(British Approved Name, rINN)
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Adverse Effects, Treatment, and Precautions
Acute infusion reactions during or within 1 to 2 hours of infusion are common with infliximab, and other TNF inhibitors, particularly with the first or second dose. Symptoms include fever, chills, pruritus, urticaria, dyspnoea, chest pain, and hypertension or hypotension. Mild reactions may respond to a reduced rate of infusion or a temporary interruption. If reactions are more severe, therapy should be stopped. Pretreatment with paracetamol, corticosteroids, and antihistamines may be considered. TNF inhibitors should only be given where facilities for resuscitation are available. Delayed reactions have occurred 3 to 12 days after infliximab treatment symptoms include myalgia, arthralgia, fever, and rash. Similar delayed reactions may also be seen when infliximab has been restarted after an extended period without treatment (see below). Other, common, adverse effects include nausea and vomiting, abdominal pain, diarrhoea, fatigue, dizziness, headache, and back pain. Antibodies to infliximab (human antichimeric antibodies) may develop, and are associated with an increased incidence of hyper sensitivity reactions. Antinuclear antibodies and anti-double-stranded-DNA antibodies have also developed with TNF inhibitor therapy. A lupus-like syndrome has occurred rarely treatment should be stopped if it develops.
Infections are common in patients treated with infliximab or other drugs that inhibit TNF, and most often affect the upper respiratory tract and the urinary tract. TNF inhibitors have also been associated rarely with the development of serious opportunistic infections, sepsis, pneumonia, and onset or reactivation of tuberculosis (see below), particularly in patients with underlying conditions predisposing them to infections in some cases death has resulted. TNF inhibitors should not be given to patients with severe infection, including active tuberculosis, abscesses, and opportunistic infections, and should be stopped if these develop. Patients should be evaluated for latent and active tuberculosis before beginning therapy if evidence of latent tuberculosis is found, the risks and benefits of treatment should be considered carefully and chemoprophylaxis should be started before giving a TNF inhibitor. They should also be used with care in those with chronic infections, a history of recurrent infections, or with underlying conditions that may predispose to infections. Patients with fistulising Crohn’s disease with suppurative fistulas should not be given infliximab until possible infection sources such as abscesses have been ruled out. Patients should be instructed to seek medical advice if symptoms suggestive of tuberculosis (such as persistent cough, weight loss, or low grade fever) occur. Patients should be monitored for signs of infection after stopping treatment: for adalimumab and infliximab, which both have long half-lives, monitoring should continue for 5 or 6 months, respectively because of its relatively shorter half-life, the elimination of etaner-cept may be quicker.
There have been rare reports of severe hepatic reactions such as acute liver failure, jaundice, hepatitis, and cholestasis with infliximab some cases have been fatal or required transplantation. Patients with signs or symptoms of hepatotoxicity should be evaluated and infliximab should be stopped in those patients with jaundice or marked elevations in liver enzyme values. Infliximab and other TNF inhibitors have also been associated with the reactivation of hepatitis B in chronic carriers, which has resulted in fatalities in some cases. Patients at risk of hepatitis B infection should be screened before starting treatment it is recommended that carriers treated with a TNF inhibitor are closely monitored during, and for several months after stopping, treatment.
Blood dyscrasias, including leucopenia, thrombocytopenia, pancytopenia, and aplastic anaemia, have been reported rarely with TNF inhibitors in some cases the outcome was fatal. They should be used with caution in patients with a history of blood dyscrasias. Rare, and sometimes fatal, cases of interstitial lung disease including pulmonary fibrosis and pneumonitis have been reported with TNF inhibitors. Infliximab and other TNF inhibitors are also associated with an increased incidence of malignancies including lymphoma (see also Carcinogenicity, below), although occurrences are rare. Some groups of patients treated with TNF inhibitors may already have an increased background risk of developing malignancies, regardless of drug treatment. Care has been advocated in patients with a history of malignancy. Anaphylactic reactions have been reported rarely with TNF inhibitors. Infliximab should be avoided in patients with a history of hyper sensitivity to the drug or other murine proteins.
TNF inhibitors have been associated in rare cases with seizures and clinical or radiological worsening of demyelinating disorders such as multiple sclerosis or optic neuritis care is required in prescribing it to patients with such disorders or symptoms suggestive of their onset.
Worsening and, in some cases, new-onset heart failure has been reported with TNF inhibitors (see Effects on the Heart, below). (NYHA class III or IV). In the UK, infliximab is contra-indicated in patients with moderate to severe heart failure however, US licensed product information advises that doses up to 5 mg/kg may be used in such patients. It should be used with caution in patients with mild heart failure (NYHA class I or II). All patients with heart failure should be closely monitored and infliximab stopped in those who develop new or worsening symptoms of heart failure. Similar recommendations are given for the TNF inhibitors adalimumab and etanercept, although UK licensed information for etanercept only advises caution in patients with heart failure.
Carcinogenicity. Malignancies, especially lymphomas, have been seen in patients treated with TNF inhibitors for rheumatoid arthritis and Crohn’s disease however, the suggestion of a causal relationship is controversial. A meta-analysis in 2006 identified 24 published reports of malignancies in 3493 study patients with rheumatoid arthritis who had received at least one dose of a TNF inhibitor (adalimumab or infliximab) along with 2 cases in 1512 control patients further, unpublished, cases were also found using FDA data to give 29 malignancies in the treatment groups and 3 in the control groups. Based on these figures, there was a 3.3-fold increase in the risk of malignancy in patients receiving TNF inhibitors when compared with controls. These results have, however, been criticised on a number of points including the difficulty in applying them to current practice because etanercept was not included in the analysis, and, in particular, the unexpectedly low rate of malignancies in the control groups. Other studies in patients with rheumatoid arthritis’ and Crohn’s disease have generally concluded that the overall risk of malignancies is not significantly increased in patients taking TNF inhibitors when compared with patients who have not taken these drugs. Some studies’ in patients with rheumatoid arthritis have, however, shown a possible increased risk of lymphoma with TNF inhibitor treatment, but caution in interpreting these results was recommended as they were based on a small number of cases in addition, the background risk of lymphoma is increased in rheumatoid arthritis regardless of treatment. The risk of malignancies with TNF inhibitors requires further study. Rare cases of hepatosplenic T-cell lymphoma have been seen in adolescents and young adults given infliximab for the treatment of Crohn’s disease. In July 2006, the manufacturer was aware of 6 cases of this type of lymphoma in 5 adolescents aged 12 to 19 years and one 31 -year-old adult 4 of the 6 cases occurred in males. The treatment duration ranged from 1 or 2 infusions to over 4 years of therapy in all cases, patients were also taking or had taken azathioprine or 6-mercaptopurine. This type of lymphoma is aggressive and 5 of the above patients died. A causal relationship was not clearly established although it could neither be excluded. Further cases have since been reported.
Delayed reactions. Ten of 37 patients with Crohn’s disease retreated with infliximab after a 2 to 4 year period without treatment had delayed hypersensitivity reactions, of which 6 were considered serious. None of the patients had had infusion-related adverse effects with their original infliximab therapy. Adverse reactions developed in 9 of the 23 patients originally treated with a discontinued liquid formulation, and in 1 of the 14 patients who previously received the marketed formulation, leading to speculation that the formulation may have been a contributing factor.
Effects on blood lipids. A 35-year-old man with psoriatic arthritis and psoriasis developed markedly elevated triglyceride levels and a mildly increased total cholesterol level after a single infusion of infliximab tests prior to therapy had shown a mild hypertriglyceridaemia for which he had received no treatment. No further doses of infliximab were given and his triglyceride levels subsequently improved.
Effects on the CNS. Aseptic meningitis developed in a patient after his fifth injection of infliximab for rheumatoid arthritis. Similar symptoms also occurred after a sixth injection. Two patients with inflammatory bowel disease developed acute motor neuropathy with multiple conduction blocks following infliximab treatment both patients improved after infliximab was stopped. Similar adverse effects were reported in 2 further patients : one was taking etanercept for rheumatoid arthritis and the other infliximab for ankylosing spondylitis. Three cases of bilateral optic neuropathy associated with infliximab therapy have also been reported. Other neuropathies have been associated with TNF inhibitor treatment, including Guillain-Barre syndrome.
Effects on the heart. The FDA has reported on 47 patients who developed heart failure during long-term therapy with TNF antibodies (etanercept and infliximab) for arthritic conditions or Crohn’s disease. Of these, 38 developed new-onset heart failure, 19 having documented risk factors for heart failure, and 9 had exacerbation of existing heart failure. The median time to new-onset heart failure was 3.5 months. However, studies investigating a possible association between TNF inhibitors and the development of heart failure have been equivocal and further investigation is warranted.
Preliminary investigations on the use of infliximab in the treatment of moderate to severe heart failure failed to show any clinical improvement in patients given infliximab 5 mg/kg or 10 mg/kg when compared with placebo in addition, those given the higher dose had an increased risk of death or hospitalisation due to worsening heart failure.
Effects on the lungs. Infliximab treatment has been associated with a fatal exacerbation of previously asymptomatic fibrosing alveolitis in 3 patients with chronic rheumatoid arthritis all 3 patients were also taking azathioprine and prednisolone. There was no evidence of infection or other underlying causes for the decline in respiratory function.
Effects on the skin. Patients with rheumatoid arthritis receiving TNF inhibitor therapy are more likely to develop adverse skin reactions than those who are not. Of 289 patients taking TNF inhibitors (infliximab, etanercept, adalimumab, and lenercept), 72 (25%) reported 128 dermatological events including skin infections, eczema, drug-related eruptions, and malignancies such as actinic keratosis of the 289 patients not taking TNF inhibitors, 37 (13%) reported dermatological events. In another review, cutaneous adverse effects were seen in 35 out of 150 patients receiving TNF inhibitors (adalimumab, etanercept, or infliximab) for rheumatic disorders cases included dermatitis herpetiformis and leucocytoclastic vasculitis although eczematous and skin infections were more common or infectious. Perhaps unexpectedly, psoriasis-like lesions were seen in 8 patients, 6 of whom had no history of psoriasis similar effects have also been noted in other patients with rheumatoid arthritis or Crohn’s disease.
Rare cases of serious skin reactions have been associated with TNF inhibitor treatment. Since approval in 1998, the FDA has received 15 cases of erythema multiforme, 5 cases of Stevens-Johnson syndrome, and 1 case of toxic epidermal necrolysis associated with infliximab cases for etanercept, approved in the same year, included 13 reports of erythema multiforme, and 4 reports each of Stevens-Johnson syndrome and toxic epidermal necrolysis. For adalimumab, which was marketed late in 2002, there have been 4 cases of erythema multiforme and 2 of Stevens-Johnson syndrome.
Infection. There have been spontaneous reports of onset or reactivation of tuberculosis in patients treated with infliximab, including cases of miliary tuberculosis and unusual extrapulmo-nary disease. The UK CSM noted in February 2001 that there had been 28 such reports worldwide. The US manufacturers subsequently reported (in October 2001) that other serious opportunistic infections, including histoplasmosis, listeriosis, and pneumocystosis had occurred, and had led to some deaths the number of reported cases of tuberculosis had risen to 84. Further opportunistic infections also continued to be reported FDA data up to August 2002 included reports of candidiasis, coccidioidomycosis, nocardiosis, aspergillosis, and infections due to non-tuberculous mycobacteria. Health Canada reported in October 2004 that it had received 188 and 109 reports of infections associated with infliximab and etanercept, respectively, from January 2000 to May 2004. Of these, 10 and 2 reports were of tuberculosis associated with infliximab and etanercept, respectively. The FDA also received 25 reports of tuberculosis associated with etanercept between November 1998 and March 2002. Although the majority of patients also had a history of treatment with im-munosuppressants including corticosteroids, the inhibition of TNF may affect normal immune responses and predispose patients to opportunistic infections.
Guidelines have been issued by the British Thoracic Society to quantify the risks of reactivation of tuberculosis with TNF inhibitors and to advise on the treatment of such infection in patients being assessed for TNF inhibitor therapy.
Live vaccines should not be given with infliximab or other drugs that inhibit TNF as the effect of such drugs on vaccine efficacy or the risk of infection transmission is unknown. The use of TNF inhibitors with the interleukin-1 receptor antagonist anakinra may increase the risk of serious infections and neutropenia such combinations are not recommended. A similar interaction has been seen with TNF inhibitors and the co-stimulation blocker abatacept.
Abatacept. Use of the TNF inhibitor etanercept with abatacept has resulted in an increase in the incidence of serious adverse effects including serious infections in addition, there was no increase in clinical benefit. Combinations of abatacept with TNF inhibitors are not recommended by UK licensed product information.
Anakinra. The incidence of serious infections, injection site reactions, and neutropenia is increased when anakinra is given with the TNF inhibitor etanercept. In addition, the combination did not provide any further clinical benefit when compared to etanercept alone. Similar findings may be expected if anakinra is given with other TNF inhibitors.
Infliximab shows linear pharmacokinetics. It is distributed primarily in the vascular compartment and, after single doses, has a terminal elimination half-life of 8 to 9.5 days. After repeated doses, infliximab has been detected in serum for at least 8 weeks.
Uses and Administration
Infliximab is a chimeric monoclonal antibody to tumour necrosis factor a (TNF), a pro-inflammatory mediator. Elevated levels of TNF have been found in the affected tissues and fluids of patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, and Crohn’s disease and ulcerative colitis. Elevated TNF levels are also found in psoriatic plaques. Infliximab is given by intravenous infusion over a usual period of not less than 2 hours shorter infusion times have been used in some patients with rheumatoid arthritis (see below for further details).
Infliximab is used with methotrexate in the management of moderate to severe, active rheumatoid arthritis to reduce the signs and symptoms of the disease, delay structural damage, and improve physical function in the UK it is licensed for use in patients who have had an inadequate response to standard disease-modifying antirheumatic drugs (DMARDs) although, in severe progressive cases, it may be used in patients not previously treated with methotrexate or other DMARDs in the USA it may be used for treating early rheumatoid arthritis. Infliximab is given in a dose of 3 mg/kg, repeated at 2 and 6 weeks, then every 8 weeks thereafter. For the first 3 doses infliximab should be infiised for at least 2 hours however, UK licensed product information suggests that subsequent infusion times may be reduced to a minimum period of 1 hour in those who tolerate the initial infusions. A clinical response is usually achieved within 12 weeks of starting treatment.
Patients with an inadequate response during this period or who later relapse may benefit by increasing the dose: in the UK, a maximum dose of 7.5 mg/kg every 8 weeks (with increases made in steps of 1.5 mg/kg) is recommended whereas, in the USA, a maximum dose of 10 mg/kg is allowed. Alternatively, a dose of 3 mg/kg may be given as often as every 4 weeks in such patients. Continuing therapy in those who show no response within the first 12 weeks of treatment or after dose adjustment should be carefully reconsidered: in the UK NICE recommends that infliximab be withdrawn if there is no adequate response within 6 months of starting treatment. Patients with moderate to severe, active Crohn’s disease unresponsive to conventional treatment may be given a single infliximab dose of 5 mg/kg. This may be followed by a maintenance regimen of additional infusions of 5 mg/kg at 2 and 6 weeks after the initial infusion and then every 8 weeks, or the drug may be read-ministered when signs and symptoms of the disease recur (but see below). UK licensed product information does not recommend further doses in patients who are unresponsive after the first 2 doses in the USA, a patient is not considered to be unresponsive until 3 doses have been given. A similar regimen is used in patients with fistulising Crohn’s disease although therapy should not be considered ineffective until after the third dose of infliximab. US product information suggests that doses of up to 10 mg/kg may be used in patients who relapse after an initial response. Infliximab is also used in the treatment of moderate to severe, active ulcerative colitis in patients unresponsive to conventional therapy the recommended dose is 5 mg/kg given as a regimen similar to that used for Crohn’s disease (see above). Therapy should not be considered ineffective until after the third dose of infliximab.
In the treatment of ankylosing spondylitis, UK licensed product information recommends that infliximab should only be used in patients with severe disease who have had an inadequate response to conventional treatment however, in the USA it may be used in early treatment, to reduce the signs and symptoms. The initial dose is 5 mg/kg, repeated at 2 and 6 weeks and then every 6 to 8 weeks if there is no response after 2 doses no further treatment should be given.
Infliximab is also used in the treatment of active and progressive psoriatic arthritis in the UK, its use is limited to patients who have had an inadequate response to standard DMARD but, as before, US licensed product information allows earlier use. In the USA, it may be given with or without methotrexate however, UK product information only recommends use without methotrexate in those patients who are intolerant of or have contra-indications to such treatment. It is given in a single dose of 5 mg/kg, repeated at 2 and 6 weeks and then every 8 weeks thereafter. Guidance issued by NICE in the UK recommends that treatment with infliximab is stopped after 12 weeks in those who show an inadequate response. Infliximab is used in the treatment of moderate to severe plaque psoriasis. Its use is usually limited to patients in whom other treatments are not suitable. Infliximab is given in a dose of 5 mg/kg, repeated at 2 and 6 weeks, then every 8 weeks thereafter. Treatment should be stopped after 14 weeks (4 doses) in patients who show no response.
If the signs and symptoms of rheumatoid arthritis or Crohn’s disease recur infliximab may be readminis-tered if within 16 weeks of the last infusion. Readministration after a drug-free interval of more than 16 weeks may be associated with an increased risk of delayed hypersensitivity (see Delayed Reactions, above) and consequently is not recommended. Recommendations regarding the readministration of infliximab for other indications (other than those detailed above) have not been established. Limited data from readministration with a single dose of infliximab in psoriasis after an interval of 20 weeks suggest reduced efficacy and a higher incidence of mild to moderate infusion reactions when compared with the initial regimen. For details of infliximab use in children, see below.
Administration in children. Infliximab is licensed for use in moderate to severe, active Crohn’s disease in children aged 6 years and over who have not responded to conventional therapy, or who have contraindication for or are intolerant of such treatments doses are the same as those used in adults (see above). UK licensed product information suggests that the dosage interval may be adjusted to maintain any benefits however, further treatment is unlikely to be of use in patients not responding within the first 10 weeks.
Although unlicensed for such use in the UK, infliximab has also been used in children with fistulising Crohn’s disease the BNFC recommends that those aged 6 to 18 years may be treated with the same dosage regimen that is used for this indication in adults (see above).
Asthma. TNF inhibitors such as infliximab have been investigated in the treatment of refractory asthma. There is some evidence that only a minority of patients will respond to such therapy, and that the benefits and risks must therefore be carefully assessed.
Inflammatory bowel disease. Infliximab is used in adults for the treatment of Crohn’s disease and ulcerative colitis (see Inflammatory Bowel Disease) it has also been used in children in the treatment of inflammatory bowel disease, particularly Crohn’s disease.
In the treatment of Crohn’s disease, guidance issued in the UK by NICE recommends that infliximab is used in patients with severe disease when treatment with immunomodulators and corticosteroids has failed or is not tolerated, and when surgery is inappropriate.
In the treatment of ulcerative colitis, guidance issued by NICE recommends against the use of infliximab in subacute manifestations of moderately to severely active disease (defined as that which would normally be managed in an outpatient setting, and does not require hospitalisation or the consideration of urgent surgical intervention). The use of infliximab in acute manifestations of moderately to severely active ulcerative colitis is under review by NICE.
Leprosy. Infliximab has been used in the treatment of recurrent type 2 (erythema nodosum leprosum) lepra reactions (see Leprosy). However, 2 cases of rapidly progressive leprosy developing in patients given infliximab for rheumatoid arthritis have also been described reversal (type 1) reactions occurred in both when infliximab was stopped.
Psoriasis. Infliximab is used in the treatment of moderate to severe plaque psoriasis. In the UK, NICE recommends that it be reserved for severe cases, unresponsive to standard therapies (including ciclosporin, methotrexate, and PUVA) or where such therapies cannot be used.
Rheumatoid arthritis. TNF inhibitors play an increasingly important role in the management of rheumatoid arthritis they tend to be reserved for patients who are unresponsive to more conventional disease-modifying drugs, although some favour use earlier in management.
Some references to the use of infliximab in rheumatoid arthritis and juvenile idiopathic arthritis.
Sarcoidosis. For a mention of possible benefit from infliximab in sarcoidosis.
Spondyloarthropathies. References to the use of infliximab in the treatment of ankylosing spondylitis and psoriatic arthritis. In the UK, NICE considers that TNF inhibitors should be reserved for severe active psoriatic arthritis unresponsive to at least 2 standard disease-modifying drugs etanercept or adalimumab are preferred to infliximab.
Uveitis. Infliximab has been tried with some success in the treatment of uveitis including that associated with Behcet’s syndrome. Uveitis can also develop as a complication of other inflammatory disorders such as rheumatoid arthritis treatment with infliximab may improve ocular symptoms in addition to its effect on the primary disorder. References.
Vasculitic syndromes. For a preliminary report on the use of infliximab in Takayasu’s arteritis. Infliximab has also been investigated in the management of Kawasaki disease in patients who are unresponsive to standard treatment.
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