4.1. Therapeutic indications

Rheumatoid arthritis

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

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

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

In these patient populations, a reduction in the rate of the progression of joint damage, as measured by X-ray, has been demonstrated (see section 5.1).

Adult Crohn's disease

Flixabi is indicated for:

• treatment of moderately to severely active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies.

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

Paediatric Crohn's disease

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

Ulcerative colitis

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

Paediatric ulcerative colitis

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

Ankylosing spondylitis

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

Psoriatic arthritis

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

Flixabi should be administered

• in combination with methotrexate

• or alone in patients who show intolerance to methotrexate or for whom methotrexate is contraindicated.

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

Psoriasis

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

4.2. Posology and method of administration

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

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

Posology

Adults (≥ 18 years)

Rheumatoid arthritis

3 mg/kg given based on the body weight (bw) as an intravenous infusion followed by additional 3 mg/kg bw infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.

Flixabi must be given concomitantly with methotrexate.

Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. If a patient has an inadequate response or loses response after this period, consideration may be given to increase the dose step-wise by approximately 1.5 mg/kg bw, up to a maximum of 7.5 mg/kg bw every 8 weeks. Alternatively, administration of 3 mg/kg bw as often as every 4 weeks may be considered. If adequate response is achieved, patients should be continued on the selected dose or dose frequency. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within the first 12 weeks of treatment or after dose adjustment.

Moderately to severely active Crohn's disease

5 mg/kg bw given as an intravenous infusion followed by an additional 5 mg/kg bw infusion 2 weeks after the first infusion. If a patient does not respond after 2 doses, no additional treatment with infliximab should be given. Available data do not support further infliximab treatment, in patients not responding within 6 weeks of the initial infusion.

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

• Maintenance: Additional infusion of 5 mg/kg bw at 6 weeks after the initial dose, followed by infusions every 8 weeks or

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

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

Fistulising, active Crohn's disease

5 mg/kg bw given as an intravenous infusion followed by additional 5 mg/kg bw infusions at 2 and 6 weeks after the first infusion. If a patient does not respond after 3 doses, no additional treatment with infliximab should be given.

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

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

• Re-administration: Infusion of 5 mg/kg bw if signs and symptoms of the disease recur followed by infusions of 5 mg/kg bw every 8 weeks (see 'Re-administration' below and section 4.4).

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

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

Ulcerative colitis

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

Available data suggest that the clinical response is usually achieved within 14 weeks of treatment, i.e. three doses. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.

Ankylosing spondylitis

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

Psoriatic arthritis

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

Psoriasis

5 mg/kg bw given as an intravenous infusion followed by additional 5 mg/kg bw infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. If a patient shows no response after 14 weeks (i.e. after 4 doses), no additional treatment with infliximab should be given.

Re-administration for Crohn's disease and rheumatoid arthritis

If the signs and symptoms of disease recur, infliximab can be re-administered within 16 weeks following the last infusion. In clinical studies, delayed hypersensitivity reactions have been uncommon and have occurred after infliximab-free intervals of less than 1 year (see sections 4.4 and 4.8). The safety and efficacy of re-administration after an infliximab-free interval of more than 16 weeks has not been established. This applies to both Crohn's disease patients and rheumatoid arthritis patients.

Re-administration for ulcerative colitis

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

Re-administration for ankylosing spondylitis

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

Re-administration for psoriatic arthritis

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

Re-administration for psoriasis

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

Limited experience from re-treatment following disease flare by a re-induction regimen suggests a higher incidence of infusion-related reactions, including serious ones, when compared to 8-weekly maintenance treatment (see section 4.8).

Re-administration across indications

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

Special populations

Elderly

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

Renal and/or hepatic impairment

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

Paediatric population

Crohn's disease (6 to 17 years)

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

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

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

Ulcerative colitis (6 to 17 years)

5 mg/kg bw given as an intravenous infusion followed by additional 5 mg/kg bw infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Available data do not support further infliximab treatment in paediatric patients not responding within the first 8 weeks of treatment (see section 5.1).

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

Psoriasis

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

Juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis

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

Juvenile rheumatoid arthritis

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

Method of administration

Infliximab should be administered intravenously over a 2 hour period. All patients administered infliximab are to be observed for at least 1-2 hours post-infusion for acute infusion-related reactions. Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol and infusion rate may be slowed in order to decrease the risk of infusion-related reactions especially if infusion-related reactions have occurred previously (see section 4.4).

Shortened infusions across adult indications

In carefully selected adult patients who have tolerated at least 3 initial 2-hour infusions of infliximab (induction phase) and are receiving maintenance therapy, consideration may be given to administering subsequent infusions over a period of not less than 1 hour. If an infusion-related reaction occurs in association with a shortened infusion, a slower infusion rate may be considered for future infusions if treatment is to be continued. Shortened infusions at doses > 6 mg/kg bw have not been studied (see section 4.8).

For preparation and administration instructions, see section 6.6.

4.3. Contraindications

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

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

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

4.4. Special warnings and precautions for use

Traceability

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

Infusion-related reactions (IRR) and hypersensitivity

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

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

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

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

Infections

Patients must be monitored closely for infections including tuberculosis or other severe infections such as sepsis, abscesses, and opportunistic infections before, during and after treatment 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 be given if a patient develops a serious infection or sepsis.

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

Tumour necrosis factor alpha (TNFα) mediates inflammation and modulates cellular immune responses. Experimental data show that TNFα is essential for the clearing of intracellular infections. Clinical experience shows that host defence against infection is compromised in some patients treated with infliximab.

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

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

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

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

Tuberculosis

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

Before starting treatment with infliximab, all patients must be evaluated for both active and inactive ('latent') tuberculosis. This evaluation should include a detailed medical history with personal history of tuberculosis or possible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests (e.g. tuberculin skin test, chest X-ray, and/or Interferon Gamma Release Assay) should be performed in all patients (local recommendations may apply). It is recommended that the conduct of these tests should be recorded in the patient's reminder card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.

If active tuberculosis is diagnosed, 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 be consulted. In all situations described below, the benefit/risk balance of infliximab therapy should be very carefully considered.

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

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

Use of anti-tuberculosis therapy should also be considered before the initiation of infliximab in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.

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

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

Invasive fungal infections

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

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

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

Fistulising Crohn's disease

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

Hepatitis B (HBV) reactivation

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

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

Hepatobiliary events

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

Concurrent administration of TNF-alpha inhibitor and anakinra

Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse reactions seen with combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the combination of infliximab and anakinra is not recommended.

Concurrent administration of TNF-alpha inhibitor and abatacept

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

Concurrent administration with other biological therapeutics

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

Switching between biological DMARDS

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

Vaccinations

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

In a subset of 90 adult patients with rheumatoid arthritis from the ASPIRE study a similar proportion of patients in each treatment group (methotrexate plus: placebo [n = 17], 3 mg/kg [n = 27] or 6 mg/kg infliximab [n = 46]) mounted an effective two-fold increase in titres to a polyvalent pneumococcal vaccine, indicating that infliximab did not interfere with T-cell independent humoral immune responses. However, studies from the published literature in various indications (e.g. rheumatoid arthritis, psoriasis, Crohn's disease) suggest that non-live vaccinations received during treatment with anti-TNF therapies, including infliximab, may elicit a lower immune response than in patients not receiving anti-TNF therapy.

Live vaccines/therapeutic infectious agents

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

Infant exposure in utero

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

Infant exposure via breast milk

Administration of a live vaccine to a breastfed infant while the mother is receiving infliximab is not recommended unless infant infliximab serum levels are undetectable (see section 4.6).

Therapeutic infectious agents

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

Autoimmune processes

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

Neurological events

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

Malignancies and lymphoproliferative disorders

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

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

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

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

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

Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Almost all patients had received treatment with AZA or 6-MP concomitantly with or immediately prior to a TNF-blocker. The vast majority of infliximab cases have occurred in patients with Crohn's disease or ulcerative colitis and most were reported in adolescent or young adult males. The potential risk with the combination of AZA or 6-MP and infliximab should be carefully considered. A risk for the development for hepatosplenic T-cell lymphoma 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 blocker therapy, including infliximab (see section 4.8). Periodic skin examination is recommended, particularly for patients with risk factors for skin cancer.

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

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

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

Heart failure

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

Haematologic reactions

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

Others

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 and non-infectious complications, and appropriate actions should be taken (see section 4.8).

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

Special populations

Elderly

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

Paediatric population

Infections

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

Vaccinations

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

Malignancies and lymphoproliferative disorders

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

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

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'. Flixabi is however, diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion. This should be taken into consideration for patients on a controlled sodium diet (see section 6.6).

Polysorbate 80 content

This medicine contains 0.50 mg of polysorbate 80 (E433) in each dosage unit which is equivalent to 0.05 mg/ml. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

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

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

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

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

Administration of a live vaccine to a breastfed infant while the mother is receiving infliximab is not recommended unless infant infliximab serum levels are undetectable (see sections 4.4 and 4.6).

It is recommended that therapeutic infectious agents not be given concurrently with infliximab (see section 4.4).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

The moderate number of prospectively collected pregnancies exposed to infliximab resulting in live birth with known outcomes, including approximately 1,100 exposed during the first trimester, does not indicate an increase in the rate of malformation in the newborn.

Based on an observational study from Northern Europe, an increased risk (OR, 95% CI; p-value) for C-section (1.50, 1.14-1.96; p=0.0032), preterm birth (1.48, 1.05-2.09; p=0.024), small for gestational age (2.79, 1.54-5.04; p=0.0007), and low birth weight (2.03, 1.41-2.94; p=0.0002) was observed in women exposed during pregnancy to infliximab (with or without immunomodulators/corticosteroids, 270 pregnancies) as compared to women exposed to immunomodulators and/or corticosteroids only (6,460 pregnancies). The potential contribution of exposure to infliximab and/or the severity of the underlying disease in these outcomes remains unclear.

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

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

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

Breast-feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

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

Table 1

Adverse reactions in clinical studies and from post-marketing experience

Infections and infestations

Very Common:

Viral infection (e.g. influenza, herpes virus infection).

Common:

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

Uncommon:

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

Rare:

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

Not known:

Vaccine breakthrough infection (after in utero exposure to infliximab)*.

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

Rare:

Lymphoma, non-Hodgkin's lymphoma, Hodgkin's disease, leukaemia, melanoma, cervical cancer.

Not known:

Hepatosplenic T-cell lymphoma (primarily in adolescents and young adult males with Crohn's disease or ulcerative colitis), Merkel cell carcinoma, Kaposi's sarcoma.

Blood and lymphatic system disorders

Common:

Neutropenia, leucopenia, anaemia, lymphadenopathy.

Uncommon:

Thrombocytopenia, lymphopenia, lymphocytosis.

Rare:

Agranulocytosis (including infants exposed in utero to infliximab), thrombotic thrombocytopenic purpura, pancytopenia, haemolytic anaemia, idiopathic thrombocytopenic purpura.

Immune system disorders

Common:

Allergic respiratory symptom.

Uncommon:

Anaphylactic reaction, lupus-like syndrome, serum sickness or serum sickness-like reaction.

Rare:

Anaphylactic shock, vasculitis, sarcoid-like reaction.

Metabolism and nutrition disorders

Uncommon:

Dyslipidaemia.

Psychiatric disorders

Common:

Depression, insomnia.

Uncommon:

Amnesia, agitation, confusion, somnolence, nervousness.

Rare:

Apathy.

Nervous system disorders

Very common:

Headache.

Common:

Vertigo, dizziness, hypoaesthesia, paraesthesia.

Uncommon:

Seizure, neuropathy.

Rare:

Transverse myelitis, central nervous system demyelinating disorders (multiple sclerosis-like disease and optic neuritis), peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy).

Not known:

Cerebrovascular accidents in close temporal association with infusion.

Eye disorders

Common:

Conjunctivitis.

Uncommon:

Keratitis, periorbital oedema, hordeolum.

Rare:

Endophthalmitis.

Not known:

Transient visual loss occurring during or within 2 hours of infusion.

Cardiac disorders

Common:

Tachycardia, palpitation.

Uncommon:

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

Rare:

Cyanosis, pericardial effusion.

Not known:

Myocardial ischaemia/myocardial infarction.

Vascular disorders

Common:

Hypotension, hypertension, ecchymosis, hot flush, flushing.

Uncommon:

Peripheral ischaemia, thrombophlebitis, haematoma.

Rare:

Circulatory failure, petechia, vasospasm.

Respiratory, thoracic and mediastinal disorders

Very common:

Upper respiratory tract infection, sinusitis.

Common:

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

Uncommon:

Pulmonary oedema, bronchospasm, pleurisy, pleural effusion.

Rare:

Interstitial lung disease (including rapidly progressive disease, lung fibrosis and pneumonitis).

Gastrointestinal disorders

Very common:

Abdominal pain, nausea.

Common:

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

Uncommon:

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

Hepatobiliary disorders

Common:

Hepatic function abnormal, transaminases increased.

Uncommon:

Hepatitis, hepatocellular damage, cholecystitis.

Rare:

Autoimmune hepatitis, jaundice.

Not known:

Liver failure.

Skin and subcutaneous tissue disorders

Common:

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

Uncommon:

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

Rare:

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

Not known:

Worsening of symptoms of dermatomyositis.

Musculoskeletal and connective tissue disorders

Common:

Arthralgia, myalgia, back pain.

Renal and urinary disorders

Common:

Urinary tract infection.

Uncommon:

Pyelonephritis.

Reproductive system and breast disorders

Uncommon:

Vaginitis.

General disorders and administration site conditions

Very common:

Infusion-related reaction, pain.

Common:

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

Uncommon:

Impaired healing.

Rare:

Granulomatous lesion.

Investigations

Uncommon:

Autoantibody positive, weight increased1.

Rare:

Complement factor abnormal.

Injury, poisoning, and procedural complications

Not known

Post-procedural complication (including infectious and non- infectious complications)

* including bovine tuberculosis (disseminated BCG infection), see section 4.4

1 At month 12 of the controlled period for adult clinical trials across all indications, the median weight increase was 3.50 kg for infliximab-treated subjects vs. 3.00 kg for placebo-treated subjects. The median weight increase for inflammatory bowel disease indications was 4.14 kg for infliximab-treated subjects vs. 3.00 kg for placebo-treated subjects, 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 reactions

Infusion-related reactions

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

In a clinical study of patients with rheumatoid arthritis (ASPIRE), infusions were to be administered over 2 hours for the first 3 infusions. The duration of subsequent infusions could be shortened to not less than 40 minutes in patients who did not experience serious infusion-related reactions. In this trial, sixty six percent of the patients (686 out of 1,040) received at least one shortened infusion of 90 minutes or less and 44% of the patients (454 out of 1,040) received at least one shortened infusion of 60 minutes or less. Of the infliximab-treated patients who received at least one shortened infusion, infusion-related reactions occurred in 15% of patients and serious infusion-related reactions occurred in 0.4% of patients.

In a clinical study of patients with Crohn's disease (SONIC), infusion-related reactions occurred in 16.6% (27/163) of patients receiving infliximab monotherapy, 5% (9/179) of patients receiving infliximab in combination with AZA, and 5.6% (9/161) of patients receiving AZA monotherapy. One serious infusion-related reaction (< 1%) occurred in a patient on infliximab monotherapy.

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

Infusion-related reactions following re-administration of infliximab

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

Delayed hypersensitivity

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

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

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

Immunogenicity

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

In clinical studies using single and multiple infliximab doses ranging from 1 to 20 mg/kg, antibodies to infliximab were detected in 14% of patients with any immunosuppressant therapy, and in 24% of patients without immunosuppressant therapy. In rheumatoid arthritis patients who received the recommended repeated treatment dose regimens with methotrexate, 8% of patients developed antibodies to infliximab. In psoriatic arthritis patients who received 5 mg/kg with and without methotrexate, antibodies occurred overall in 15% of patients (antibodies occurred in 4% of patients receiving methotrexate and in 26% of patients not receiving methotrexate at baseline). In Crohn's disease patients who received maintenance treatment, antibodies to infliximab occurred overall in 3.3% of patients receiving immunosuppressants and in 13.3% of patients not receiving immunosuppressants. The antibody incidence was 2-3 fold higher for patients treated episodically. Due to methodological limitations, a negative assay did not exclude the presence of antibodies to infliximab. Some patients who developed high titres of antibodies to infliximab had evidence of reduced efficacy. In psoriasis patients treated with infliximab as a maintenance regimen in the absence of concomitant immunomodulators, approximately 28% developed antibodies to infliximab (see section 4.4: “Infusion-related reactions and hypersensitivity”).

Infections

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

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

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

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

Malignancies and lymphoproliferative disorders

In clinical studies with infliximab in which 5,780 patients were treated, representing 5,494 patient years, 5 cases of lymphomas and 26 non-lymphoma malignancies were detected as compared with no lymphomas and 1 non-lymphoma malignancy in 1,600 placebo-treated patients representing 941 patient years.

In long-term safety follow-up of clinical studies with infliximab of up to 5 years, representing 6,234 patients-years (3,210 patients), 5 cases of lymphoma and 38 cases of non-lymphoma malignancies were reported.

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

In an exploratory clinical study involving patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 adult patients were treated with infliximab at doses similar to those used in rheumatoid arthritis and Crohn's disease. Nine of these patients developed malignancies, including 1 lymphoma. The median duration of follow-up was 0.8 years (incidence 5.7% [95% CI 2.65%-10.6%]. There was one reported malignancy amongst 77 control patients (median duration of follow-up 0.8 years; incidence 1.3% [95% CI 0.03%-7.0%]). The majority of the malignancies developed in the lung or head and neck.

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

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

Heart failure

In a Phase II study aimed at evaluating infliximab in CHF, higher incidence of mortality due to worsening of heart failure were seen in patients treated with infliximab, especially those treated with the higher dose of 10 mg/kg (i.e. twice the maximum approved dose). In this study 150 patients with NYHA Class III-IV CHF (left ventricular ejection fraction ≤ 35%) were treated with 3 infusions of infliximab 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 38 weeks, 9 of 101 patients treated with infliximab (2 at 5 mg/kg and 7 at 10 mg/kg) died compared to one death among the 49 patients on placebo.

There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking infliximab. There have also been post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age.

Hepatobiliary events

In clinical studies, mild or moderate elevations of ALT and AST have been observed in patients receiving infliximab without progression to severe hepatic injury. Elevations of ALT ≥ 5 x Upper Limit of Normal (ULN) have been observed (see Table 2). Elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving infliximab than in controls, both when infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents. Most aminotransferase abnormalities were transient; however, a small number of patients experienced more prolonged elevations. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of infliximab, or modification of concomitant therapy. In post-marketing surveillance, cases of jaundice and hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving infliximab (see section 4.4).

Table 2

Proportion of patients with increased ALT activity in clinical studies

Indication

Number of patients3

Median follow-up

(wks)4

≥ 3 x ULN

≥ 5 x ULN

placebo

infliximab

placebo

infliximab

placebo

infliximab

placebo

infliximab

Rheumatoid arthritis1

375

1,087

58.1

58.3

3.2%

3.9%

0.8%

0.9%

Crohn's disease2

324

1,034

53.7

54.0

2.2%

4.9%

0.0%

1.5%

Paediatric Crohn's disease

N/A

139

N/A

53.0

N/A

4.4%

N/A

1.5%

Ulcerative colitis

242

482

30.1

30.8

1.2%

2.5%

0.4%

0.6%

Paediatric Ulcerative colitis

N/A

60

N/A

49.4

N/A

6.7%

N/A

1.7%

Ankylosing spondylitis

76

275

24.1

101.9

0.0%

9.5%

0.0%

3.6%

Psoriatic arthritis

98

191

18.1

39.1

0.0%

6.8%

0.0%

2.1%

Plaque psoriasis

281

1,175

16.1

50.1

0.4%

7.7%

0.0%

3.4%

1 Placebo patients received methotrexate while infliximab patients received both infliximab and methotrexate. 2 Placebo patients in the 2 Phase III studies in Crohn's disease, ACCENT I and ACCENT II, received an initial dose of 5 mg/kg infliximab at study start and were on placebo in the maintenance phase. Patients who were randomised to the placebo maintenance group and then later crossed over to infliximab are included in the infliximab group in the ALT analysis. In the Phase IIIb trial in Crohn's disease, SONIC, placebo patients received AZA 2.5 mg/kg/day as active control in addition to placebo infliximab infusions. 3 Number of patients evaluated for ALT. 4 Median follow-up is based on patients treated.

Antinuclear antibodies (ANA)/Anti-double-stranded DNA (dsDNA) antibodies

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

Paediatric population

Juvenile rheumatoid arthritis patients

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

Infusion-related reactions

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

Immunogenicity

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

Infections

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

Paediatric Crohn's disease patients

The following adverse reactions were reported more commonly in paediatric Crohn's disease patients in the REACH study (see section 5.1) than in adult Crohn's disease patients: anaemia (10.7%), blood in stool (9.7%), leucopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bacterial infection (5.8%), and respiratory tract allergic reaction (5.8%). In addition, bone fracture (6.8%) was reported, however, a causal association has not been established. Other special considerations are discussed below.

Infusion-related reactions

In REACH, 17.5% of randomised patients experienced 1 or more infusion-related reactions. There were no serious infusion-related reactions, and 2 subjects in REACH had non-serious anaphylactic reactions.

Immunogenicity

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

Infections

In the REACH study, infections were reported in 56.3% of randomised subjects treated with infliximab. Infections were reported more frequently for subjects who received q8 week as opposed to q12 week infusions (73.6% and 38.0%, respectively), while serious infections were reported for 3 subjects in the q8 week and 4 subjects in the q12 week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Three cases of pneumonia (1 serious) and 2 cases of herpes zoster (both non-serious) were reported.

Paediatric ulcerative colitis patients

Overall, the adverse reactions reported in the paediatric ulcerative colitis trial (C0168T72) and adult ulcerative colitis (ACT 1 and ACT 2) studies were generally consistent. In C0168T72, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache. The most common adverse event was worsening of ulcerative colitis, the incidence of which was higher in patients on the q12 week vs. the q8 week dosing regimen.

Infusion-related reactions

Overall, 8 (13.3%) of 60 treated patients experienced one or more infusion-related reactions, with 4 of 22 (18.2%) in the q8 week and 3 of 23 (13.0%) in the q12 week treatment maintenance group. No serious infusion-related reactions were reported. All infusion-related reactions were mild or moderate in intensity.

Immunogenicity

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

Infections

Infections were reported in 31 (51.7%) of 60 treated patients in C0168T72 and 22 (36.7%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in C0168T72 was similar to that in the paediatric Crohn's disease study (REACH) but higher than the proportion in the adults ulcerative colitis studies (ACT 1 and ACT 2). The overall incidence of infections in C0168T72 was 13/22 (59%) in the every 8 week maintenance treatment group and 14/23 (60.9%) in the every 12 week maintenance treatment group. Upper respiratory tract infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequently reported respiratory system infections. Serious infections were reported in 12% (7/60) of all treated patients.

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

Post-marketing experience

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

Additional information on special populations

Elderly

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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