Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Celltrion Healthcare Hungary Kft., 1062 Budapest, Váci út 1-3. WestEnd Office Building B torony, Hungary
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).
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Infliximab has been associated with systemic injection reactions, anaphylactic shock and delayed hypersensitivity reactions (see section 4.8).
Acute reactions including anaphylactic reactions may develop during (within seconds) or within a few hours following administration of infliximab. If acute reactions occur, medical treatment should be sought immediately. For this reason, the initial intravenous administrations should take place where emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway is immediately available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol to prevent mild and transient effects.
Localised injection site reactions predominantly of mild to moderate in nature included the following reactions limited to injection site: erythema, pain, pruritus, swelling, induration, bruising, haematoma, oedema, coldness, paraesthesia, haemorrhage, irritation, rash, ulcer, urticaria, application site vesicles and scab were reported to be associated with infliximab subcutaneous treatment. Most of these reactions may occur immediately or within 24 hours after subcutaneous injection. Most of these reactions resolved spontaneously without any treatment.
Antibodies to infliximab may develop and have been associated with an increased frequency of infusion reactions when administered by intravenous infusion. A low proportion of the infusion reactions was serious allergic reactions. An association between development of antibodies to infliximab and reduced duration of response has also been observed with intravenously administered infliximab. Concomitant administration of immunomodulators has been associated with lower incidence of antibodies to infliximab and in the case of intravenously administered infliximab, 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 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 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.
Patients must be monitored closely for infections including tuberculosis 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, 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 pneumocystosis, candidiasis, listeriosis and aspergillosis.
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.
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 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 antituberculosis 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.
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.
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).
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.
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.
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.
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.
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.
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 Remsima 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 titers 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.
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.
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).
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).
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.
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).
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.
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.
Although subcutaneous administration is not indicated for children under age of 18 years, it should be noted that malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-blocking agents (initiation of therapy ≤18 years of age), including infliximab in the post-marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies 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.
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).
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.
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.
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).
Remsima contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free' and 45 mg sorbitol per 1 mL (in each 120 mg dose).
This medicine contains 0.5 mg of polysorbate 80 in each pre-filled syringe/pre-filled pen which is equivalent to 0.5 mg/mL. Polysorbates may cause allergic reactions. Tell your doctor if you have any known allergies.
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 Remsima. 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).
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.
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).
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.
There are insufficient preclinical data to draw conclusions on the effects of infliximab on fertility and general reproductive function (see section 5.3).
Remsima may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of infliximab (see section 4.8).
Upper respiratory tract infection was the most common adverse drug reaction (ADR) reported in clinical trials with infliximab, occurring in 25.3% of infliximab-treated patients compared with 16.5% of control patients. The most serious ADRs associated with the use of TNF blockers that have 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, sarcoidosis/sarcoid-like reaction, intestinal or perianal abscess (in Crohn's disease) and serious infusion reactions (see section 4.4).
The safety profile of Remsima subcutaneous formulation from active rheumatoid arthritis (evaluated in 168 and 175 patients for the subcutaneous infliximab group and the intravenous infliximab group, respectively), active Crohn's disease (evaluated in 297, 38 and 105 patients for the subcutaneous infliximab group, the intravenous infliximab group and the placebo group, respectively) and active ulcerative colitis patients (evaluated in 334, 40 and 140 patients for the subcutaneous infliximab group, the intravenous infliximab group and the placebo group, respectively) was overall similar to the safety profile of the intravenous formulation.
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, undesirable effects are presented in order of decreasing seriousness.
Table 1. Adverse reactions in clinical studies and from post-marketing experience of infliximab:
| Infections and infestations | |
| Very common: | Viral infection (e.g. influenza, herpes virus infection, COVID-19*). |
| Common: | Bacterial infections (e.g. sepsis, cellulitis, abscess). |
| Uncommon: | Tuberculosis, fungal infections (e.g. candidiasis, onychomycosis). |
| Rare: | Meningitis, opportunistic infections (such as invasive 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)). |
* COVID-19 was seen with the SC administered Remsima
** 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
The safety profile of Remsima subcutaneous formulation in combination with methotrexate was evaluated in a Phase I/III parallel group study in patients with active rheumatoid arthritis. The safety population consisted of 168 patients in the Remsima subcutaneous group and 175 patients in the Remsima intravenous group. For study details, see Section 5.1.
The incidence rate of systemic injection reactions (e.g. rash, pruritus, flushing and oedema) was 1.2 patients per 100 patient-years in the Remsima subcutaneous group (from Week 6) and 2.1 patients per 100 patient-years in the Remsima intravenous group who switched to Remsima subcutaneous administration (from Week 30). All systemic injection reactions were mild to moderate.
The incidence rate of localised injection site reactions (e.g. injection site erythema, pain, pruritus and swelling) was 17.6 patients per 100 patient-years in the Remsima subcutaneous group (from Week 6) and 21.4 patients per 100 patient-years in those who switched to Remsima subcutaneous administration (from Week 30). Most of these reactions were mild to moderate and resolved spontaneously without any treatment within a day.
In the integrated analysis including a Phase I study conducted in patients with active Crohn's disease and active ulcerative colitis, a Phase III study conducted in patients with active Crohn's disease and a Phase III study conducted in patients with active ulcerative colitis, the safety population consisted of 631 patients in the Remsima subcutaneous group (297 patients with active Crohn's disease and 334 patients with active ulcerative colitis) and 245 patients in the Placebo group (105 patients with active Crohn's disease and 140 patients with active ulcerative colitis). For study details, see Section 5.1.
The incidence rate of systemic injection reactions (e.g. nausea and dizziness) was 3.56 patients per 100 patient-years in the Remsima subcutaneous group.
The incidence rate of localised injection site reactions (e.g. injection site erythema, pain, pruritus, bruising) was 8.68 patients per 100 patient-years in the Remsima subcutaneous group. Most of these reactions were mild to moderate and mostly resolved spontaneously without any treatment within a few days.
In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngeal oedema and severe bronchospasm, and seizure have been associated with infliximab intravenous 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.
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 with intravenous infliximab, 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 of IV infliximab in patients with Crohn's disease (ACCENT I study), the incidence of serum sickness-like reactions was 2.4%.
Patients who developed antibodies to infliximab were more likely (approximately 2-3 fold) to 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: "Systemic injection reaction/ localised injection site reaction/ hypersensitivity").
Because immunogenicity analyses are assay-specific, comparison of the incidence of antibodies to infliximab reported in this section with the incidence of antibodies in other studies may be misleading.
In rheumatoid arthritis patients on maintenance treatment, the incidence of anti-infliximab antibodies following the subcutaneous infliximab was demonstrated to be not higher than that of the intravenous infliximab and anti-infliximab antibodies had no significant impact on efficacy (determined by disease activity score in 28 joints [DAS28] and American College of Rheumatology criteria 20 [ACR20]) and the safety profile.
In Crohn's disease and ulcerative colitis patients on maintenance treatment, the incidence of anti-infliximab antibodies was not higher in patients who received subcutaneous infliximab in comparison to those who received intravenous infliximab. In Crohn's disease and ulcerative colitis patients, there was a correlation between loss of response and anti-infliximab antibodies, while anti-infliximab antibodies had no significant impact on the safety profile.
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).
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).
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.
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 using intravenous infliximab:
| 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% |
| Ulcerative colitis | 242 | 482 | 30.1 | 30.8 | 1.2% | 2.5% | 0.4% | 0.6% |
| 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.
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).
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 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 national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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