Safety profile¹

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

Flixabi™ has been associated with acute infusion-related reactions, including anaphylactic shock, and delayed hypersensitivity reactions (see section 4.8 of Summary of Product Characteristics).

Acute infusion reactions, including anaphylactic reactions may develop during (within seconds) or within a few hours following infusion. If acute infusion 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 Flixabi™ may develop and have been associated with an increased frequency of infusion reactions. A low proportion of the infusion reactions was serious allergic reactions. An association between development of antibodies to Flixabi™ and reduced duration of response has also been observed. Concomitant administration of immunomodulators has been associated with lower incidence of antibodies to Flixabi™ and a reduction in the frequency of infusion 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 Flixabi™ treatment are at greater risk of developing these antibodies. Antibodies to Flixabi™ cannot always be detected in serum samples. If serious reactions occur, symptomatic treatment must be given and further Flixabi™ infusions must not be administered (see section 4.8 of the Summary of Product Characteristics).

In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest an increased risk for delayed hypersensitivity with increasing Flixabi™-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.

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

Caution should be exercised when considering the use of Flixabi™ 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 Flixabi™.

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, bacterial infections, including sepsis and pneumonia, invasive fungal, viral, and other opportunistic infections have been observed in patients treated with Flixabi™. 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.

Patients who develop a new infection while undergoing treatment with Flixabi™, should be monitored closely and undergo a complete diagnostic evaluation. Administration of Flixabi™ 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 Flixabi™. 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 Flixabi™, 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, Flixabi™ therapy must not be initiated (see section 4.3 of the Summary of Product Characteristics).

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 Flixabi™ 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 Flixabi™, 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 Flixabi™.

Use of anti-tuberculosis therapy should also be considered before the initiation of Flixabi™ 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 Flixabi™ 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 Flixabi™ treatment.

Invasive fungal infections

In patients treated with Flixabi™, 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 FlixabiTM treatment should be carefully considered before initiation of Flixabi™ therapy.

Fistulising Crohn’s disease

Patients with fistulising Crohn’s disease with acute suppurative fistulas must not initiate Flixabi™ therapy until a source for possible infection, specifically abscess, has been excluded (see section 4.3 of the Summary of Product Characteristics).

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

Patients should be tested for HBV infection before initiating treatment with Flixabi™. 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 Flixabi™ 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, Flixabi™ should be stopped and effective antiviral therapy with appropriate supportive treatment should be initiated.

Cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have been observed in the post-marketing experience of Flixabi™. 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), Flixabi™ should be discontinued, and a thorough investigation of the abnormality should be undertaken.

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 Flixabi™ and anakinra is not recommended.

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 Flixabi^TM and abatacept is not recommended.

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

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.

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

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 Flixabi™ [n = 46]) mounted an effective two-fold increase in titers to a polyvalent pneumococcal vaccine, indicating that Flixabi™ 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 Flixabi™, may elicit a lower immune response than in patients not receiving anti-TNF therapy.

In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with 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 Flixabi^TM is not recommended.

In infants exposed in utero to Flixabi^TM, 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 Flixabi^TM. If infant Flixabi^TM 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 of the Summary of Product Characteristics).

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 Flixabi^TM.

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 of the Summary of Product Characteristics).

The relative deficiency of TNF-Alpha 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 Flixabi™ and is positive for antibodies against double-stranded DNA, further treatment with Flixabi™ must not be given (see section 4.8 of the Summary of Product Characteristics).

Use of TNF-blocking agents, including Flixabi™, 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 Flixabi™ therapy. Discontinuation of Flixabi™ should be considered if these disorders develop.

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 Flixabi™ across all approved indications the incidence of lymphoma in Flixabi™-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 Flixabi™ in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies were reported in Flixabi™-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 of the Summary of Product Characteristics). 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 Flixabi™ 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 Flixabi™. 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 Flixabi™ 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 Flixabi™ should be carefully considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with Flixabi™ cannot be excluded (see section 4.8 of the Summary of Product Characteristics).

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including Flixabi™ (see section 4.8 of the Summary of Product Characteristics). 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 Flixabi™ compared to biologics-naïve patients or the general population, including those over 60 years of age. Periodic screening should continue in women treated with Flixabi™, 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 Flixabi™ 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 Flixabi™ is not established, the risk and benefits of continued therapy to the individual patients should be carefully considered by the clinician.

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

There have been reports of pancytopenia, leucopenia, neutropenia, and thrombocytopenia in patients receiving TNF-blockers, including Flixabi™. 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 Flixabi™ therapy should be considered in patients with confirmed significant haematologic abnormalities.

There is limited safety experience of Flixabi™ treatment in patients who have undergone surgical procedures, including arthroplasty. The long half-life of Flixabi™ should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Flixabi™ should be closely monitored for infections, and appropriate actions should be taken.

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 Flixabi™ worsens or causes fibrotic strictures.

The incidence of serious infections in Flixabi™-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 of the Summary of Product Characteristics).

Infections

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

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 Flixabi™ therapy. Paediatric patients on Flixabi™ may receive concurrent vaccinations, except for live vaccines (see sections 4.5 and 4.6 of the Summary of Product Characteristics).

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 Flixabi™ 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 Flixabi™. 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 Flixabi™ 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 Flixabi™ should be carefully considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with Flixabi™ cannot be excluded (see section 4.8 of the Summary of Product Characteristics).

Flixabi™ contains less than 1 mmol sodium (23 mg) per dose, i.e. 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 of the Summary of Product Characteristics).

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 Flixabi™ and increases the plasma concentrations of Flixabi™. However, the results are uncertain due to limitations in the methods used for serum analyses of Flixabi™ and antibodies against Flixabi™.

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

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

It is recommended that live vaccines not be given concurrently with Flixabi^TM. It is also recommended that live vaccines not be given to infants after in utero exposure to Flixabi^TM for 12 months following birth. If infant Flixabi^TM serum levels are undetectable or Flixabi^TM 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 of the Summary of Product Characteristics).

It is recommended that therapeutic infectious agents not be given concurrently with Flixabi^TM (see section 4.4 of the Summary of Product Characteristics).

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 Flixabi™ treatment.

The moderate number of prospectively collected pregnancies exposed to Flixabi™ resulting in live birth with known outcomes, including approximately 1100 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 Flixabi™ (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 Flixabi™ and/or the severity of the underlying disease in these outcomes remains unclear.

Due to its inhibition of TNF-Alpha, Flixabi™ 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 of the Summary of Product Characteristics).

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

Flixabi^TM 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 Flixabi^TM in utero is not recommended for 12 months after birth (see sections 4.4 and 4.5). If infant Flixabi^TM serum levels are undetectable or Flixabi^TM 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 sections 4.4 and 4.5 of the Summary of Product Characteristics).

Cases of agranulocytosis have also been reported (see section 4.8 of the Summary of Product Characteristics).

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

There are insufficient preclinical data to draw conclusions on the effects of Flixabi™ on fertility and general reproductive function (see section 5.3 of the Summary of Product Characteristics).