It is also recommendedthat live vaccines not be given to infants after in utero exposure to infliximab for 12 months followingbirth. If infant infliximab serum levels are undetectable or infliximab administration was limited to thefirst trimester of pregnancy, administration of a live vaccine might be considered at an earliertimepoint 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 infliximab (seesection 4.4).

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

The moderate number of prospectively collected pregnancies exposed to infliximab resulting in livebirth with known outcomes, including approximately 1,100 exposed during the first trimester, does notindicate an increase in the rate of malformation in the newborn.

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

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

Due to its inhibition of TNFα, infliximab administered during pregnancy could affect normal immuneresponses in the newborn. In a developmental toxicity study conducted in mice using an analogousantibody that selectively inhibits the functional activity of mouse TNFα, there was no indication ofmaternal toxicity, embryotoxicity or teratogenicity (see section 5.3).

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

Infliximab crosses the placenta and has been detected in the serum of infants up to 12 monthsfollowing birth. After in utero exposure to infliximab, infants may be at increased risk of infection,including serious disseminated infection that can become fatal. Administration of live vaccines (e.g.,

BCG vaccine) to infants exposed to infliximab in utero is not recommended for 12 months after birth(see sections 4.4 and 4.5). If infant infliximab serum levels are undetectable or infliximabadministration was limited to the first trimester of pregnancy, administration of a live vaccine might beconsidered at an earlier timepoint if there is a clear clinical benefit for the individual infant. Cases ofagranulocytosis have also been reported (see section 4.8).

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

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

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

Upper respiratory tract infection was the most common adverse drug reaction (ADR) reported inclinical trials with infliximab, occurring in 25.3% of infliximab-treated patients compared with 16.5%of control patients. The most serious ADRs associated with the use of TNF blockers that have beenreported for 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, demyelinatingdisorders, hepatobiliary events, lymphoma, HSTCL, leukaemia, Merkel cell carcinoma, melanoma,sarcoidosis/sarcoid-like reaction, intestinal or perianal abscess (in Crohn’s disease) and seriousinfusion reactions (see section 4.4).

The safety profile of Remsima subcutaneous formulation from active rheumatoid arthritis (evaluatedin 168 and 175 patients for the subcutaneous infliximab group and the intravenous infliximab group,respectively), active Crohn’s disease (evaluated in 297, 38 and 105 patients for the subcutaneousinfliximab group, the intravenous infliximab group and the placebo group, respectively) and activeulcerative colitis patients (evaluated in 334, 40 and 140 patients for the subcutaneous infliximabgroup, the intravenous infliximab group and the placebo group, respectively) was overall similar to thesafety profile of the intravenous formulation.

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

Table 1

Adverse reactions in clinical studies and from post-marketing experience of infliximab

Very common: Viral infection (e.g. influenza, herpes virus infection,

COVID-19*).

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

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

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

B reactivation.

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

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

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

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

Merkel cell carcinoma, Kaposi’s sarcoma.

Common: Neutropenia, leucopenia, anaemia, lymphadenopathy.

Uncommon: Thrombocytopenia, lymphopenia, lymphocytosis.

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

Common: Depression, insomnia.

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

Rare: Apathy.

Very common: Headache.

Common: Vertigo, dizziness, hypoaesthesia, paraesthesia.

Uncommon: Seizure, neuropathy.

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

Not known: Cerebrovascular accidents in close temporal association withinfusion.

Common: Conjunctivitis.

Uncommon: Keratitis, periorbital oedema, hordeolum.

Rare: Endophthalmitis.

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

Common: Tachycardia, palpitation.

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

Rare: Cyanosis, pericardial effusion.

Not known: Myocardial ischaemia/myocardial infarction.

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

Uncommon: Peripheral ischaemia, thrombophlebitis, haematoma.

Rare: Circulatory failure, petechia, vasospasm.

Very common: Upper respiratory tract infection, sinusitis.

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

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

Rare: Interstitial lung disease (including rapidly 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.

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

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

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

Not known: Worsening of symptoms of dermatomyositis.

Common: Arthralgia, myalgia, back pain.

Common: Urinary tract infection.

Uncommon: Pyelonephritis.

Uncommon: Vaginitis.

Very common: Infusion-related reaction, pain.

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

Uncommon: Impaired healing.

Rare: Granulomatous lesion.

Uncommon: Autoantibody positive, weight increased1.

Rare: Complement factor abnormal.

Injury, poisoning, and procedural complications

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

* COVID-19 was seen with the SC administered Remsima

** 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

Systemic injection reaction and localised injection site reaction in adult patients administered with

Remsima subcutaneous formulation

The safety profile of Remsima subcutaneous formulation in combination with methotrexate wasevaluated in a Phase I/III parallel group study in patients with active rheumatoid arthritis. The safetypopulation consisted of 168 patients in the Remsima subcutaneous group and 175 patients in the

Remsima intravenous group. For study details, see Section 5.1.

The incidence rate of systemic injection reactions (e.g. rash, pruritus, flushing and oedema) was 1.2patients per 100 patient-years in the Remsima subcutaneous group (from Week 6) and 2.1 patients per100 patient-years in the Remsima intravenous group who switched to Remsima subcutaneousadministration (from Week 30). All systemic injection reactions were mild to moderate.

The incidence rate of localised injection site reactions (e.g. injection site erythema, pain, pruritus andswelling) was 17.6 patients per 100 patient-years in the Remsima subcutaneous group (from Week 6)and 21.4 patients per 100 patient-years in those who switched to Remsima subcutaneousadministration (from Week 30). Most of these reactions were mild to moderate and resolvedspontaneously without any treatment within a day.

In the integrated analysis including a Phase I study conducted in patients with active Crohn’s diseaseand active ulcerative colitis, a Phase III study conducted in patients with active Crohn’s disease and a

Phase III study conducted in patients with active ulcerative colitis, the safety population consisted of631 patients in the Remsima subcutaneous group (297 patients with active Crohn’s disease and334 patients with active ulcerative colitis) and 245 patients in the Placebo group (105 patients withactive Crohn’s disease and 140 patients with active ulcerative colitis). For study details, see

Section 5.1.

The incidence rate of systemic injection reactions (e.g. nausea and dizziness) was 3.56 patients per 100patient-years in the Remsima subcutaneous group.

The incidence rate of localised injection site reactions (e.g. injection site erythema, pain, pruritus,bruising) was 8.68 patients per 100 patient-years in the Remsima subcutaneous group. Most of thesereactions were mild to moderate and mostly resolved spontaneously without any treatment within afew days.

In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngealoedema and severe bronchospasm, and seizure have been associated with infliximab intravenousadministration (see section 4.4). Cases of transient visual loss occurring during or within 2 hours ofinfliximab infusion have been reported. Events (some fatal) of myocardial ischaemia/infarction andarrhythmia have been reported, some in close temporal association with infusion of infliximab;cerebrovascular accidents have also been reported in close temporal association with infusion ofinfliximab.

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

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

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

Intravenous formulation

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

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

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

Because immunogenicity analyses are assay-specific, comparison of the incidence of antibodies toinfliximab reported in this section with the incidence of antibodies in other studies may be misleading.

Subcutaneous formulation

In rheumatoid arthritis patients on maintenance treatment, the incidence of anti-infliximab antibodiesfollowing the subcutaneous infliximab was demonstrated to be not higher than that of the intravenousinfliximab and anti-infliximab antibodies had no significant impact on efficacy (determined by diseaseactivity score in 28 joints [DAS28] and American College of Rheumatology criteria 20 [ACR20]) andthe safety profile.

In Crohn's disease and ulcerative colitis patients on maintenance treatment, the incidence ofanti-infliximab antibodies was not higher in patients who received subcutaneous infliximab incomparison to those who received intravenous infliximab and anti-infliximab antibodies had nosignificant impact on efficacy (determined by clinical response and clinical remission according to

CDAI score for Crohn's disease patients or partial Mayo score for ulcerative colitis patients) and thesafety profile.

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

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

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

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

Some of the cases have resulted in a fatal outcome. Nearly 50% of reported deaths have beenassociated with infection. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis andtuberculosis with extra-pulmonary location have been reported (see section 4.4).

In clinical studies with infliximab in which 5,780 patients were treated, representing 5,494 patientyears, 5 cases of lymphomas and 26 non-lymphoma malignancies were detected as compared with nolymphomas and 1 non-lymphoma malignancy in 1,600 placebo-treated patients representing941 patient years.

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

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

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

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

In addition, post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patientstreated with infliximab with the vast majority of cases occurring in Crohn’s disease and ulcerativecolitis, and most of whom were adolescent or young adult males (see section 4.4).

In a Phase II study aimed at evaluating infliximab in CHF, higher incidence of mortality due toworsening of heart failure were seen in patients treated with infliximab, especially those treated withthe higher dose of 10 mg/kg (i.e. twice the maximum approved dose). In this study 150 patients with

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

There have been post-marketing reports of worsening heart failure, with and without identifiableprecipitating factors, in patients taking infliximab. There have also been post-marketing reports of newonset heart failure, including heart failure in patients without known pre-existing cardiovasculardisease. Some of these patients have been under 50 years of age.

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

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

ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with eithercontinuation or discontinuation of infliximab, or modification of concomitant therapy. Inpost-marketing surveillance, cases of jaundice and hepatitis, some with features of autoimmunehepatitis, have been reported in patients receiving infliximab (see section 4.4).

Table 2

Proportion of patients with increased ALT activity in clinical studies using intravenousinfliximab

Median follow-up

Number of patients3 ≥ 3 x ULN ≥ 5 x ULN

Indication (wks)4placebo infliximab placebo infliximab placebo infliximab placebo infliximab

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

Crohn’s2 324 1,034 53.7 54.0 2.2% 4.9% 0.0% 1.5%disease

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

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

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

Plaque281 1,175 16.1 50.1 0.4% 7.7% 0.0% 3.4%psoriasis1 Placebo patients received methotrexate while infliximab patients received both infliximab andmethotrexate.

2 Placebo patients in the 2 Phase III studies in Crohn’s disease, ACCENT I and ACCENT II,received an initial dose of 5 mg/kg infliximab at study start and were on placebo in themaintenance phase. Patients who were randomised to the placebo maintenance group and then latercrossed over to infliximab are included in the infliximab group in the ALT analysis. In the Phase

IIIb trial in Crohn’s disease, SONIC, placebo patients received AZA 2.5 mg/kg/day as activecontrol in addition to placebo infliximab infusions.

3 Number of patients evaluated for ALT.

4 Median follow-up is based on patients treated.

Approximately half of infliximab-treated patients in clinical studies who were ANA negative atbaseline developed a positive ANA during the study compared with approximately one fifth ofplacebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately 17% ofinfliximab-treated patients compared with 0% of placebo-treated patients. At the last evaluation, 57%of infliximab-treated patients remained anti-dsDNA positive. Reports of lupus and lupus-likesyndromes, however, remain uncommon (see section 4.4).

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

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

Single intravenous doses up to 20 mg/kg have been administered without toxic effects and repeateddoses of Remsima subcutaneous formulation up to 240 mg have been administered without toxiceffects. There is no specific treatment for Remsima overdose. In the event of an overdose, the patientshould be treated symptomatically and supportive measures instituted as required.

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

ATC code: L04AB02.

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

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

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

Infliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays. Infliximabprevented disease in transgenic mice that develop polyarthritis as a result of constitutive expression ofhuman TNFα and when administered after disease onset, it allowed eroded joints to heal. In vivo,infliximab rapidly forms stable complexes with human TNFα, a process that parallels the loss of TNFαbioactivity.

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

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

Adult rheumatoid arthritis

Intravenous formulation

The efficacy of infliximab intravenous formulation was assessed in two multicentre, randomised,double-blind, pivotal clinical studies: ATTRACT and ASPIRE. In both studies concurrent use ofstable doses of folic acid, oral corticosteroids (≤10 mg/day) and/or non-steroidal anti-inflammatorydrugs (NSAIDs) was permitted.

The primary endpoints were the reduction of signs and symptoms as assessed by the ACR criteria(ACR20 for ATTRACT, landmark ACR-N for ASPIRE), the prevention of structural joint damage,and the improvement in physical function. A reduction in signs and symptoms was defined to be atleast a 20% improvement (ACR20) in both tender and swollen joint counts, and in 3 of the following5 criteria: (1) evaluator’s global assessment, (2) patient’s global assessment, (3) functional/disabilitymeasure, (4) visual analogue pain scale and (5) erythrocyte sedimentation rate or C-reactive protein.

ACR-N uses the same criteria as the ACR20, calculated by taking the lowest percent improvement inswollen joint count, tender joint count, and the median of the remaining 5 components of the ACRresponse. Structural joint damage (erosions and joint space narrowing) in both hands and feet wasmeasured by the change from baseline in the total van der Heijde-modified Sharp score (0-440). The

Health Assessment Questionnaire (HAQ; scale 0-3) was used to measure patients’ average changefrom baseline scores over time, in physical function.

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

Results from week 54 (ACR20, total van der Heijde-modified Sharp score and HAQ) are shown in

Table 3. Higher degrees of clinical response (ACR50 and ACR70) were observed in all infliximabgroups at 30 and 54 weeks compared with methotrexate alone.

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

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

Table 3

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

Infliximabb

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

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

Total scored (van der Heijde-modified Sharp score)

Infliximabb

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

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

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

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

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

Mean ± SDc 0.2 ± 0.3 0.4 ± 0.3 0.5 ± 0.4 0.5 ± 0.5 0.4 ± 0.4 0.4 ± 0.4a control = All patients had active RA despite treatment with stable methotrexate doses for 6 monthsprior to enrolment and were to remain on stable doses throughout the study. Concurrent use of stable doses oforal corticosteroids (≤10 mg/day) and/or NSAIDs was permitted, and folate supplementation was given.

b all infliximab doses given in combination with methotrexate and folate with some on corticosteroidsand/or NSAIDsc p <0.001, for each infliximab treatment group vs. controld greater values indicate more joint damage.

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

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

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

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

Table 4

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

Infliximab + MTX

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

Subjects randomised 282 359 363 722

Percentage ACR improvement

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

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

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

Median 0.43 0.00 0.00 0.00

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

Mean ± SDd 0.68 ± 0.63 0.80 ± 0.65 0.88 ± 0.65 0.84 ± 0.65a p <0.001, for each infliximab treatment group vs. control.

b greater values indicate more joint damage.

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

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

Data to support dose titration in rheumatoid arthritis come from ATTRACT, ASPIRE and the STARTstudy. START was a randomised, multicentre, double-blind, 3-arm, parallel-group safety study. In oneof the study arms (group 2, n=329), patients with an inadequate response were allowed to dose titratewith 1.5 mg/kg increments from 3 up to 9 mg/kg. The majority (67%) of these patients did not requireany dose titration. Of the patients who required a dose titration, 80% achieved clinical response andthe majority (64%) of these required only one adjustment of 1.5 mg/kg.

Subcutaneous formulation

The efficacy of subcutaneous infliximab in rheumatoid arthritis patients was assessed in a randomised,parallel-group pivotal Phase I/III study consisting of two parts: Part 1 to determine the optimal dose ofsubcutaneous infliximab and Part 2 to demonstrate non-inferiority in terms of efficacy of subcutaneousinfliximab compared to intravenous infliximab treatment in a double-blind setting.

In Part 2 of this study, among 357 patients who were enrolled to receive 2 doses of Remsima 3 mg/kgintravenously at Weeks 0 and 2, 167 patients were randomised to receive Remsima 120 mgsubcutaneously at Week 6 and every 2 weeks up to Week 54, while 176 patients were randomised toreceive Remsima 3 mg/kg intravenously at Weeks 6, 14 and 22 and then switched to Remsima 120 mgsubcutaneous at Week 30 once-every 2 weeks up to Week 54. Methotrexate was given concomitantly.

The primary endpoint of the study was the treatment difference of the change from baseline of DAS28(CRP) at Week 22. The estimate of treatment difference was 0.27 with corresponding lower limit ofthe two-sided 95% confidence interval [CI] of 0.02 (95% CI: 0.02, 0.52), which was greater than thepre-specified non-inferiority margin of -0.6 indicating non-inferiority of Remsima subcutaneousformulation to Remsima intravenous formulation.

The analysis of other efficacy endpoints showed that efficacy profile of Remsima subcutaneousformulation compared to Remsima intravenous formulation in RA patients was generally comparablein terms of disease activity measured by DAS28 (CRP and ESR) and ACR response up to Week 54.

The mean scores for DAS28 (CRP) and DAS28 (ESR) gradually decreased from baseline at each timepoint until Week 54 in each treatment arm (see Table 5 and Table 6, respectively).

Table 5

Mean (SD) Actual Values of DAS28 (CRP and ESR)

DAS28 (CRP) DAS28 (ESR)

Remsima IV Remsima SC Remsima IV Remsima SC3 mg/kgb 120 mg 3 mg/kgb 120 mg

Visit (N=174) (N=165) (N=174) (N=165)

Baseline 5.9 (0.8) 6.0 (0.8) 6.6 (0.8) 6.7 (0.8)

Week 6 4.1 (1.2) 4.0 (1.2) 4.8 (1.3) 4.6 (1.2)

Week 22 3.5 (1.2)a 3.3 (1.1)a 4.1 (1.3) 4.0 (1.1)

Week 54 2.9 (1.2)b 2.8 (1.1) 3.4 (1.3)b 3.4 (1.2)a Two-sided 95% CI for difference in the mean change from baseline for DAS28 (CRP) at Week 22 waswell above the pre-defined non-inferiority margin of -0.6b Remsima IV was switched to Remsima SC at Week 30

Table 6

Proportions of Patients Achieving Clinical Response According to the ACR Criteria

ACR20 ACR50 ACR70

Remsima IV Remsima SC Remsima IV Remsima SC Remsima IV Remsima SC3 mg/kga 120 mg 3 mg/kga 120 mg 3 mg/kga 120 mg

Visit (N=174) (N=165) (N=174) (N=165) (N=174) (N=165)

Week 6 103 (59.2%) 107 (64.8%) 45 (25.9%) 47 (28.5%) 18 (10.3%) 19 (11.5%)

ACR20 ACR50 ACR70

Remsima IV Remsima SC Remsima IV Remsima SC Remsima IV Remsima SC3 mg/kga 120 mg 3 mg/kga 120 mg 3 mg/kga 120 mg

Visit (N=174) (N=165) (N=174) (N=165) (N=174) (N=165)

Week 22 137 (78.7%) 139 (84.2%) 90 (51.7%) 85 (51.5%) 49 (28.2%) 46 (27.9%)

Week 54 125 (71.8%)a 132 (80.0%) 101 (58.0%)a 108 (65.5%) 68 (39.1%)a 77 (46.7%)a Remsima IV was switched to Remsima SC at Week 30

There are no clinical trials with Remsima 120 mg given subcutaneously without intravenous loadingdoses of infliximab in patients with rheumatoid arthritis. However, population pharmacokinetic andpharmacokinetic/pharmacodynamic modelling and simulation predicted comparable infliximabexposure (AUC over 8 weeks) and efficacy (DAS28 and ACR20 response) from Week 6 onward inrheumatoid arthritis patients treated with Remsima 120 mg given without intravenous loading doses ofinfliximab when compared with Remsima 3 mg/kg given intravenously at Weeks 0, 2 and 6, and thenevery 8 weeks.

Intravenous formulation

The efficacy of a single dose treatment with infliximab intravenous formulation was assessed in108 patients with active Crohn’s disease (CDAI ≥220 ≤400) in a randomised, double-blinded,placebo-controlled, dose-response study. Of these 108 patients, 27 were treated with the recommendeddosage of infliximab 5 mg/kg. All patients had experienced an inadequate response to priorconventional therapies. Concurrent use of stable doses of conventional therapies was permitted, and92% of patients continued to receive these therapies.

The primary endpoint was the proportion of patients who experienced a clinical response, defined as adecrease in CDAI by ≥70 points from baseline at the 4-week evaluation and without an increase in theuse of medicinal products or surgery for Crohn’s disease. Patients who responded at week 4 werefollowed to week 12. Secondary endpoints included the proportion of patients in clinical remission atweek 4 (CDAI <150) and clinical response over time.

At week 4, following administration of a single dose, 22/27 (81%) of infliximab-treated patientsreceiving a 5 mg/kg dose achieved a clinical response vs. 4/25 (16%) of the placebo-treated patients(p <0.001). Also at week 4, 13/27 (48%) of infliximab-treated patients achieved a clinical remission(CDAI <150) vs. 1/25 (4%) of placebo-treated patients. A response was observed within 2 weeks, witha 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 intravenous infliximab was studied in a 1-year clinical study(ACCENT I). A total of 573 patients with moderately to severely active Crohn’s disease (CDAI ≥220≤400) received a single infusion of 5 mg/kg at week 0. 178 of the 580 enrolled patients (30.7%) 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 treatment groups; aplacebo maintenance group, 5 mg/kg maintenance group and 10 mg/kg maintenance group. All3 groups received repeated infusions at week 2, 6 and every 8 weeks thereafter.

Of the 573 patients randomised, 335 (58%) achieved clinical response by week 2. These patients wereclassified as week-2 responders and were included in the primary analysis (see Table 7). Amongpatients classified as non-responders at week 2, 32% (26/81) in the placebo maintenance group and42% (68/163) in the infliximab group achieved clinical response by week 6. There was no differencebetween groups in the number of late responders thereafter.

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

Table 7

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

ACCENT I (week-2 responders)% of Patients

Placebo Infliximab Infliximab

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

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

Week 30

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

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

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

Week 54

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

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

Sustained Steroid-Free 5.7 (3/53) 17.9 (10/56) 28.6 (16/56)

Remissionb (0.075) (0.002)a Reduction in CDAI ≥25% and ≥70 points.

b CDAI <150 at both Week 30 and 54 and not receiving corticosteroids in the 3 months prior to

Week 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 which theywere originally randomised. Eighty nine percent (50/56) of patients who lost clinical response oninfliximab 5 mg/kg maintenance therapy after week 14 responded to treatment with infliximab10 mg/kg.

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

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

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

The primary endpoint of the study was corticosteroid-free clinical remission at week 26, defined aspatients in clinical remission (CDAI of <150) who, for at least 3 weeks, had not taken oral systemiccorticosteroids (prednisone or equivalent) or budesonide at a dose >6 mg/day. For results see Table 8.

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

Table 8

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

AZA Infliximab Infliximab + AZA

Monotherapy Monotherapy Combination therapy

Week 26

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

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

Similar trends in the achievement of corticosteroid-free clinical remission were observed at week 50.

Furthermore, improved quality of life as measured by IBDQ was observed with infliximab.

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

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

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

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

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

Table 9

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

ACCENT II (Week-14 responders)

Placebo Infliximab p-value

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

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

Week 54

Fistula Response (%)a 23.5 46.2 0.001

Complete fistula response (%)b 19.4 36.3 0.009a A ≥50% reduction from baseline in the number of draining fistulas over a period of ≥4 weeks.

b Absence of any draining fistulas.

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

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

Maintenance therapy with infliximab every 8 weeks significantly reduced disease-relatedhospitalisations and surgeries compared with placebo. Furthermore, a reduction in corticosteroid useand improvements in quality of life were observed.

Subcutaneous formulation

The efficacy of subcutaneous infliximab in active Crohn’s disease and active ulcerative colitis patientswas assessed in an open-label, randomised, parallel-group, Phase I study consisting of two parts: Part1 to determine the optimal dose of subcutaneous infliximab and Part 2 to demonstrate non-inferiorityin terms of PK of subcutaneous infliximab compared to intravenous infliximab treatment.

In Part 1 of this study, 45 patients with active Crohn’s disease were enrolled to receive 2 doses of

Remsima 5 mg/kg intravenously at Weeks 0 and 2 and subsequently 44 patients were randomised intofour cohorts to receive Remsima 5 mg/kg intravenously (n=13) at Week 6 and every 8 weeks up to

Week 54, Remsima 120 mg subcutaneously (n=11), Remsima 180 mg subcutaneously (n=12) or

Remsima 240 mg subcutaneously (n=8) at Week 6 and every 2 weeks up to Week 54.

In Part 2 of this study, among 136 patients (57 patients with active Crohn’s disease and 79 patientswith active ulcerative colitis) who were enrolled to receive 2 doses of Remsima 5 mg/kg intravenouslyat Weeks 0 and 2, 66 patients (28 patients with active Crohn’s disease and 38 patients with activeulcerative colitis) were randomised to receive Remsima 120/ 240 mg subcutaneously at Week 6 andevery 2 weeks up to Week 54, while 65 patients (25 patients with active Crohn’s disease and 40patients with active ulcerative colitis) were randomised to receive Remsima 5 mg/kg intravenously at

Week 6, 14 and 22 and then switched to Remsima 120/ 240 mg subcutaneous formulation at Week 30once-every 2 weeks up to Week 54. The dosage of Remsima 120/ 240 mg subcutaneous formulationwas determined based on the patient’s body weight at Week 6 for those who received Remsimasubcutaneously and at Week 30 for those who switched to Remsima subcutaneous formulation(Remsima subcutaneous 120 mg for patients <80 kg; 240 mg for patients ≥80 kg).

In active Crohn’s disease patients, the descriptive efficacy results following Remsima 120 mgsubcutaneous formulation were generally comparable to Remsima 5 mg/kg intravenous formulation interms of clinical response (CDAI-70 response defined as a decrease in CDAI by ≥70 points and

CDAI-100 response defined as ≥100 points from baseline), clinical remission (defined as an absolute

CDAI score of <150 points) and endoscopy assessments (endoscopic response defined as a decrease in≥50% of overall Simplified Endoscopic Activity Score for Crohn’s Disease (SES-CD) score from thebaseline value and endoscopic remission defined as an absolute SES-CD score of ≤2 points).

The efficacy of subcutaneous infliximab in active Crohn’s disease patients was also assessed in arandomized, double-blind, placebo-controlled clinical study in 343 adult patients with moderately toseverely active CD (CDAI of 220 to 450 points) with an inadequate response to conventional therapies(LIBERTY-CD). Concomitant treatment with stable doses of aminosalicylates, corticosteroids,antibiotics and/or immunomodulatory agents were permitted. Corticosteroids dose was tapered after

Week 10. Patients who were classified as CDAI-100 responders at Week 10 following three IVinfusions of infliximab 5 mg/kg at Weeks 0, 2 and 6 were randomized to receive an injection of eithersubcutaneous infliximab 120 mg or placebo every 2 weeks thereafter from Week 10 through Week 54.

The co-primary endpoints were clinical remission (based on CDAI) and endoscopic response at

Week 54. Clinical remission was defined as an absolute CDAI score of <150 points, and endoscopicresponse was defined as a 50% decrease in SES-CD score from the baseline value.

Key secondary endpoints were CDAI -100 response and endoscopic remission at Week 54.

In LIBERTY-CD, patients treated with subcutaneous infliximab at the recommended dosage (120 mgevery 2 weeks) achieved clinical remission (based on CDAI), endoscopic response, CDAI-100response, and endoscopic remission more often compared to placebo (Table 10).

Table 10

Clinical Remission, Endoscopic Response, CDAI-100 Response and Endoscopic Remission in

LIBERTY-CD

Infliximab sc Treatmenta Placebo

Endpoint 120 mg Difference and(N=112)(N=231) 95% CI

Clinical remission (based on CDAI) 32.1%b 62.3% 32.1%at Week 54 (20.9, 42.1)34.6%

Endoscopic response at Week 54c 51.1% 17.9%(24.1, 43.5)28.9%

CDAI-100 response at Week 54d 65.8% 38.4%(17.7, 39.2)24.9%

Endoscopic remission at Week 54e 34.6% 10.7%(15.4, 32.8)a Patient who had loss of response between Week 22 and 54 were allowed to switch to 240 mginfliximab sc both in the infliximab and placebo arms. The patients who switched are considerednon-responders.

b Defined as an absolute CDAI score of <150 points.

c Defined as a 50% decrease in SES-CD score from the baseline value.

d Defined as a decrease in CDAI score of 100 points or more from the baseline value.

e Defined as an absolute SES-CD score of ≤4 and at least 2-point reduction from the baseline valuewith no sub-score of >1.

In LIBERTY-CD, dose adjustment to subcutaneous infliximab 240 mg was allowed from Week 22 forpatients who initially responded but then lost response in both subcutaneous infliximab 120 mg andplacebo groups. Loss of response was defined as an increase in CDAI of ≥100 points from the

Week 10 CDAI score with a total score ≥220. Among patients who were responders to intravenousinfliximab at week 10, who met loss of response criteria at or after week 22 and received a doseincrease to subcutaneous infliximab 240 mg, 21/34 (61.8%) had regained CDAI-100 response at

Week 54. Spontaneous regain of response, without dose adjustment, occurred in 1/7 patients in eachgroup (infliximab sc 120 mg and placebo). Including an open-label extension phase of the

LIBERTY-CD study, overall 73 patients have received infliximab 240 mg as maintenance treatmentfor at least 44 weeks with no relevant additional safety findings compared to the 120 mg dose.

In LIBERTY-CD, the impact of use of immunosuppressant (azathioprine, 6-mercaptopurine andmethotrexate) on efficacy was evaluated. There was no significant difference between patients withand without immunosuppressants in the primary and the key secondary efficacy endpoints.

Intravenous formulation

The safety and efficacy of intravenous infliximab were assessed in two (ACT 1 and ACT 2)randomised, double-blind, placebo-controlled clinical studies in adult patients with moderately toseverely active ulcerative colitis (Mayo score 6 to 12; Endoscopy subscore ≥ 2) with an inadequateresponse to conventional 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 receive eitherplacebo, 5 mg/kg infliximab, or 10 mg/kg infliximab at weeks 0, 2, 6, 14 and 22, and in ACT 1 atweeks 30, 38 and 46. Corticosteroid taper was permitted after week 8.

Table 11

Effects on clinical response, clinical remission and mucosal healing at weeks 8 and 30. Combineddata from ACT 1 & 2

Infliximab

Placebo 5 mg/kg 10 mg/kg Combined

Subjects randomised 244 242 242 484

Percentage of subjects in clinical response and in sustained clinical response

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

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

Sustained response (clinicalresponse at both week 8 and week 19.3% 45.0% 49.6% 47.3%30)a

Percentage of subjects in clinical remission and sustained remission

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

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

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

Percentage of subjects with mucosal healing

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

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

The efficacy of infliximab through week 54 was assessed in the ACT 1 study.

At 54 weeks, 44.9% of patients in the combined infliximab treatment group were in clinical responsecompared to 19.8% in the placebo treatment group (p<0.001). Clinical remission and mucosal healingoccurred in a greater proportion of patients in the combined infliximab treatment group compared tothe placebo treatment group at week 54 (34.6% vs. 16.5%, p<0.001 and 46.1% vs. 18.2%, p<0.001,respectively). The proportions of patients in sustained response and sustained remission at week 54were greater in the combined infliximab treatment group than in the placebo treatment group (37.9%vs. 14.0%, p<0.001; and 20.2% vs. 6.6%, p<0.001, respectively).

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

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

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

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

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

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

Subcutaneous formulation

The efficacy of subcutaneous infliximab in active ulcerative colitis patients was assessed in Part 2 ofan open-label, randomised, parallel-group, Phase I study. For study details, see Section 5.1 on Crohn’sdisease, subcutaneous formulation.

In active ulcerative colitis patients, the descriptive efficacy results following Remsima 120 mgsubcutaneous formulation were generally comparable to Remsima 5 mg/kg intravenous formulation interms of clinical response (defined as a decrease from baseline in total Mayo score of at least 3 pointsand at least 30% or a decrease from baseline in partial Mayo score at least 2 points, with anaccompanying decrease from baseline in the subscore for rectal bleeding of at least 1 point, or anabsolute subscore for rectal bleeding of 0 or 1), clinical remission (defined as a total Mayo score of ≤2points with no individual subscore exceeding 1 point, or partial Mayo score of ≤1 point) and mucosalhealing (defined as absolute endoscopic subscore of 0 or 1 from Mayo Scoring System).

Intravenous formulation

Efficacy and safety of infliximab intravenous formulation were assessed in two multicentre,double-blind, placebo-controlled studies in patients with active ankylosing spondylitis (Bath

Ankylosing Spondylitis Disease Activity Index [BASDAI] score ≥ 4 and spinal pain ≥ 4 on a scale of1-10).

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

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

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

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

BASDAI 50 responders.

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

Intravenous formulation

Efficacy and safety of infliximab intravenous formulation were assessed in two multicentre,double-blind, placebo-controlled studies in patients with active psoriatic arthritis.

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

In the second clinical study (IMPACT 2), efficacy and safety of infliximab were studied in200 patients with active psoriatic arthritis (≥5 swollen joints and ≥5 tender joints). Forty six percent ofpatients continued on stable doses of methotrexate (≤25 mg/week). During the 24-week double-blindphase, patients received either 5 mg/kg infliximab or placebo at weeks 0, 2, 6, 14, and 22 (100 patientsin each group). At week 16, 47 placebo patients with <10% improvement from baseline in bothswollen and tender joint counts were switched to infliximab induction (early escape). At week 24, allplacebo-treated patients crossed over to infliximab induction. Dosing continued for all patientsthrough week 46.

Key efficacy results for IMPACT and IMPACT 2 are shown in Table 12 below:

Table 12

Effects on ACR and PASI in IMPACT and IMPACT 2

IMPACT IMPACT 2*

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

Patients 52 52 N/Aa 100 100 100randomised

ACR response(% ofpatients)52 52 78 100 100 100

N

ACR 205 (10%) 34 (65%) 48 (62%) 16 (16%) 54 (54%) 53 (53%)response*

ACR 500 (0%) 24 (46%) 35 (45%) 4 (4%) 41 (41%) 33 (33%)response*

ACR 700 (0%) 15 (29%) 27 (35%) 2 (2%) 27 (27%) 20 (20%)response*

PASIresponse(% ofpatients)b 87 83 82

N

PASI1 (1%) 50 (60%) 40 (48.8%)75 response**

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

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

b Based on patients with PASI ≥2.5 at baseline for IMPACT, and patients with ≥3% BSA psoriasisskin involvement at baseline in IMPACT 2.

** PASI 75 response for IMPACT not included due to low N; p<0.001 for infliximab vs. placebo atweek 24 for IMPACT 2.

In IMPACT and IMPACT 2, clinical responses were observed as early as week 2 and were maintainedthrough week 98 and week 54, respectively. Efficacy has been demonstrated with or withoutconcomitant use of methotrexate. Decreases in parameters of peripheral activity characteristic ofpsoriatic arthritis (such as number of swollen joints, number of painful/tender joints, dactylitis andpresence of enthesopathy) were seen in the infliximab-treated patients.

Radiographic changes were assessed in IMPACT 2. Radiographs of hands and feet were collected atbaseline, weeks 24 and 54. Infliximab treatment reduced the rate of progression of peripheral jointdamage compared with placebo treatment at the week 24 primary endpoint as measured by changefrom baseline in total modified vdH-S score (mean ± SD score was 0.82 ± 2.62 in the placebo groupcompared with -0.70 ± 2.53 in the infliximab group; p<0.001). In the infliximab group, the meanchange in total modified vdH-S score remained below 0 at the week 54 timepoint.

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

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

Intravenous formulation

The efficacy of infliximab intravenous formulation was assessed in two multicentre, randomised,double-blind studies: SPIRIT and EXPRESS. Patients in both studies had plaque psoriasis (Body

Surface Area [BSA] ≥10% and Psoriasis Area and Severity Index [PASI] score ≥12). The primaryendpoint in both studies was the percent of patients who achieved ≥75% improvement in PASI frombaseline at week 10.

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

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

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

EXPRESS evaluated the efficacy of infliximab induction and maintenance therapy in 378 patientswith plaque psoriasis. Patients received 5 mg/kg infliximab- or placebo-infusions at weeks 0, 2 and 6followed by maintenance therapy every 8 weeks through week 22 in the placebo group and throughweek 46 in the infliximab group. At week 24, the placebo group crossed over to infliximab inductiontherapy (5 mg/kg) followed by infliximab maintenance therapy (5 mg/kg). Nail psoriasis was assessedusing the Nail Psoriasis Severity Index (NAPSI). Prior therapy with PUVA, methotrexate, ciclosporin,or acitretin had been received by 71.4% of patients, although they were not necessarily therapyresistant. Key results are presented in Table 13. In infliximab treated subjects, significant PASI 50responses were apparent at the first visit (week 2) and PASI 75 responses by the second visit (week 6).

Efficacy was similar in the subgroup of patients that were exposed to previous systemic therapiescompared to the overall study population.

Table 13

Summary of PASI response, PGA response and percent of patients with all nails cleared atweeks 10, 24 and 50. EXPRESS

Placebo → Infliximab Infliximab5 mg/kg 5 mg/kg(at week 24)

Week 10

N 77 301≥90% improvement 1 (1.3%) 172 (57.1%) a≥75% improvement 2 (2.6%) 242 (80.4%) a≥50% improvement 6 (7.8%) 274 (91.0%)

PGA of cleared (0) or minimal (1) 3 (3.9%) 242 (82.9%) ab

PGA of cleared (0), minimal (1), or 14 (18.2%) 275 (94.2%) abmild (2)

Week 24

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

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

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

Week 50

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

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

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

All nails clearedc

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

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

Week 50 27/64 (42.2%) 92/226 (40.7%)a p <0.001, for each infliximab treatment group vs. control.

b n = 292.

c Analysis was based on subjects with nail psoriasis at baseline (81.8% of subjects). Mean baseline

NAPSI scores were 4.6 and 4.3 in infliximab and placebo group.

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

The European Medicines Agency has waived the obligation to submit the results of studies with thereference medicinal product containing infliximab in all subsets of the paediatric population inrheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis and

Crohn’s disease (see section 4.2 for information on paediatric use).

Single subcutaneous injections of 120, 180 and 240 mg of infliximab yielded approximately doseproportional increases in the maximum serum concentration (Cmax) and area under the concentration-time curve (AUC). The apparent volume of distribution during the terminal phase (mean of 7.3 to 8.8litres) was not dependent on the administered dose.

After single doses of 120, 180 and 240 mg of subcutaneous infliximab administered to healthysubjects, the mean Cmax values were 10.0, 15.1 and 23.1 µg/mL, respectively, and for all dosesinfliximab could be detected in the serum for at least 12 weeks thereafter.

The bioavailability of subcutaneous infliximab, estimated in a population PK model, was 62% (95%

CI: 60% - 64%).

After administration of infliximab 120 mg subcutaneously every 2 weeks (from Week 6 after 2 dosesof intravenous infliximab at Weeks 0 and 2) to patients with active rheumatoid arthritis who wereconcomitantly treated with MTX, the median (CV%) Ctrough level at Week 22 (steady state) was12.8 µg/mL (80.1%).

After administration of infliximab 120 mg subcutaneously every 2 weeks (from Week 6 after 2 dosesof intravenous infliximab at Weeks 0 and 2) to patients with active Crohn’s disease and activeulcerative colitis, the median (CV%) Ctrough level at Week 22 (steady state) was 20.1 µg/mL (48.9%).

Based on PK results from clinical studies in patients with active rheumatoid arthritis, active Crohn’sdisease and active ulcerative colitis and population PK modelling, Ctrough levels at steady state wouldbe higher after administration of infliximab 120 mg subcutaneous formulation given every 2 weekscompared with infliximab 5 mg/kg intravenous formulation given every 8 weeks.

For the dosing regimen with subcutaneous loading in patients with rheumatoid arthritis, the predictedmedian AUC value was 17,400 μg·h/mL from Week 0 to 6 which was approximately 1.8 fold lowerthan the predicted median AUC value for the dosing regimen with infliximab intravenous loadingdoses (32,100 μg·h/mL). Whereas, the predicted median AUC values from Week 6 to 14 werecomparable between the two dosing regimens with subcutaneous loading and intravenous loading(19,600 and 18,100 μg·h/mL, respectively).

The elimination pathways for infliximab have not been characterised. Unchanged infliximab was notdetected in urine. No major age- or weight-related differences in clearance or volume of distributionwere observed in rheumatoid arthritis patients.

In studies in healthy subjects, the mean (± SD) apparent clearance of Remsima 120 mg administeredsubcutaneously was 19.3 ± 6.9 mL/hr.

In the RA patients, the mean (± SD) apparent clearance of Remsima 120 mg subcutaneous at steadystate was 18.8 ± 8.3 mL/hr. In the active Crohn’s disease and active ulcerative colitis patients, themean (± SD) apparent clearance of Remsima 120 mg subcutaneous at steady state was 16.1 ±6.9 mL/hr.

The mean terminal half-life ranged from 11.3 days to 13.7 days for 120, 180 and 240 mg ofsubcutaneous infliximab administered to healthy subjects.

The pharmacokinetics of infliximab injected via subcutaneous route in elderly patients has not beenstudied.

Subcutaneous administration of Remsima is not recommended for paediatric use and no data areavailable on the use of Remsima administered subcutaneously in the paediatric population.

Studies with infliximab have not been performed in patients with liver or renal disease.

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

Therefore, conventional preclinical safety data with infliximab are limited. In a developmental toxicitystudy conducted in mice using an analogous antibody that selectively inhibits the functional activity ofmouse TNFα, there was no indication of maternal toxicity, embryotoxicity or teratogenicity. In afertility and general reproductive function study, the number of pregnant mice was reduced followingadministration of the same analogous antibody. It is not known whether this finding was due to effectson the males and/or the females. In a 6-month repeated dose toxicity study in mice, using the sameanalogous antibody against mouse TNFα, crystalline deposits were observed on the lens capsule ofsome of the treated male mice. No specific ophthalmologic examinations have been performed inpatients to investigate the relevance of this finding for humans.

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

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

The subcutaneous administration of Remsima to New Zealand White rabbits was well tolerated at theactual concentration to be used in humans.

Acetic acid

Sodium acetate trihydrate

Sorbitol

Polysorbate 80

Water for injections

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

4 years

Store in a refrigerator (2°C - 8°C).

Do not freeze. Keep the pre-filled syringe and pre-filled pen in the outer carton in order to protectfrom light.

The medicinal product may be stored at temperatures up to a maximum of 25°C for a period of up to28 days. The medicinal product must be discarded if not used within the 28-day period.

Remsima 120 mg solution for injection in pre-filled syringe

Remsima 120 mg solution for injection in single-use pre-filled syringe (type I glass) with a plungerstopper (flurotec-coated elastomer) and needle with a rigid needle shield.

Packs of:

* 1 prefilled syringe (1 mL sterile solution) with 2 alcohol pads.

* 2 prefilled syringes (1 mL sterile solution) with 2 alcohol pads.

* 4 prefilled syringes (1 mL sterile solution) with 4 alcohol pads.

* 6 prefilled syringes (1 mL sterile solution) with 6 alcohol pads.

Remsima 120 mg solution for injection in pre-filled syringe with automatic needle guard

Remsima 120 mg solution for injection in single-use pre-filled syringe with automatic needle guard.

The syringe is made from type I glass with a plunger stopper (flurotec-coated elastomer) and needlewith a rigid needle shield.

Packs of:

* 1 prefilled syringe with automatic needle guard (1 mL sterile solution) with 2 alcohol pads.

* 2 prefilled syringes with automatic needle guard (1 mL sterile solution) with 2 alcohol pads.

* 4 prefilled syringes with automatic needle guard (1 mL sterile solution) with 4 alcohol pads.

* 6 prefilled syringes with automatic needle guard (1 mL sterile solution) with 6 alcohol pads.

Remsima 120 mg solution for injection in pre-filled pen

Remsima 120 mg solution for injection in single-use pre-filled pen. The syringe inside the pen is madefrom type 1 glass with a plunger stopper (flurotec-coated elastomer) and needle with a rigid needleshield.

Packs of:

* 1 prefilled pen (1 mL sterile solution) with 2 alcohol pads.

* 2 prefilled pens (1 mL sterile solution) with 2 alcohol pads.

* 4 prefilled pens (1 mL sterile solution) with 4 alcohol pads.

* 6 prefilled pens (1 mL sterile solution) with 6 alcohol pads.

Not all pack sizes may be marketed.

Remsima is a solution that is clear to opalescent, colourless to pale brown. Do not use if the solution iscloudy, discoloured or contains visible particulate matter.

After use, place the pre-filled syringe/ pre-filled syringe with automatic needle guard/ pre-filled peninto a puncture resistant container and discard as required by local regulations. Do not recycle theinjecting device. Always keep the medicinal product out of the sight and reach of children.

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

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

EU/1/13/853/006

EU/1/13/853/007

EU/1/13/853/008

EU/1/13/853/009

EU/1/13/853/010

EU/1/13/853/011

EU/1/13/853/012

EU/1/13/853/013

EU/1/13/853/014

EU/1/13/853/015

EU/1/13/853/016

EU/1/13/853/017

Date of first authorisation: 10 September 2013

Date of latest renewal: 21 June 2018

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

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