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

Infliximab has been associated with acute infusion effects, systemic injection reactions, anaphylactic shock and a delayed hypersensitivity reaction. These differ in their time of onset. Hypersensitivity reactions, which include urticaria, dyspnoea, and/or bronchospasm, laryngeal oedema, pharyngeal oedema, and hypotension, have occurred during or within 2 hours of infliximab infusion. Therefore, all patients receiving infliximab should be observed for at least one to two hours post infusion for side effects.

To minimise the incidence of hypersensitivity reactions, including infusion reactions and serum sickness-like reactions, infliximab should be administered as regular maintenance therapy after an induction regimen at weeks 0, 2, 6. Acute infusion reactions may develop immediately or within a few hours of infusion and are most likely to occur during the first and second infusion. If acute reactions occur, medical treatment should be sought immediately. These effects may be related to the rate of infusion of infliximab. If acute infusion reactions occur, the infusion must be interrupted immediately. Some of these effects have been described as anaphylaxis. Medications (e.g. antihistamines, corticosteroids, adrenaline and/or paracetamol), an artificial airway and other appropriate materials for the treatment of these effects must be available for immediate use.

Patients may be pretreated with e.g. antihistamine, hydrocortisone and/or paracetamol to prevent mild and transient effects. The infusion rate may be slowed in order to decrease infusion reactions especially if infusion reactions have occurred previously.

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, irritation, rash, ulcer, urticaria, haemorrhage 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 in some patients. These antibodies have been associated with an increased frequency of infusion reactions, and may be associated with an increased risk of serious infusion reactions. A low proportion of the infusion reactions were serious allergic reactions. An association between development of antibodies to infliximab and reduced duration of response has also been observed with intravenously administered infliximab.

Patients who are not receiving immunosuppressants prior to or during infliximab treatment are potentially at greater risk of developing these antibodies. These antibodies cannot always be detected in serum samples. If serious reactions occur, symptomatic treatment must be given and further infliximab infusions must not be administered.

Long-term efficacy of retreatments with infliximab has not yet been established. Reactions following re-administration, including delayed hypersensitivity reactions have been observed in a significant number of patients (25% in one clinical trial) with Crohn's disease who were retreated with a liquid formulation of infliximab, which is no longer in use, following a 2 to 4 year period without infliximab treatment. Signs and symptoms included myalgia and/or arthralgia with fever and/or rash within 12 days following retreatment. Some patients also experienced pruritus, facial, hand or lip oedema, dysphagia, urticaria, sore throat and/or headache. These effects have sometimes been described as serum-sickness-like reactions. In post-marketing studies, some patients required steroid therapy to treat the delayed hypersensitivity reaction rather than symptomatic treatment alone.

Advise patients to seek immediate medical advice if they experience any delayed adverse events. If patients are retreated after a prolonged period, they should be closely monitored for signs and symptoms of delayed hypersensitivity.

Infusion reactions following re-administration of infliximab. In a psoriasis clinical trial, a 3-dose re-induction of infliximab after a period of no treatment resulted in a higher incidence of serious infusion reactions during the re-induction regimen than had been observed in rheumatoid arthritis, psoriasis, and Crohn’s disease trials in which a period of no drug treatment was followed by regular maintenance therapy without re-induction. In the case where infliximab maintenance therapy for psoriasis is interrupted, infliximab should be reinitiated as a single dose followed by maintenance therapy. In general, the benefit-risk of re-administration of infliximab after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2, and 6, should be carefully considered.

Patients must be monitored closely for infections including tuberculosis before, during and after treatment with infliximab. Bacterial (including sepsis and pneumonia), mycobacterial [including tuberculosis (frequently disseminated or extrapulmonary at clinical presentation)], 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 pneumocytosis, candidiasis, listeriosis and aspergillosis. Tumour necrosis factor alpha (TNFα) mediates inflammation and modulates cellular immune response. 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. In clinical studies in rheumatoid arthritis, starting infliximab therapy with doses higher than 3 mg/kg has been associated with an increased risk of infection compared to the risk of infection associated with the starting dose of 3 mg/kg. This increase in the risk of infection was not evident in patients receiving the starting regimen of 3 mg/kg at weeks 0, 2 and 6 and subsequently receiving higher or more frequent doses. However, caution should be exercised when continuing a rheumatoid arthritis patient on doses above 3 mg/kg or administering infliximab more frequently than every 8 weeks.

Infliximab should not be given to patients with a clinically important, active infection. Caution should be exercised when considering the use of infliximab in patients with a chronic infection or a history of recurrent infection, including concomitant immunosuppressive therapy. Patients should be advised of and avoid exposure to potential risk factors for infection as appropriate. Opportunistic infections including tuberculosis, viral infections, invasive fungal infections and other serious infections including sepsis and pneumonia have been reported in patients treated with infliximab.

Serious infections, including sepsis and fatal infections, have been reported in patients receiving TNF-blocking agents. Many of the serious infections in patients treated with infliximab have occurred in patients on concomitant immunosuppressive therapy that, in addition to their Crohn’s disease or rheumatoid arthritis, could predispose them to infections.

Patients who have clinically manifested infections and/or abscesses must be treated for these conditions prior to treatment with infliximab as infliximab should not be given to patients with a clinically important, active infection.

Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation), has been observed in patients receiving infliximab. Patients must be evaluated for the risk of tuberculosis, including latent tuberculosis, prior to initiation of infliximab. 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, i.e. tuberculin skin test and chest x-ray, and/or Inteferon Gamma Release Assay, should be performed in all patients. 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. If latent tuberculosis is diagnosed, treatment must be initiated prior to treatment with infliximab, in accordance with local recommendations. 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. Patients must be monitored closely for infections, including miliary tuberculosis, while on and after treatment with infliximab.

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 or continuation of infliximab therapy.

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. The decision to administer empiric antifungal therapy should be made, if feasible, in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of anti-fungal 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.

Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including infliximab, who are chronic carriers of this virus. 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. 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.

Concurrent administration of etanercept (another agent that inhibits TNFα) and anakinra (a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist) has been associated with an increased risk of serious infections, an increased risk of neutropaenia and no additional benefit compared to these medicinal products alone. The safety and efficacy of anakinra used in combination with infliximab has not been established. 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, combination of infliximab and anakinra is contraindicated.

In clinical studies, concurrent administration of TNF-blocking agents and abatacept have been associated with an increased risk of infections including serious infections compared with TNF-blocking agents alone, without increased clinical benefit. Because of the nature of the adverse events seen with the combination of TNF-blocking agents and abatacept therapy, the combination of infliximab and abatacept is not recommended.

There is insufficient information regarding the concomitant use of REMSIMA^® with other biological therapeutics used to treat the same conditions as REMSIMA^®. The concomitant use of REMSIMA^® 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.

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. At least a six month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab. 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.

Infliximab and other agents that inhibit TNFα have been associated in rare cases with seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders including multiple sclerosis, and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barre syndrome. Prescribers should exercise caution in considering the use of infliximab in patients with these neurological disorders and should consider discontinuation of infliximab if these disorders develop.

In the controlled portions of clinical trials of TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. During clinical trials of infliximab in patients with rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, ankylosing spondylitis, psoriasis, and ulcerative colitis, the incidence of lymphoma in infliximab-treated patients was higher than expected in the general population, but the occurrence of lymphoma was rare. Furthermore, there is an increased background lymphoma risk even in the absence of TNF blocking therapy in rheumatoid arthritis and Crohn’s disease patients with longstanding, highly active, inflammatory disease, and/or active chronic exposure to immunosuppressant therapies, which complicates the risk estimation.

In a clinical trial exploring the use of infliximab in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, the majority of lung or head and neck origin, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Prescribers should exercise caution when considering the use of infliximab in patients with moderate to severe COPD. With the current knowledge, a possible risk for the development of lymphomas or other malignancies in patients treated with a TNF-blocking agent cannot be excluded. 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.

Rare postmarketing 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. All infliximab cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were reported in adolescent or young adult males. All of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with or immediately prior to infliximab. It is uncertain whether the occurrence is related to infliximab or infliximab in combination with these other immunosuppressants.

Cases of acute and chronic leukaemia have been reported with post-marketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukaemia.

Colon Carcinoma/Dysplasia 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. With current data it is not known if 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 to the individual patients must be carefully reviewed and consideration should be given to discontinuation of therapy.

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. Psoriasis patients should be monitored for non-melanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment.

Cervical 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. A causal relationship between infliximab and cervical cancer cannot be excluded. Periodic screening should continue in women treated with infliximab, including those over 60 years of age.

Do not initiate therapy in patients with congestive heart failure. Infliximab should be used with caution in patients with mild heart failure (NYHA class I/II). Treatment should be discontinued in patients whose congestive heart failure is worsening. Treatment discontinuation should be considered in patients with stable congestive heart failure, especially in those who have not had a significant clinical response to infliximab therapy. If a decision is made to continue treatment, cardiac status should be closely monitored and only the lower doses of Remsima^® should be considered, infliximab must not be continued in patients who develop new or worsening symptoms of heart failure.

Cases of leukopaenia, neutropaenia, thrombocytopaenia, and pancytopaenia, some with a fatal outcome, have been reported in patients receiving TNF-blockers, including infliximab. The causal relationship to infliximab therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with infliximab who have ongoing or a history of significant haematological abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g. persistent fever, bruising, bleeding, pallor) while on infliximab. Discontinuation of infliximab therapy should be considered in patients who develop significant haematological abnormalities.

There is limited safety experience of infliximab treatment in patients who have undergone surgical procedures, including arthroplasty. 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 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 infliximab worsens or causes fibrotic strictures.

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• viral infection (e.g., influenza, herpes infections)
• fever
• serum-sickness-like reactions
• headache, vertigo/dizziness
• flushing
• upper or lower respiratory tract infection (e.g., bronchitis, pneumonia)
• dyspnoea
• sinusitis
• nausea
• diarrhoea
• abdominal pain
• dyspepsia
• abnormal hepatic function
• rash
• pruritus
• urticaria
• increased sweating or dry skin
• fatigue
• chest pain
• infusion-related reactions

• abscess, cellulitis, moniliasis, sepsis, impaired healing, bacterial infection, tuberculosis, fungal infection
• autoantibodies, lupus-like syndrome, complement factor abnormality
• blood disorders - anaemia, leukopaenia, lymphadenopathy, lymphocytosis, lymphopaenia, neutropaenia, thrombocytopaenia
• psychiatric disorders - depression, confusion, agitation, nervousness, somnolence, insomnia
• central and peripheral nervous system disorders
• exacerbation of demyelinating disease suggestive of multiple sclerosis
• conjunctivitis, endophthalmitis, keratoconjunctivitis
• ecchymosis/haematoma
• hypertension, hypotension, syncope
• petechia, thrombophlebitis
• palpitation
• vasospasm, cyanosis, peripheral ischaemia
• arrhythmia
• worsening heart failure
• bradycardia
• epistaxis
• bronchospasm
• pleurisy
• respiratory tract allergic reaction
• pulmonary oedema
• constipation
• gastro-oesophageal reflux
• cheilitis
• diverticulitis
• intestinal obstruction
• cholecystitis
• fungal dermatitis/onychomycosis
• eczema/seborrhoea, hordeolum
• bullous eruption
• furunculosis
• periorbital oedema, oedema
• hyperkeratosis
• rosacea
• verruca
• abnormal skin pigmentation/colouring
• alopecia
• myalgia, arthralgia, back pain
• urinary tract infection, pyelonephritis
• vaginitis
• hot flashes
• infusion syndrome
• pain
• chills/rigors
• anaphylactic reactions

• granulomatous lesion
• lymphoma
• sarcoid-like reaction
• meningitis
• circulatory failure
• tachycardia
• pleural effusion
• intestinal perforation, intestinal stenosis, gastrointestinal
• haemorrhage
• hepatitis