Infliximab is a chimeric IgG1k monoclonal antibody targeted against tumor necrosis factor-alpha (TNF-alpha), also known as a TNF-blocker. Infliximab was the first of the tumor necrosis factor (TNF) modifiers marketed in the U.S. Infliximab, like other TNF blockers, is effective in a variety of inflammatory conditions. Infliximab is approved in adults for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. In adults with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) the drug improves clinical signs and symptoms, inhibits the radiographic progression of structural joint damage, and improves physical function; in adults with ankylosing spondylitis (AS), the drug improves clinical signs and symptoms of active disease, which can improve quality of life. For adult RA, infliximab is usually given along with methotrexate. For adult PsA or AS, infliximab may be used as monotherapy; the drug may also be used with other disease-modifying antirheumatic agents (DMARDs). The ideal combination of therapy for individual patients with inflammatory arthritis conditions is determined by treat to target strategies and severity of disease. For PsA, TNF-blockers are considered a first-line treatment, even in treatment-naive patients. Infliximab is beneficial in adults with moderate to severe plaque psoriasis; TNF-blockers may be used as first-line systemic treatments alone or in combination with other therapies. Infliximab is also used for patients with inflammatory bowel disease (IBD). It is administered intravenously to adult and pediatric patients 6 years of age and older for Crohn's disease and ulcerative colitis. Infliximab may be administered subcutaneously to adults only for maintenance treatment of moderately to severely active Crohn's disease and ulcerative colitis, starting at week 10 following intravenous infliximab induction regimen. The effectiveness of infliximab has been demonstrated for both active moderately to severely active luminal Crohn's disease and for fistulizing Crohn's disease, where the drug helps induce and maintain clinical remission. In moderately to severely active ulcerative colitis patients with an inadequate response to conventional therapy, the drug can induce and maintain clinical remission and mucosal healing, and may reduce corticosteroid use. As with other TNF blockers, infliximab labeling carries a boxed warning regarding the risk for serious infections, including tuberculosis, and the potential risk of malignancy.
Updates for coronavirus disease 2019 (COVID-19):
According to the National Institutes of Health (NIH) COVID-19 treatment guidelines, infliximab may be used as an alternative to baricitinib or tocilizumab for the treatment of COVID-19 in hospitalized patients:
-on conventional oxygen who are exhibiting signs of systemic inflammation and rapidly increasing oxygen needs while receiving dexamethasone
-on high-flow oxygen or noninvasive ventilation
Infliximab must be given in combination with dexamethasone (with or without remdesivir), and is only recommended for use when baricitinib and tocilizumab are unavailable or cannot be administered. The drug is not recommended for use in patients requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO), as benefit in these patients has not been established.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Prior to initiating infliximab therapy, patients must be evaluated for latent tuberculosis infection.
-Visually inspect products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
General Information
-Vials of infliximab are administered as an intravenous (IV) infusion, after dilution as instructed.
-Calculate the dose, total volume of reconstituted solution required, and the number of infliximab vials needed. More than 1 vial may be needed for the full dose.
-Upon removal of an unopened vial from refrigerated storage in preparation for reconstitution, infliximab cannot be returned to refrigerated storage. However, unopened vials may be stored at temperatures up to a maximum of 30 degrees C (86 degrees F) for a single period of up to 6 months but not exceeding the original expiration date.
Reconstitution of infliximab vials
-Reconstitute each vial (100 mg) with 10 mL of Sterile Water for Injection, to obtain a concentration of 10 mg/mL. Use a syringe equipped with a 21-gauge or smaller needle.
-Insert the syringe needle into the vial and direct the stream of Sterile Water for Injection to the glass wall of the vial.
-Gently swirl the solution by rotating the vial to dissolve the lyophilized powder. Avoid prolonged or vigorous agitation. Do not shake.
-Allow the reconstituted solution to stand for 5 minutes.
-The solution should be colorless to light yellow and opalescent; a few translucent particles may develop. Do not use if opaque particles, discoloration, or other foreign particles are present. Do not use if the lyophilized powder is not fully dissolved.
-The reconstituted solution in the vials must be further diluted prior to administration. Do not store unused reconstituted solution.
Dilution for Infusion
-Further dilute the total dose of the reconstituted solution to 250 mL with 0.9% Sodium Chloride Injection. Do not dilute the reconstituted infliximab solution with any other diluent.
-Withdraw a volume of 0.9% Sodium Chloride Injection equal to the total dosage volume of reconstituted infliximab from a 250 mL glass bottle or bag containing 0.9% Sodium Chloride Injection.
-Slowly add the total dosage volume of reconstituted infliximab solution to the 250 mL infusion bottle or bag. Gently invert the bag or bottle to mix the solution.
-The final infusion concentration should be 0.4 mg/mL (minimum recommended concentration) to 4 mg/mL (maximum recommended concentration). For volumes greater than 250 mL, a larger infusion bag (e.g. 500 mL) or multiple 250 mL infusion bags may be used to ensure that the final concentration does not exceed 4 mg/mL.
Intravenous Infusion Administration
-Prior to IV infusion, premedication may be administered at the prescriber's discretion. Premedication could include antihistamines, acetaminophen and/or corticosteroids.
-The IV infusion should begin within 3 hours of reconstitution and dilution.
-Do not administer the solution if visibly opaque particles, discoloration, or other foreign particles are observed.
-Do not infuse the infliximab solution concomitantly in the same intravenous line with other agents.
-Infuse IV over a period of not less than 2 hours. Use an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 microns or less). Discard any unused portion.
If Infusion Reactions Occur During Administration
-During infusion, mild to moderate infusion reactions may improve if the infusion rate is slowed or the infusion is temporarily discontinued.
-Upon resolution of the reaction, reinitiate administration at a lower infusion rate and/or the prescriber may order treatment with antihistamines, acetaminophen, and/or corticosteroids.
-For patients that do not tolerate the infusion following these interventions, infliximab should be discontinued.
-Discontinue infliximab if severe hypersensitivity reactions occur. Most such reactions occur within 2 hours of an infusion. Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the event of a serious reaction.
Subcutaneous Administration
Zymfentra Prefilled Subcutaneous Injection:
-Zymfentra is indicated for maintenance therapy only and is for subcutaneous use only.
-All patients must complete infliximab intravenous induction therapy prior to starting Zymfentra at week 10.
-Missed dose: If a dose is missed, administer the next subcutaneous dose as soon as possible and then every 2 weeks after.
Administration:
-Patients may self inject if deemed appropriate by a healthcare professional.
-Do not administer the solution if visibly opaque particles, discoloration, or other foreign particles are observed.
-Do NOT shake or reuse the prefilled syringe or pen.
-Do NOT use damaged or dropped syringes or pens.
-Inject into the front of the thighs or the abdomen except for the 2 inches around the navel.
-Injection in the outer area of the upper arms should be given by caregiver or healthcare professional only.
-Rotate the injection site each time an injection is given and allow at least 1.2 inches between new injection site and previous injection site.
-Never inject into red, bruised, tender, or indurated skin.
-Storage: Prefilled syringes and pens are single-use. Store in the refrigerator between 2 and 8 degrees C (36 and 46 degrees F). Do not freeze. Keep in the original carton until time of administration in order to protect from light.
In general, the types and frequencies of adverse reactions observed during clinical trials were similar in infliximab-treated patients, regardless of indication for use.
Gastrointestinal (GI) adverse events experienced by the 1129 patients who received at least 4 infliximab infusions for rheumatoid arthritis included nausea (21%), diarrhea (12%), and dyspepsia (10%). Of note, patients receiving infliximab for treatment of Crohn's disease reported a higher incidence of abdominal pain (26%) than those receiving treatment for rheumatoid arthritis (12%). Other medically relevant adverse GI events experienced by a smaller percentage (0.2% or more) of infliximab-treated patients included constipation, GI obstruction, and dehydration. Abdominal pain was reported in 3% of patients with ulcerative colitis treated with subcutaneous infliximab compared to 1% of patients treated with placebo, during maintenance phase trials. Diarrhea was reported in 5% of patients with Crohn's disease treated with subcutaneous infliximab compared to 1% of patients treated with placebo, during maintenance phase trials.
Adverse events affecting the body as a whole and that were experienced by the 1,129 patients who received at least 4 infliximab infusions for rheumatoid arthritis included fatigue (9%) and pain (8%). Additional medically relevant adverse events experienced by a smaller percentage (0.2% or more) of patients included edema, dizziness, and hyperhidrosis (increased sweating). Dizziness was reported in 3% of patients with Crohn's disease treated with subcutaneous infliximab compared to no reports in placebo treated patients. Fatigue and malaise were reported during postmarketing experience with subcutaneous infliximab.
Evaluate patients with signs or symptoms of hepatic dysfunction or hepatic encephalopathy while receiving infliximab for evidence of liver injury. Discontinue infliximab if jaundice or if elevated liver function tests occur with AST or ALT concentrations at least 5 times the upper limit of normal (ULN), and thoroughly investigate the cause. Postmarketing reports of severe hepatic reactions such as acute hepatic failure, jaundice, hepatitis (including autoimmune hepatitis), and cholestasis associated with infliximab have been received; some cases were fatal or necessitated liver transplantation. Onset of severe hepatic reactions varied between 2 and greater than 52 weeks after infliximab initiation and elevated hepatic enzymes were not noted prior to discovery of the liver injury in many cases. In adults with rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, or psoriatic arthritis, mild or moderate elevations of serum ALT and AST concentrations without progression to severe hepatic injury were observed. Elevations of aminotransferases less than 3 times the ULN were observed (ALT more common than AST) in a greater proportion in infliximab recipients (17 to 51%) as compared with placebo recipients (12% to 34%). Also, 2% to 10% of infliximab recipients had elevations in ALT at least 3 times the ULN vs. 4% or less of placebo recipients, and, up to 4% of infliximab recipients had elevations in ALT at least 5 times the ULN vs. less than 1% of placebo recipients. Elevations were more common both when infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents. Among pediatric patients in clinical trials, elevations of ALT up to 3 times the ULN were seen in 17% to 18%; 4% to 7% of pediatric patients had ALT elevations at least 3 times the ULN, and 1% to 2% had elevations greater than 5 times ULN. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with modification of concomitant medications or either continuation or discontinuation of infliximab. During clinical trials with subcutaneous infliximab, 3 patients developed drug induced liver injury based on hepatic transaminase elevations, including on subject with accompanying bilirubin elevation. Increased alanine aminotransferase was reported in 3% of patients with ulcerative colitis treated with subcutaneous infliximab compared to 1% of placebo treated patients. In patients with Crohn's disease, increased alanine aminotransferase was reported by 4% of patients treated with subcutaneous infliximab compared to 1% of placebo treated patients. Two patient with ulcerative colitis reached peak values of to 4 to 11 times ULN for ALT and 2 to 7 times the ULN for AST after starting subcutaneous infliximab. One patient with Crohn's disease reached peak values 18 times the ULN for ALT, 14.9 times the ULN for AST, and 2.5 ULN for total bilirubin. Monitor hepatic enzymes and liver function tests every 3 to 4 months in patients treated with subcutaneous infliximab, Interrupt subcutaneous infliximab therapy if drug induced liver injury is suspected and resume once diagnosis is excluded. Reactivation of hepatitis B virus (HBV) may occur in persons who are chronic carriers and may be fatal; most cases have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. If reactivation occurs, discontinue treatment and initiate antiviral medications. The safety of infliximab resumption after HBV reactivation is controlled is unknown; thus, exercise caution when considering infliximab resumption.
Pulmonary adverse events experienced by the 1129 patients who received at least 4 infliximab infusions, for rheumatoid arthritis, included increased cough (12%), pleurisy (0.2% or more), and pulmonary edema (0.2% or more). Adverse pulmonary reactions reported with postmarketing use include pulmonary fibrosis and interstitial pneumonitis. Due to the voluntary nature of postmarket reports, neither the frequency nor a causal relationship to infliximab can be established.
Acute infusion-related reactions occur during or within 1 to 2 hours of administration in 20% of adults and in 18% of children and adolescents. Monitor patients during infliximab infusion and if serious infusion-related reactions occur, discontinue the infusion. Further management of reactions should be dictated by signs and symptoms. Approximately 3% of patients in clinical trials discontinued the drug because of infusion reactions, such as dyspnea, flushing, headache, and rash (unspecified). All patients recovered with treatment and/or discontinuation of the infusion. Among all infliximab infusions during clinical trials, 3% were accompanied by nonspecific symptoms such as fever or chills, and 1% were accompanied by cardiopulmonary reactions such as chest pain (unspecified), hypotension, hypertension, or dyspnea. Less than 1% of these infusion-related reactions were accompanied by pruritus, urticaria, or the combined symptoms of itching/urticaria and cardiopulmonary reactions. Serious acute infusion-related reactions including anaphylaxis, seizure, erythematous rash, and hypotension occurred in less than 1% of adults treated during clinical trials. Serious infusion-related cardiovascular events, including cerebrovascular accidents (stroke), myocardial ischemia, myocardial infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported within the first 24 hours of infliximab infusion. Adverse events, such as fever or headache, were not always related to the infusion period during clinical trials included fever (7%) and headache (18%), and cardiovascular events such as hypertension (7%), hypotension (0.2% or more), and bradycardia (0.2% or more). Among patients with Crohn's disease who were treated with subcutaneous infliximab during clinical trials, 8% reported headache compared to 4% reported by placebo treated patients. Hypertension (essential hypertension) was reported in 3% of patients with Crohn's disease treated with subcutaneous infliximab compared to 2% in placebo treated patients. Pericardial effusion has been reported with the postmarketing use of infliximab.
Cases of worsening heart failure with and without identifiable precipitating factors and reports of new onset heart failure, including cases in patients without known pre-existing cardiovascular disease during the infliximab postmarketing period have been received. In a phase II trial evaluating infliximab in patients with NYHA class III/IV congestive heart failure (left ventricular ejection fraction 35% or less) higher incidences of mortality and hospitalization due to worsening heart failure were seen in infliximab-treated patients, especially in those receiving doses greater than 10 mg/kg. One hundred and fifty patients were treated with 3 infusions of 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 1 year, 8 patients treated with infliximab 10 mg/kg and 4 patients in the 5 mg/kg and placebo groups had died. According to the manufacturer, there were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 5 mg/kg and 10 mg/kg groups compared to the placebo group. Avoid administering infliximab doses of more than 5 mg/kg in patients with moderate to severe heart failure. Discontinue infliximab in patients who develop new or worsening symptoms of heart failure.
Most hypersensitivity reactions have occurred during or within 2 hours of an infusion. Discontinue infliximab for severe hypersensitivity reactions and have immediate availability of medications used for the treatment of hypersensitivity reactions. Do not re-administer to patients who have experienced a severe hypersensitivity reaction. Also, carefully consider the benefit-risk of readministration of infliximab after a period of no treatment, especially as a re-induction regimen given at weeks 0, 2, and 6. In the case where maintenance therapy for psoriasis is interrupted, reinitiate as a single dose followed by maintenance therapy. In rheumatoid arthritis, Crohn's disease, and psoriasis clinical trials, readministration after a period of no treatment resulted in a higher incidence of reactions relative to regular maintenance treatment. Serious acute infusion-related reactions including anaphylaxis or anaphylactoid reactions, seizure, erythematous rash, and hypotension occurred in less than 1% of adults treated during clinical trials. Among 112 pediatric patients 6 to 17 years old with Crohn's disease, 2 patients had non-serious anaphylactoid reactions; infusions beyond the initial infusion were not associated with a higher incidence of reactions. In clinical trials of subcutaneous infliximab symptoms compatible with hypersensitivity reactions have been reported including bronchospasm, dyspnea, rash, and edema. During maintenance phase clinical trials, patients with ulcerative colitis who were treated with subcutaneous infliximab experienced injection site reactions at a higher rate compared to placebo (3% vs 2%). In patients with Crohn's disease, 5% of patients reported injection site reactions with subcutaneous infliximab compared to 1% of placebo treated patients. Reactions included injection site bruising, edema, erythema, induration, pain, pruritus, rash, swelling and warmth. During postmarketing surveillance, cases of anaphylactic shock and anaphylactoid reactions (including laryngeal edema and severe bronchospasm) have been reported with infliximab use.
Arthralgia occurred in 8% of patients receiving infliximab during clinical trials, and at an incidence greater than with placebo. In maintenance clinical trials, patients with ulcerative colitis who were treated with subcutaneous infliximab experienced arthralgia at a higher rate compared placebo treated patients (4% vs. 1%). Arthralgia was reported in 4% of patients with Crohn's disease who were treated with subcutaneous infliximab compared to 3% in placebo treated patients. Increased blood creatine phosphokinase was reported in 4% of Crohn's disease patients treated with subcutaneous infliximab compared to 2% in placebo treated patients. Infliximab is associated with serum sickness-like reactions that include a constellation of symptoms such as fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema, and/or dysphagia. Serum sickness-like reactions have been observed in patients as early as after the second dose and after infliximab reinstitution following an extended period without the drug. Serum sickness was reported in at least 0.2% of patients in the rheumatoid arthritis trials in adults. In the psoriasis studies, 1% of patients receiving infliximab experienced serum sickness or a combination of arthralgia and/or myalgia with fever, and/or rash, usually early in the treatment course. These reactions generally occurred within 2 weeks after repeat infusion. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility. Discontinue infliximab for severe reactions. Readministration of infliximab after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment. In general, the benefits and risks of re-administration of infliximab after a period of no treatment should be carefully considered. Serum sickness-like reactions are associated with a marked increase in antibodies to infliximab, loss of detectable serum concentrations, and possible loss of drug efficacy.
Dermatologic and allergic adverse reactions reported during postmarket use include erythema multiforme (EM), Stevens-Johnson syndrome (SJS), linear IgA bullous dermatosis (LABD), acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN), and lichenoid reactions (lichen planus-like eruption). Over the period August 1998 to August 2006, the FDA received 15 reports of EM, 5 reports of SJS, and 1 case of TEN associated with infliximab. The median time to onset of skin reactions was 28 days from initiation (range, 4 days to 18 months). The time to onset of EM since the last dose was reported as 14 days, 20 days, and 28 days in 3 cases. One patient had a similar skin reaction to etanercept, which was started 3 months after infliximab discontinuation. In one case, cutaneous, eczema-like lesions developed 1 day after the second infusion, and SJS developed after the third infusion, which was given about a month after the second infusion. Infliximab was the only medication discontinued, and her condition improved over several weeks. In 15 cases, patients were using 1 or more concomitant medications associated with EM, SJS, and/or TEN. Recovery after discontinuation was reported in 15 of the total 21 reported cases; 2 patients had a positive rechallenge, and 1 patient had a negative rechallenge with infliximab reintroduction approximately 5 months later.
Infliximab may cause keratoderma blenorrhagicum, which is a psoriaform rash that occurs primarily on the palms and soles in some patients with reactive arthritis and is grossly and histologically indistinguishable from pustular psoriasis. A women developed erythematous, pustular, scaly skin lesions on the soles of both feet about 10 months after starting another TNF antagonist (etanercept) for rheumatoid arthritis. Affected skin was PCR positive for Chlamydia trachomatis chromosomal DNA. Importantly, in vitro, chlamydial replication is inversely proportional to TNF alpha concentrations. Expectantly, keratoderma blenorrhagicum has also been noted in patients who have received infliximab and adalimumab.
Treatment with infliximab has resulted in the development of lupus-like symptoms, and lupus-like symptoms were reported in some patients during clinical trials. All patients improved following discontinuation of infliximab therapy and appropriate medical treatment. Postmarketing reports of lupus-like symptoms were also observed among children or adolescents receiving infliximab treatment. If a patient develops symptoms of a lupus-like syndrome following treatment with infliximab, treatment should be discontinued. Patients who are infliximab antibody-positive are more likely to experience infusion-related reactions. Autoantibody formation and antibody formation against infliximab have been reported during infliximab therapy. Based on available data, antibody formation is a common effect, but the incidence (percentage) and detection of antibody formation are highly dependent on the sensitivity and specificity of the assay, and factors influencing sample collection quality. Infliximab antibody development is lower among patients receiving concurrent immunosuppressive therapy (e.g., mercaptopurine, azathioprine, or methotrexate). The original method for detecting antibody formation, enzyme immunoassay (EIA), was subject to interference by serum infliximab, possibly resulting in an underestimation of the exact rate of antibody formation. A new method for antibody detection, electrochemiluminescence immunoassay (ECLIA), is drug-tolerant and 60-fold more sensitive than the EIA. All clinical studies of infliximab used the EIA except for the Phase III pediatric ulcerative colitis (UC) study. Among pediatric patients receiving infliximab for UC, 58 were evaluated for antibodies to infliximab using the EIA and ECLIA. With the EIA method, 7% of pediatric patients had antibodies to infliximab, whereas 52% had antibodies to infliximab using the ECLIA method. The EIA-positive patients generally had undetectable infliximab trough concentrations while the ECLIA-positive patients could have detectable trough concentrations because ECLIA is more sensitive and drug-tolerant. In rheumatoid arthritis (RA) patients, 62% of patients treated with infliximab developed antinuclear antibodies (ANA) and 15% developed anti-dsDNA antibodies. The prevalence of autoantibodies in patients with RA and naivety to TNF-alpha inhibitors was determined before and after infliximab initiation. The number of RA patients positive for antinuclear antibodies was 12/50 at baseline, 22/51 at week 14, 41/53 at week 30, and 31/45 at week 54. The number of RA patients positive for anti-double-stranded DNA antibodies was 1/50 at baseline, 23/51 at week 14, 35/53 at week 30, and 20/44 at week 54. The number of RA patients positive for antinuclear antibodies was 5/50 at baseline, 13/50 at week 30, and 10/40 at week 54. In Crohn's disease patients, 44% developed ANA, and 22% developed anti-dsDNA antibodies. No association between infliximab dose/schedule and the development of autoantibodies was seen. However, in Crohn's disease patients, baseline therapy with an immunosuppressant was associated with a decreased incidence of anti-dsDNA antibodies (3% vs. 21% in patients not receiving an immunosuppressant treatment). Crohn's disease patients were 2-times more likely to develop anti-dsDNA antibodies if they were ANA-positive at study entry. In patients with ulcerative colitis and Crohn's disease who were treated with subcutaneous infliximab, 64% developed anti-drug antibodies by week 54 following intravenous induction and subcutaneous maintenance therapy. Among subjects with anti-drug antibodies, 92% of patients had neutralizing antibodies. Concomitant immunosupressant agents appeared to reduce the frequency of anti-drug antibodies in subcutaneous infliximab. A genomewide association study found that the HLA-DQA1*05 allele increased the risk of infliximab antibody formation by 2-fold in patients with Crohn's disease, regardless of concomitant immunomodulator use. The formation of antibodies to infliximab can be reduced by the use of immunomodulators.
Postmarketing reports of systemic and cutaneous vasculitis associated with infliximab have been received; 15 cases of leukocytoclastic vasculitis were identified following infliximab administration by examination of reports to the Adverse Events Reporting System of the U.S. Food and Drug Administration. Four of the 15 were biopsy-proven cases, and the other patients had skin lesions that were clinically typical for leukocytoclastic vasculitis. Nine of the 15 patients had complete or marked improvement of skin lesions upon infliximab cessation. Leukocytoclastic vasculitis lesions improved in patients despite continuing use of concomitant medications reportedly associated with leukocytoclastic vasculitis. The outcome was unknown for 5 cases and 1patient had continuing lesions despite infliximab discontinuation and treatment with prednisone and antihistamines. Of 2 rechallenges, 1 was positive (recurrence of leukocytoclastic vasculitis on restarting infliximab). If a patient develops leukocytoclastic vasculitis while taking infliximab, infliximab discontinuation and other possible etiologies should be considered. A cautious rechallenge with infliximab may be warranted.
Infliximab has been associated in cases with optic neuritis, seizures, and new onset or exacerbation of clinical symptoms or radiographic evidence of central demyelinating disorders such as multiple sclerosis. Also, infliximab has been associated with central nervous system (CNS) manifestations of systemic vasculitis. Postmarketing reports of transient visual loss, transverse myelitis, neuropathies (i.e., chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy), and Guillain-Barre syndrome associated with infliximab have been received. Carefully consider infliximab usage in patients with pre-existing or recent onset CNS demyelinating or seizure disorders. Subcutaneous infliximab should be avoided in patients with pre-existing or recent onset CNS demyelinating disorders or seizure disorders. Multiple sclerosis was reported in postmarketing experience of subcutaneous infliximab as well. Consider infliximab discontinuation if significant neurologic adverse reactions develop. Cases of transient visual loss (visual impairment) have also been reported during or within 2 hours of infusion.
Overall, the incidence of infliximab-associated infection ranges from 5.3% to 56%. In clinical trials, treated infections were reported by 36% of infliximab-treated adults (average of 51 weeks of follow-up) and by 25% of placebo-treated patients (average of 37 weeks of follow-up). The infections most frequently reported were upper respiratory tract infections (32%) such as sinusitis (14%), pharyngitis (12%), and bronchitis (10%) and urinary tract infections (8%). Monoliasis (candidiasis) was reported in 5% of treated patients. Reported serious infections include pneumonia (0.2% or more), cellulitis (0.2% or more), sepsis (0.2% or more), skin ulcer, abscesses, and bacterial infections. In trials with subcutaneous infliximab, at least 1 serious infection was reported in 3% of patients with ulcerative colitis compared to 1% in the placebo group. Infections included COVID-19, cystitis, pneumonia, salpingitis, and urinary tract infection. During maintenance phase clinical trials for ulcerative colitis, a higher incidence of COVID-19 and COVID-19 pneumonia occurred in subcutaneous infliximab treated patients compared to placebo treated patients (10% vs. 6%). For patients with Crohn's disease, COVID-19 occurred in 10% of patients treated with subcutaneous infliximab compared to 5% of placebo treated patients. In patients with Crohn's disease, infections were observed in 30% of subcutaneous infliximab treated patients compared to 17% of placebo treated patients. At least 1 serious infection was reported in 3% of patients with Crohn's disease compared to 1% of placebo treated patients. Serious infections included urinary tract infection, abscess, appendicitis, bacterial arthritis, bartholinitis, and bronchiolitis. Urinary tract infections and pyelonephritis have been reported in 3% of patients with Crohn's disease who were treated with subcutaneous infliximab compared to 2% of placebo treated patients. Upper respiratory infections occurred in 7% of patients with Crohn's disease treated with subcutaneous infliximab compared to 3% of placebo treated patients. Infections included upper respiratory tract infection, acute sinusitis, chronic sinusitis, influenza like illness, nasopharyngitis, pharyngitis, pharyngitis streptococcal, rhinitis, rhinorrhea, rhinovirus infection, sinusitis, and tonsillitis. In the 1 year placebo-controlled studies of patients with rheumatoid arthritis, 5.3% of patients receiving infliximab every 8 weeks with methotrexate developed serious infections as compared with 3.4% of placebo patients receiving methotrexate. Further, among patients who also received methotrexate, serious infections were more common with a higher infliximab dose; 5.3% of 10 mg/kg recipients as compared with 1.7% of either 3 mg/kg recipients or placebo recipients. Of 103 children and adolescents, 56% had an infection. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. In a clinical trial, the addition of infliximab to methotrexate significantly increased the incidence of pneumonia at one year compared with methotrexate therapy alone (1.7% vs. 0.3%) in patients with rheumatoid arthritis. Tuberculosis was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of tuberculosis including disseminated disease, histoplasmosis, listeriosis, and Pneumocystis have been reported post-marketing. Most cases of tuberculosis occurred within the first 2 months after initiation of therapy and may reflect activation of latent disease. Infections due to various pathogens including viral, bacterial, fungal, and protozoal organisms have been observed. During maintenance phase clinical trials, a higher incidence of COVID-19 and COVID-19 pneumonia occurred in subcutaneous infliximab treated patients with ulcerative colitis compared to placebo treated patients (10% vs. 6%). For patients with Crohn's disease, COVID-19 occurred in 10% of patients treated with subcutaneous infliximab compared to 5% of placebo treated patients. Infections have been noted in all organ systems and have been reported with infliximab alone or in combination with other immunosuppressive agents. Patients taking TNF blockers, including infliximab, are at increased risk of serious infections including invasive fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, cryptococcosis, as well as other opportunistic infections. In clinical trials, 7 opportunistic infections were reported; 2 cases each of coccidioidomycosis (1 case was fatal) and histoplasmosis (1 case was fatal) and 1 case each of pneumocystosis, nocardiosis, and cytomegalovirus. Postmarketing reports of pulmonary and disseminated histoplasmosis, coccidioidomycosis, blastomycosis, and other opportunistic infections have also been received. The FDA reviewed 207 cases of histoplasmosis in patients receiving infliximab; most cases were from Histoplasma capsulatum-endemic areas in the Ohio and Mississippi River valleys. Histoplasmosis and other invasive fungal infections are not consistently recognized in patients taking TNF blockers, which has resulted in delayed appropriate treatment that sometimes led to death. Ascertain if patients live in or have traveled to areas of endemic mycoses, and consider empiric antifungal treatment until the pathogen(s) are identified. A complete diagnostic workup that may include fungal cultures, histopathological or cytological evaluations, antigen detection, and serum antibody titers is advised. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Signs and symptoms of possible systemic fungal infection include fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, or other serious systemic illness with or without concomitant shock. If possible, consultation with an infectious diseases specialist should be sought. Closely monitor patients for signs and symptoms of infection while on or after treatment. If a new infection occurs, conduct a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy. Infliximab should be discontinued if a patient develops a serious infection or sepsis. Strongly consider tuberculosis in a patient who develops a new infection and has previously or recently traveled to countries with a high prevalence of tuberculosis or who has close contacts with a person with active tuberculosis. The decision to restart the TNF blocker should include a reevaluation of the benefits and risks of TNF blockers, especially in patients who live in regions of endemic mycoses. During postmarketing experience with subcutaneous infliximab, cellulitis, disseminated tuberculosis, lower respiratory tract infection, pneumonia, sepsis have been reported.
Although the causal relationship to infliximab therapy is unclear, cases of leukopenia, neutropenia, thrombocytopenia (0.2% or more), pancytopenia, anemia (0.2% or more), hemolytic anemia (0.2% or more), thrombo-phlebitis (0.2% or more), leukopenia (0.2% or more), and lymphadenopathy (0.2% or more), some with fatal outcome, have been reported in adults treated with infliximab. Of 103 children or adolescents, 11% had anemia, 9% had leukopenia, and 7% had neutropenia. Idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), agranulocytosis (including in infants exposed in utero to infliximab) have been reported with postmarketing use of infliximab. Exercise caution in patients with ongoing or a history of significant hematologic abnormalities. Clinically significant events of neutropenia were observed in patients during clinical trials with subcutaneous infliximab. During maintenance phase clinical trials, anemia and iron deficiency anemia was reported in 5% of subcutaneous infliximab treated patients compared to 4% of placebo treated patients. Subcutaneous infliximab should be avoided in patients with current or past significant hematological abnormalities. Both neutropenia and leukopenia were reported in 3% of patients with Crohn's disease who were treated with subcutaneous infliximab compared to no reports by placebo treated patients. Patients who develop signs and symptoms suggestive of blood dyscrasias or infection should get immediate medical attention. Consider discontinuing infliximab in patients who develop significant hematologic abnormalities.
Infliximab may cause a new primary malignancy. Malignancies, including lymphoma and hepatosplenic T-cell lymphoma (HSTCL), an aggressive cancer that is usually fatal, have been reported in children and adolescents treated with TNF blockers such as infliximab. Approximately half of the cancer cases when infliximab was initiated in patients 18 years of age or younger were lymphomas including Hodgkin and non-Hodgkin lymphoma. Other cancers included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range, 1 to 84 months), and most patients were receiving concomitant immunosuppressants. Most cases of HSTCL occurred in adolescent and young adult males with Crohn's disease or ulcerative colitis. Almost all of these patients had received treatment with azathioprine or mercaptopurine concomitantly with a TNF blocker at or before diagnosis. It is uncertain whether the occurrence of HSTCL is related to the use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. In the combined clinical trial population for rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were observed, which is an approximately 4-fold higher occurrence than expected in the general population. In the rheumatoid arthritis population only, the risk was approximately 3-fold higher than expected. Other types of cancer (e.g., breast, melanoma, and colorectal) developed in 14 patients. The number of patients who developed a malignancy besides lymphoma is similar to the number expected in the general population; however, the median duration of follow-up was 6 months. Of note, in the absence of TNF blocking therapy, patients with Crohn's disease, rheumatoid arthritis, or plaque psoriasis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several-fold) than the general population for the development of lymphoma. In a population-based retrospective cohort study, invasive cervical cancer was reported as a 2- to 3-fold increase in women, particularly those over 60 years of age, with rheumatoid arthritis treated with infliximab compared to patients not receiving biologics. A causal relationship between infliximab and cervical cancer cannot be excluded. Periodic cervical cancer screening should continue in women treated with infliximab. In a study, after adjustment for age, gender, and rheumatoid arthritis duration, the risk of lymphoma development in patients after exposure to infliximab, etanercept, or adalimumab was no higher than the risk in patients with the disease who did not receive treatment with one of these drugs. Further, lymphomas that occurred in patients treated with a tumor necrosis factor antagonist had similar characteristics as compared with lymphomas in patients with rheumatoid arthritis who did not receive these drugs. Of note, patients in this study received a tumor necrosis factor antagonist for a maximum of 4 years. Also, patients with rheumatoid arthritis may be at an approximately 2-fold higher risk than the general population for the development of leukemia. During post-approval use, development of acute and chronic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, melanoma, cervical cancer, and Merkel cell carcinoma have been reported. Nonmelanoma skin cancers have been reported in psoriasis patients treated with infliximab. The incidence appears to be higher in patients who have had prior prolonged phototherapy treatment. Seven of 1,123 patients in the psoriasis studies who got any dose of infliximab were diagnosed with at least one nonmelanoma skin cancer; none of the 334 patients in the placebo group developed nonmelanoma skin cancer. Before prescribing infliximab, especially in adolescents and young adults, carefully weigh the risks and benefits of using infliximab due to the potential increased risk for cancers including HSTCL. Carefully consider whether to use infliximab alone or in combination with other immunosuppressants. There is a higher risk of HSTCL with combination therapy but an observed increased risk of immunogenicity and hypersensitivity reactions with infliximab monotherapy. Educate patients and caregivers about the signs and symptoms of malignancies such as HSTCL, so that they are aware of and can seek evaluation and treatment of any signs or symptoms, including splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss. One case of prostate cancer and 1 case of non-small cell lung cancer were reported in maintenance trials in patients treated with subcutaneous infliximab. There were postmarketing reports of breast cancer, gastric cancer, and lung cancer in patients treated with subcutaneous infliximab. Monitor for malignancies when a patient has been treated with infliximab. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. Exercise caution when considering infliximab continuation in a patient who develops a malignancy while receiving infliximab.
The following adverse reactions were reported more commonly in 103 randomized pediatric Crohn's disease patients administered 5 mg/kg infliximab through 54 weeks than in 385 adult Crohn's disease patients receiving a similar treatment regimen: bone fractures (7%). Bone fractures have not been reported in clinical trials of infliximab in adult patients.
Exercise care when switching from one biologic disease-modifying antirheumatic drug to another. Overlapping biological activity may further increase the patients' susceptibility to infectious pathogens.
Infliximab is contraindicated for use by patients with known murine protein hypersensitivity or by a patient who has experienced a severe hypersensitivity reaction to infliximab. As infliximab infusions have been associated with hypersensitivity reactions, have medications for the treatment of hypersensitivity reactions available for immediate use in the event of a reaction. Most hypersensitivity reactions or infusion-related reactions occur within 2 hours of infliximab receipt. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, hypotension, and serious hypersensitivity reactions or anaphylaxis. Bronchospasm, dyspnea, rash, and edema were reported in clinical trials of subcutaneous infliximab treatment. Infusion-related reactions may be more common with repeat administration. In some cases, serum sickness-like reactions have been observed in patients after initial infliximab therapy (i.e., as early as after the second dose) and when infliximab was reinstituted after an extended period without infliximab treatment. Patients treated with infliximab may develop human anti-chimeric antibodies. In clinical studies, patients who were human anti-chimeric antibody (HACA) positive were more likely to experience an infusion-related reaction to infliximab. Patients receiving immunosuppressant therapies were less likely to develop positive HACA responses than patients not receiving these agents.
Use of TNF blockers, including infliximab, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic HBV carriers. In some instances, hepatitis B exacerbation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients should be tested for HBV before initiating TNF blocker therapy, including infliximab. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF blocker therapy in this situation and monitor patients closely.
Patients who receive infliximab are at increased risk for developing serious infection that may result in hospitalization and/or death. Do not administer infliximab to patients with a clinically important active infection like influenza or sepsis. If a patient develops a serious infection or sepsis, discontinue infliximab. Many of the serious infections in patients treated with infliximab have occurred in patients receiving concurrent immunosuppression therapy (e.g., methotrexate and corticosteroid therapy) that, in addition to their underlying conditions, may predispose them to infections. These infections involve multiple organ systems and include bacterial infection (Legionella and Listeria), mycobacterial infection (disseminated tuberculosis or extrapulmonary tuberculosis), fungal infection (histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, listeriosis, pneumocystis jiroveci pneumonia, cryptococcosis), parasitic infection, viral infection (hepatitis B, herpes infection), and other opportunistic infections. Patients with invasive fungal infections (specifically histoplasmosis) may present with disseminated rather than localized disease. Health care providers should be aware that antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Carefully consider the risks associated with infliximab prior to initiating therapy in patients who reside in histoplasmosis, blastomycosis, or coccidioidomycosis endemic zones. In patients who develop severe systemic illness, consider administering empiric antifungal therapy. Patients need to be evaluated for tuberculosis risk factors and for latent or active tuberculosis infection with a tuberculin skin test both before and during treatment. The possibility of anergy needs to be considered when interpreting the test result. If tuberculin skin testing is performed for latent tuberculosis infection, an induration size of 5 mm or greater should be considered positive even if the patient was vaccinated previously with Bacille Calmette-Guerin. Cases of new tuberculosis and reactivation of tuberculosis have occurred in patients who received infliximab, including patients who have previously received treatment for latent or active tuberculosis. Cases of tuberculosis also have been reported in patients being treated with infliximab during treatment for latent tuberculosis. Treatment of latent tuberculosis infection prior to initiation of infliximab has been shown to reduce the risk of tuberculosis reactivation during infliximab therapy. Consider antituberculosis therapy before infliximab initiation in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and in patients who have several or highly significant risk factors for tuberculosis infection and have a negative test for latent tuberculosis. Some patients who tested negative for latent tuberculosis before infliximab receipt have developed active tuberculosis. Patients with a history of recurrent infections with underlying conditions that may predispose them to infections (e.g., elderly and patients with advanced or uncontrolled diabetes mellitus, malignancy, or immunosuppression) may not be appropriate candidates for infliximab. Educate patients about the symptoms of infection, and closely monitor patients for signs and symptoms of infection during and after infliximab treatment. Patients who develop a new infection during treatment should be closely monitored and evaluated for appropriate antimicrobial therapy. Safety and efficacy in patients with bone marrow suppression or other types of immunosuppression are not known. The half-life and mode of action of prior biologics should be considered in order to avoid unintended additive immunosuppressive effects with infliximab initiation.
Infliximab should only be used in patients with heart failure after consideration of other treatment options. Infliximab at doses higher than 5 mg/kg is contraindicated for use by patients with moderate to severe heart failure (New York Heart Association (NYHA) Functional Class III/IV). If infliximab is administered to patients with moderate to severe heart failure at a dose of 5 mg/kg or less or patients with mild heart failure at any approved dose, closely monitor patients and discontinue therapy if new or worsening symptoms of heart failure develop. Receipt of infliximab 10 mg/kg by patients with moderate to severe heart failure enrolled in a randomized study was associated with an increased incidence of death and hospitalization due to worsening heart failure compared to placebo patients. Also, higher rates of cardiovascular adverse events were observed at doses of 5 mg/kg and 10 mg/kg. New onset and worsening heart failure have been reported with postmarketing use of infliximab in patients with and without any identifiable risk factors or pre-existing cardiovascular disease; some patients were less than 50 years of age. Avoid use of subcutaneous infliximab in patients with CHF, as it has not been studied in patients with a history of CHF. If subcutaneous infliximab is administered to patients with CHF, closely monitor patients during therapy for new or worsening symptoms of heart failure and discontinue if symptoms therapy appear.
Avoid subcutaneous infliximab in patients with a history of malignancy and discontinue treatment in patients who develop malignancy during treatment. Use caution when considering intravenous infliximab treatment in patients with a history of neoplastic disease or in continuing treatment in patients who develop malignancy while receiving infliximab. A new primary malignancy has been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (initiation of therapy 18 years of age or less), including infliximab. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous post-marketing reports. In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. In the controlled and open-label portions of infliximab clinical trials, 5 patients developed lymphomas among 5,707 patients treated with infliximab (median duration of follow-up 1 year) vs. 0 lymphomas in 1,600 control patients (median duration of follow-up 0.4 years). In rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately 3-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were observed for a rate of 0.10 cases per 100 patient-years of follow-up, which is approximately 4-fold higher than expected in the general population. Patients with Crohn's disease, rheumatoid arthritis or plaque psoriasis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing 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 leukemia. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including infliximab. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported infliximab cases have occurred in patients with Crohn's disease or ulcerative colitis and most were in adolescent and young adult males. It is uncertain whether the occurrence of HSTCL is related to TNF-blockers or TNF-blockers in combination with these other immunosuppressants. When treating patients, consideration of whether to use infliximab alone or in combination with other immunosuppressants such as azathioprine or 6-mercaptopurine should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with infliximab monotherapy from the clinical trial data. Skin cancer, including 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 nonmelanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for infliximab, NMSCs were more common in patients with previous phototherapy. In the controlled portions of clinical trials of some TNF-blocking agents including infliximab, more malignancies (excluding lymphoma and nonmelanoma skin cancer [NMSC]) have been observed in patients receiving those TNF-blockers compared with control patients. In a population-based retrospective cohort study, invasive cervical cancer was reported as a 2- to 3-fold increase in women, particularly those over 60 years of age, with rheumatoid arthritis treated with infliximab compared to patients not receiving biologics. Periodic cervical cancer screening should continue in women treated with infliximab. During the controlled portions of infliximab trials for labeled indications, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) among 4,019 infliximab-treated patients vs. 1 among 1,597 control patients (at a rate of 0.52/100 patient-years among infliximab-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for infliximab-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast, colorectal, and melanoma. The rate of malignancies among infliximab-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected. The potential role of TNF-blocking therapy in the development of malignancies is not known. Rates in clinical trials for infliximab cannot be compared to rates in clinical trials of other TNF-blockers and may not predict rates observed in a broader patient population.
Use infliximab with caution in patients with a history of tobacco smoking and/or patients with chronic obstructive pulmonary disease (COPD), as more cancers occurred in patients who received infliximab in a clinical trial to explore the use of infliximab in patients with moderate to severe COPD. Of 157 patients with moderate to severe COPD and a history of heavy smoking receiving infliximab at doses similar to those used in rheumatoid arthritis and Crohn's disease, 9 developed a malignancy; most developed lung cancer or cancers of the head and neck. In contrast, 1 of 77 placebo-treated patients developed a malignancy. The rate of lymphoma among infliximab recipients was 7.67 cases per 100 patient-years of follow-up as compared with a rate of 1.63 cases per 100 patient-years of follow-up among placebo recipients. Use caution when considering infliximab use for a patient with moderate to severe COPD.
Avoid the use of infliximab subcutaneous injection and use caution when considering the use of infliximab intravenous injection in patients with pre-existing or recent onset neurological disease or seizure disorder. Infliximab has been associated with seizures, central nervous system (CNS) manifestations of systemic vasculitis, and new onset or exacerbation of clinical symptoms and/or radiographic evidence of CNS demyelinating disorders including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders including Guillain-Barre syndrome. Consider infliximab discontinuation if these disorders develop.
Avoid the use of subcutaneus infliximab in patients with current or past history of significant hematologic abnormalities. Clinically significant events of neutropenia were noted in clinical trials of subcutaneous infliximab treatment. Cases of leukopenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving 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 intravenous infliximab who have ongoing or a history of significant hematological disease. 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) while on infliximab. Discontinuation of infliximab therapy should be considered in patients who develop significant hematologic abnormalities.
Severe hepatic reactions and hepatotoxicity, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported in postmarketing data in patients receiving infliximab. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks to more than 1 year after initiation of infliximab; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations [e.g., 5 times of more the upper limit of normal (ULN)] develop, infliximab should be discontinued, and a thorough investigation of the abnormality should be undertaken. In clinical trials of infliximab, mild or moderate elevations of ALT and AST were observed in patients receiving infliximab without progression to severe hepatic injury. Monitor hepatic enzymes and liver function tests every 3 to 4 months during subcutaneous infliximab treatment. Interrupt subcutaneous infliximab treatment if drug induced liver injury is suspected and hold until diagnosis is excluded. Instruct patients to seek immediate medical attention if they experience signs or symptoms of hepatic dysfunction, such as right abdominal pain, jaundice, and unusual weakness or fatigue.
Treatment with infliximab may result in the formation of autoantibodies and in the development of a syndrome suggestive of autoimmune disease or lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment, infliximab treatment should be discontinued. Have patients report if they get chest discomfort or pain that does not go away, shortness of breath, joint pain, or a typical rash on the cheeks or arms that gets worse in the sun.
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. It is recommended that all pediatric and adult patients be brought up to date with all vaccinations prior to initiating infliximab therapy. The interval between vaccination and the initiation of infliximab therapy should be in accordance with current vaccination guidelines. It also is not recommended to administer therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation) to patients concurrently receiving infliximab therapy, as this could result in clinical infections, including disseminated infections.
Available data from observational studies in women exposed to infliximab during pregnancy showed no increased risk of major malformations among live births as compared to those exposed to non-biologics. However, the findings on other birth and maternal outcomes were not consistent across studies with different study designs and conduct. In a prospective cohort study involving 294 women with inflammatory bowel disease (IBD) exposed to infliximab during pregnancy, infliximab therapy was not associated with increased rates of major congenital malformations, miscarriage/stillbirth, infants of low birth weight, small size for gestational age, or infection in the first year of the infant's life. A second study involving women with and without IBD who were exposed to infliximab during pregnancy found that infliximab monotherapy was not associated with increased rates of congenital anomalies or infant death. However, increased rates of preterm birth, small size for gestational age, low birth weight, and infant hospitalization for infection were found with coadministration of infliximab and another immunosuppressive agent (mainly corticosteroids and azathioprine) compared to non-biologic systemic therapy. Dues to methodological limitations in both studies, it is difficult to interpret study results. Infliximab is one of the TNF blockers with human pregnancy data; the available data from various studies and prospective pregnancy registries suggest low risk for use during early pregnancy as monotherapy. Infliximab does not actively cross the placenta during the first trimester, but undergoes efficient placental transfer during the late second and third trimesters and is detectable in the infant's serum for several months after birth. Because of this passage, some experts recommend that if infliximab is used during pregnancy, consideration should be given to discontinuing the drug 8 to 10 weeks prior to anticipated delivery. Other experts state that infliximab can be continued up to gestational week 20, and in select patients, longer if clinically indicated. For COVID-19, the National Institutes of Health (NIH) states that the decision to administer infliximab to a pregnant patient must be shared between the patient and their healthcare providers, and that potential maternal benefit and fetal risks must be considered. Neonates and infants born to women treated with infliximab during their pregnancy may be at increased risk of infection for up to 6 months. At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to infliximab. A fatal outcome due to disseminated BCG infection has been reported in an infant who received a BCG vaccine after in utero exposure to infliximab. Agranulocytosis has been reported in infants exposed to infliximab in utero. Because infliximab products do not cross-react with TNF-alpha in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab products.
Indication and patient-specific factors should be assessed before the use of infliximab during lactation. Data are limited regarding the use of infliximab during breast-feeding. No data are available on the effects of infliximab on the breast-fed infant or the effects on milk production. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from infliximab products, the product labels state that women should not breast-feed their infants while taking infliximab. However, experts consider infliximab compatible with breast-feeding due to the low transfer to breast milk. It is estimated that less than 0.5% of mother's plasma concentration passes to the breast milk and that peak excretion occurs 1 to 4 days following an infusion, and that much of infliximab would be destroyed in the infant's gastrointestinal tract. In a multi-center study involving breast-feeding women with inflammatory bowel disease (IBD), infants exposed to infliximab through breast milk developed normally and did not have an increase in infection rate. In a small study (n = 3) designed to evaluate maternal transfer of infliximab, samples collected from breast milk and the infants' serum resulted in drug concentrations below the limits of detection (less than 0.1 mcg/mL). For COVID-19, the National Institutes of Health (NIH) states that infliximab should be offered to lactating patients who qualify for therapy, and that breast-feeding can continue without interruption.
Intravenous infliximab has not been studied in children less than 6 years of age. Safety and effectiveness has not been established for subcutaneous infliximab in pediatric patients. Lymphoma and other malignancies that are sometimes fatal have been reported in children and adolescents treated with TNF blockers including infliximab. Most cases of hepatosplenic T-cell lymphoma (HSTCL) among patients with Crohn's disease or ulcerative colitis treated with TNF blockers were in adolescent and young adult males. A careful risk-benefit assessment is needed before infliximab is used in combination with other immunosuppressants. Further, all pediatric patients are recommended to be brought up to date with all vaccinations before infliximab initiation. The interval between vaccination and infliximab initiation should be in accordance with current vaccination guidelines.
Before starting subcutaneous infliximab, test potential drug recipients for hepatitis C (IgG) and HIV serum status (HIV-1 and HIV-2 antibodies and HIV-1 antigen). Consider ongoing screening (e.g., annually) in people who are at increased risk for HIV or hepatitis C infection. Retest for HIV infection in any person who displays symptoms or other conditions that may suggest HIV seroconversion or infection. In patients found to be infected with HIV, consider involving relevant specialists to ensure HIV viral load is suppressed on antiretroviral therapy. Similarly, retest for viral hepatitis in any person who develops unexplained elevations in hepatic enzymes. It is recommended to consult a hepatologist when using a biological therapy in patients who are infected with hepatitis C, whether newly diagnosed or chronically infected.
Patients who undergo surgery while taking a biologic therapy, such as infliximab, may be at greater risk for postoperative infections. In patients undergoing elective surgery, balance the risk of postoperative infection against the risk of developing a severe or unstable disease by stopping the biologic therapy. When possible, it is advised to stop the biologic therapy 3- to 5-times the half-live or the length of the treatment cycle (whichever is longer) between the last dose and the planned surgery. Restart the biologic therapy postoperatively if there is no evidence of infection and wound healing is satisfactory.
For the treatment of Crohn's disease:
-for moderately to severely active Crohn's disease to reduce of signs and symptoms and to induce and maintain clinical remission in persons who have an inadequate response to conventional therapy:
Intravenous dosage:
Adults: 5 mg/kg IV at weeks 0, 2, and 6, then 5 mg/kg IV every 8 weeks. May increase dose to 10 mg/kg IV infusion every 8 weeks for persons who initially respond and then lose response. The median time to response is 7 days. Maximum response is usually observed within 2 to 4 weeks. Persons who do not respond by week 14 are unlikely to respond with continued treatment; consider discontinuing therapy. Guidelines strongly recommend the use of infliximab to treat Crohn's disease that is resistant to treatment with corticosteroids. Combination therapy of infliximab with thiopurines is more effective than treatment with either agent alone in patients who are naive to those agents. In the ACCENT I trial, significantly more patients receiving maintenance therapy (5 mg/kg) achieved a clinical remission at week 30 (39%) compared to those receiving placebo (25%). In addition, 25% of subjects in remission and receiving maintenance therapy were able to discontinue corticosteroid therapy as opposed to 11% of subjects given placebo. Doses of up to 20 mg/kg IV have been studied but are not more effective in magnitude or duration of clinical response than doses of 5 mg/kg.
Children and Adolescents 6 to 17 years: 5 mg/kg IV at weeks 0, 2 and 6 weeks, then 5 mg/kg IV every 8 weeks. In clinical trials, children on a stable dose of 6-mercaptopurine, azathioprine, or methotrexate received infliximab according to this regimen. At week 10, of 112 patients, 88% had a clinical response defined as at least a 15 point reduction in their Pediatric Crohn's Disease Activity Index (PCDAI) score from baseline and a total score of 30 or less. Further, of 52 patients who received infliximab 5 mg/kg IV every 8 weeks as maintenance therapy, 60% had a clinical remission defined as a total PCDAI score of 10 or less at week 30; 56% met the endpoint at week 54.
-for patients with fistulizing Crohn's disease for the reduction in the number of draining enterocutaneous or rectovaginal fistula(s) and for the maintenance of fistula closure:
Intravenous dosage:
Adults: 5 mg/kg IV at weeks 0, 2, and 6, then 5 mg/kg IV every 8 weeks. May increase dose to 10 mg/kg IV infusion every 8 weeks for persons who initially respond and then lose response. Persons who do not respond by week 14 are unlikely to respond with continued treatment; consider discontinuing therapy. In a placebo-controlled study, closure of at least 50% of perianal or abdominal fistulae was obtained in 68% of subjects treated with infliximab and 26% of subjects given placebo. Among those receiving infliximab, the median time to response and duration of response was 2 weeks and 12 weeks, respectively. Closure of all fistulas was seen in 52% of those receiving infliximab compared to 13% of those in the placebo group. Guidelines state that infliximab is effective and should be considered in treating perianal fistulas due to Crohn's disease; the addition of antibiotics to infliximab is more effective than infliximab alone for treating perianal fistulas and should be considered. Infliximab may be effective and should be considered for the treatment of enterocutaneous and rectovaginal fistulas.
-for maintenance treatment of moderately to severely active Crohn's disease following treatment with an infliximab product administered intravenously:
Subcutaneous dosage:
Adults: 120 mg subcutaneously once every 2 weeks starting at week 10 and thereafter. All patients must complete an intravenous induction regimen with an infliximab product prior to subcutaneous infliximab therapy. To switch patients who are responding to maintenance therapy with an infliximab product administered intravenously, administer the first subcutaneous dose of infliximab in place of the next scheduled intravenous infusion and every 2 weeks thereafter.
For the treatment of moderately to severely active ulcerative colitis, in persons who have an inadequate response to conventional therapy:
Intravenous dosage:
Adults: 5 mg/kg/dose IV at weeks 0, 2, and 6, then 5 mg/kg/dose IV every 8 weeks. Guidelines strongly recommend infliximab in combination with a thiopurine for the induction of remission in persons with moderately to severely active ulcerative colitis and for maintenance of remission.
Children and Adolescents 6 to 17 years: 5 mg/kg/dose IV at weeks 0, 2, and 6, then 5 mg/kg/dose IV every 8 weeks.
-for maintenance treatment of moderately to severely active ulcerative colitis following treatment with an infliximab product administered intravenously:
Subcutaneous dosage:
Adults: 120 mg subcutaneously once every 2 weeks starting at week 10 and thereafter. All patients must complete an intravenous induction regimen with an infliximab product prior to subcutaneous infliximab therapy. To switch patients who are responding to maintenance therapy with an infliximab product administered intravenously, administer the first subcutaneous dose of infliximab in place of the next scheduled intravenous infusion and every 2 weeks thereafter.
For the treatment of moderately to severely active rheumatoid arthritis in combination with methotrexate:
Intravenous dosage:
Adults: 3 mg/kg/dose IV at 0, 2, and 6 weeks, then 3 mg/kg/dose IV every 8 weeks. May consider increasing the dose up to 10 mg/kg IV every 8 weeks or treating as often as every 4 weeks for persons with an incomplete response. In clinical trials, maximal doses were 6 mg/kg/dose or 10 mg/kg/dose IV every 4 weeks in some patients. The risk of serious infections is increased at higher doses or more frequent dosing. Infliximab reduces signs and symptoms, inhibits the progression of joint structural damage (erosions and the degree of joint space narrowing), and improves the physical functioning of patients when added to methotrexate therapy. In methotrexate-naive patients with a disease duration 3 or fewer years, concurrent use of infliximab with methotrexate improved these disease parameters to a greater extent than methotrexate alone. Guidelines recommend infliximab plus methotrexate as an option for patients with a disease duration less than 6 months and high disease activity with poor prognostic feature presence. For established disease, adding or switching to an anti-TNF biologic is an option for patients with moderate or high disease activity after 3 months of methotrexate monotherapy or DMARD combination therapy. A switch to a different anti-TNF biologic is an option for patients with moderate or high disease activity after greater than or equal to 3 months of a TNF blocker or with a non-serious adverse event. Also, a switch to an anti-TNF biologic is an option for patients with moderate or high disease activity after greater than or equal to 6 months of a non-TNF biologic or with a serious or non-serious adverse event to the drug. The goal is low disease activity or remission.
For the treatment of active ankylosing spondylitis:
Intravenous dosage:
Adults: 5 mg/kg IV infusion at 0, 2, and 6 weeks for induction. Thereafter, a maintenance dose of 5 mg/kg IV infusion every 6 weeks. Infliximab improves the signs and symptoms of disease (a 20% or greater improvement in the Assessment in SpondyloArthritis International Society (ASAS) response criteria, or ASAS 20). The ASAS guidelines state that anti-TNF therapy should be given to patients with persistently high disease activity despite conventional treatments.
For the treatment of chronic severe plaque psoriasis in persons who are candidates for systemic therapy and when other systemic therapies are less appropriate:
Intravenous dosage:
Adults: 5 mg/kg/dose IV at weeks 0, 2, and 6, then 5 mg/kg/dose IV every 8 weeks. May increase the dose to 5 mg/kg/dose IV every 6 weeks if an inadequate primary response may be due to insufficient drug exposure (e.g., known subtherapeutic drug concentrations, obesity, relapse during treatment); however, consider the increased risk for infection and adverse reactions.
Children* and Adolescents*: 5 mg/kg/dose IV at weeks 0, 2, and 6, then 5 mg/kg/dose IV every 8 weeks. Guidelines recommend infliximab as monotherapy or in combination with methotrexate for use in children with severe plaque or pustular psoriasis that is unresponsive to other systemic medications, rapidly progressive, unstable, and/or life-threatening.
For the treatment of active psoriatic arthritis to reduce signs and symptoms, inhibit progression of structural damage, and improve physical function:
Intravenous dosage:
Adults: 5 mg/kg/dose IV at weeks 0, 2 and 6, then 5 mg/kg/dose IV every 8 weeks. Infliximab can be used with or without methotrexate.
For the treatment of uveitis* associated with Behcet's syndrome*:
Intravenous dosage:
Adults: 3 to 10 mg/kg/dose IV at weeks 0, 2, and 6, then every 4 to 8 weeks.
For the treatment of IVIG-resistant Kawasaki disease*:
Intravenous dosage:
Infants, Children, and Adolescents: 5 to 10 mg/kg/dose IV as a single dose may be considered as an alternative to a second infusion of IVIG or corticosteroids for IVIG-resistant children.
For the management of multisystem inflammatory syndrome in children (MIS-C) post SARS-CoV-2 exposure*:
Intravenous dosage:
Infants, Children, and Adolescents: 5 to 10 mg/kg IV as a single dose in patients with refractory MIS-C who do not improve within 24 hours of initial immunomodulatory therapy. Do not use in patients with features of macrophage activation syndrome (MAS).
For the treatment of sarcoidosis*:
Intravenous dosage:
Adults: 3 to 5 mg/kg/dose IV at weeks 0, 2, and 6, then 3 to 5 mg/kg/dose IV every 4 to 8 weeks.
For the treatment of juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA)*:
Intravenous dosage:
Children and Adolescents: 3 to 6 mg/kg/dose (Max: 20 mg/kg/dose) IV initially at intervals of 0, 2, and 6 weeks, and then administered every 4 to 8 weeks thereafter. Higher doses of 10 to 20 mg/kg/dose IV every 2 to 8 weeks have been reported in a study of pediatric patients (age 2 to 18 years) with recalcitrant or highly active JIA. A randomized, placebo-controlled trial in patients 4 to 17 years demonstrated no significant difference between patients receiving infliximab 3 mg/kg/dose (n = 60) or placebo (n = 62) in American College of Rheumatology Pediatric 30 (ACR Pedi 30) response criteria for improvement at week 14 (63.8% vs. 49.2%, respectively). Patients randomized to placebo were treated with infliximab 6 mg/kg/dose beginning at week 14. ACR Pedi 50 and ACR Pedi 70 responses were 69.6% and 51.8%, respectively, for all patients at week 52; there were no significant differences between the infliximab dose groups. Approximately 40% of patients in both dose groups had 0 joints with active arthritis. Initial therapy with a biologic, such as infliximab, is recommended in patients with involvement of high-risk joints, high disease activity, or patients at high risk of disabling joint damage. Infliximab may also be used as subsequent therapy in combination with a disease-modifying antirheumatic drug.
INVESTIGATIONAL USE: For the treatment of coronavirus disease 2019 (COVID-19)*, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection*, in certain hospitalized patients who are receiving systemic corticosteroids and require supplemental oxygen, including high-flow oxygen or noninvasive mechanical ventilation:
Intravenous dosage:
Adults: 5 mg/kg using actual body weight administered as a single IV dose is recommended by the National Institutes of Health (NIH) COVID-19 treatment guidelines for use in combination with dexamethasone (with or without remdesivir) to treat hospitalized adults requiring supplemental oxygen, IF the patient is exhibiting signs of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone OR the patient requires high-flow oxygen or noninvasive mechanical ventilation. Infliximab is to be used as an alternative to baricitinib and tocilizumab when these medications are unavailable or cannot be administered.
For the treatment of acute graft-versus-host disease (GVHD)*:
Intravenous dosage:
Adults: 10 mg/kg/dose IV once weekly for at least 2 weeks. Guidelines suggest infliximab as a second-line treatment option for steroid-refractory acute GVHD.
Infants, Children, and Adolescents: 10 mg/kg/dose IV once weekly for at least 2 weeks. Guidelines suggest infliximab as a second-line treatment option for steroid-refractory acute GVHD.
Therapeutic Drug Monitoring:
Target concentrations of infliximab in patients with Inflammatory Bowel Disease per guidelines
-Week 2: at least 20 to 25 mcg/mL
-Week 6: at least 15 to 20 mcg/mL, higher concentrations at week 6 are associated with higher rates of positive clinical outcomes
-Week 14: at least 7 to 10 mcg/mL, higher concentrations at week 14 are associated with higher rates of positive clinical outcomes
-Maintenance therapy: at least 5 to 10 mcg/mL
-When performing reactive therapeutic drug monitoring for secondary loss of response to infliximab, treatment discontinuation should not be considered until a drug concentration of at least 10 to 15 mcg/mL is achieved.
Maximum Dosage Limits:
-Adults
120 mg subcutaneously once every 2 weeks or 10 mg/kg/dose IV; investigational doses of 5 mg/kg IV have been used for COVID-19.
-Geriatric
120 mg subcutaneously once every 2 weeks or 10 mg/kg/dose IV; investigational doses of 5 mg/kg IV have been used for COVID-19.
-Adolescents
5 mg/kg/dose IV for Crohn's disease and ulcerative colitis; doses up to 20 mg/kg/dose IV have been used off-label for juvenile idiopathic arthritis.
-Children
6 to 12 years: 5 mg/kg/dose IV for Crohn's disease and ulcerative colitis; doses up to 20 mg/kg/dose IV have been used off-label for juvenile idiopathic arthritis.
1 to 5 years: Safety and efficacy have not been established; however, doses up to 20 mg/kg/dose IV have been used off-label for juvenile idiopathic arthritis.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; use with caution. It is not known if there are differences in clearance or other pharmacokinetic parameters in patients with marked impairment of hepatic function. Specific guidelines for dosage adjustments in hepatic impairment are not available. During treatment, evaluate patients with signs or symptoms of hepatic dysfunction. Discontinue infliximab if jaundice or AST or ALT concentrations at least 5 times the upper limit of normal (ULN) develop.
Patients with Renal Impairment Dosing
It is not known if there are differences in clearance or other pharmacokinetic parameters in patients with marked impairment of renal function. Specific guidelines for dosage adjustments in renal impairment are not available.
*non-FDA-approved indication
Abatacept: (Major) Concomitant use of abatacept with other biologic agents, such as tumor necrosis factor (TNF) inhibitors, is not recommended because of the possibility of additive immunosuppression and increased risk of infection. In controlled clinical trials, patients receiving concomitant abatacept and TNF inhibitor therapy experienced more infections (63%) and serious infections (4.4%) as compared with patients treated with only TNF inhibitors (43% and 0.8%, respectively). These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of abatacept with a TNF inhibitor. Monitor patients for signs of infection during the transition from TNF antagonist therapy to abatacept therapy.
Adalimumab: (Contraindicated) Do not use infliximab in combination with other tumor necrosis factor (TNF) modifier therapy, including adalimumab, due to the potential for additive effects and drug toxicity. It is unknown if any adverse effects would occur if infliximab is used concomitantly with adalimumab. A potential exists for increased risk of infection or an impact on the development of malignancies from increased activity toward TNF.
Anakinra: (Major) Avoid the concomitant use of anakinra with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection with no additional clinical benefit. Data suggest a higher rate of serious infections when anakinra and a TNF inhibitor is used in combination with anakinra compared with either drug given alone. Neutropenia (1,000/mcL or less) was observed in 2% of patients receiving the combination. The use of anakinra with a TNF inhibitor in combination did not yield any additional clinical benefit as compared to the use of the TNF inhibitor alone.
Anifrolumab: (Major) Coadministration is not recommended. Anifrolumab has not been studied in combination with other biologic therapies including tumor necrosis factor modifiers (TNF blockers). Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
Antithymocyte Globulin: (Moderate) Many serious infections during infliximab therapy have occurred in patients receiving concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposes patients to infections.
Azathioprine: (Moderate) Most infliximab recipients who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids. The concurrent use of infliximab and immunosuppressants may also contribute to malignancy risk. However, the use of concomitant immunosuppressives such as 6-mercaptopurine, azathioprine, or methotrexate with infliximab appeared to reduce the frequency of antibodies to infliximab. Patients with Crohn's disease receiving immunosuppressives tended to have fewer infusion-related reactions as compared to patients not receiving immunosuppressive therapy. Also, concomitant methotrexate use, for example, may increase infliximab concentrations. Patients who were antibody-positive were more likely to have higher rates of infliximab clearance and reduced efficacy than were patients who were antibody negative. For patients with inflammatory bowel disease especially adolescents and young adults, consider the possibility that there is a higher risk of hepatosplenic T-cell lymphoma with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with infliximab monotherapy from the clinical trial data.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Baricitinib: (Major) Concomitant use of baricitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Belimumab: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including tumor necrosis factor modifiers (TNF blockers). Therefore, belimumab use is not recommended in combination with TNF blockers. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
Canakinumab: (Major) Avoid concomitant administration of canakinumab with tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection. An increased incidence of serious infections and an increased risk of neutropenia have been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Based upon the potential for similar interactions, concomitant administration of canakinumab and TNF inhibitors is not recommended.
Certolizumab pegol: (Contraindicated) Do not use certolizumab in combination with other tumor necrosis factor (TNF) modifier therapy, including infliximab, due to the potential for additive effects and drug toxicity. It is unknown if any adverse effects would occur if certolizumab is used concomitantly with infliximab. A potential exists for increased risk of infection or an impact on the development of malignancies from increased activity toward TNF.
Chikungunya Vaccine, Live: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cyclosporine: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during infliximab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. If infliximab is initiated or discontinued in a patient taking cyclosporine, monitor the cyclosporine concentration; cyclosporine dose adjustment may be needed.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Dexamethasone: (Moderate) Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
Etanercept: (Contraindicated) The combination of infliximab with other biologics used to treat the same conditions as infliximab is not recommended. Both infliximab and etanercept block the actions of TNF-alpha. It is unknown if any adverse effects would occur if infliximab was used concomitantly with etanercept. A potential exists for an increased risk for serious infection or an impact on the development of malignancies from increased activity toward TNF.
Golimumab: (Contraindicated) Do not use golimumab in combination with other tumor necrosis factor (TNF) modifier therapy, including infliximab, due to the potential for additive effects and drug toxicity. It is unknown if any adverse effects would occur if golimumab is used concomitantly with infliximab. A potential exists for increased risk of infection or an impact on the development of malignancies from increased activity toward TNF.
Intranasal Influenza Vaccine: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Live Vaccines: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Mercaptopurine, 6-MP: (Moderate) Post-marketing fatal cases of hepatosplenic T-cell lymphoma have been reported, mostly in adolescent and young adult males with inflammatory bowel disease such as Crohn's disease or ulcerative colitis; almost all cases have occurred in patients who had received a TNF blocker such as infliximab concomitantly with either mercaptopurine, 6-MP or azathioprine at or before diagnosis. It is unknown whether the occurrence of hepatosplenic T-cell lymphoma is related to a TNF blocker or to a TNF blocker in combination with these other immunosuppressants. Use with caution.
Methotrexate: (Moderate) Rheumatoid arthritis patients who received methotrexate in combination with infliximab had higher serum concentrations of infliximab as compared to those who received infliximab alone. Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
Methylprednisolone: (Moderate) Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
Mycophenolate: (Moderate) Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
Natalizumab: (Major) Natalizumab for Crohn's disease should not be used in combination with tumor necrosis factor (TNF) modifiers. Coadministration may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy and other opportunistic infections. Ordinarily, patients with mulitple sclerosis who are receiving chronic TNF-modifier therapy should not be treated with natalizumab.
Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with infliximab. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
Prednisone: (Moderate) Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
Pretomanid: (Major) Avoid coadministration of pretomanid with infliximab, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
Rilonacept: (Contraindicated) Concurrent use of rilonacept and tumor necrosis factor (TNF) modifiers is not advised, as the risk of serious infections may be increased. Although concurrent use has not been evaluated in clinical trials, an increased incidence of serious infections and neutropenia has been associated with administration of another drug that blocks IL-1 in combination with TNF inhibitors.
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and infliximab. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
Rituximab: (Major) Avoid the concomitant use of rituximab and infliximab if they are used to treat the same condition due to additive immunosuppression and an increased risk of infection. If coadministration is necessary for separate conditions, monitor patients closely for signs or symptoms of infection.
Rituximab; Hyaluronidase: (Major) Avoid the concomitant use of rituximab and infliximab if they are used to treat the same condition due to additive immunosuppression and an increased risk of infection. If coadministration is necessary for separate conditions, monitor patients closely for signs or symptoms of infection.
Rotavirus Vaccine: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Sarilumab: (Major) Avoid the concomitant use of sarilumab with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Tacrolimus: (Moderate) Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
Theophylline, Aminophylline: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during infliximab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as theophylline. If infliximab is initiated or discontinued in a patient taking theophylline, monitor the theophylline concentration; theophylline dose adjustment may be needed.
Tocilizumab: (Major) Avoid the concomitant use of tocilizumab with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Tofacitinib: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Infliximab may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of infliximab therapy.
Typhoid Vaccine: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Upadacitinib: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Vedolizumab: (Major) Vedolizumab should not be used in combination with tumor necrosis factor (TNF) modifiers because of the potential for increased risk of progressive multifocal leukoencephalopathy and other infections. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with vedolizumab.
Warfarin: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during infliximab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin. If infliximab is initiated or discontinued in a patient taking warfarin, check the INR; warfarin dose adjustment may be needed.
Yellow Fever Vaccine, Live: (Contraindicated) Do not administer live vaccines to infliximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving infliximab. Before initiation of infliximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Infliximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Infliximab neutralizes the biological activity of the cytokine tumor necrosis factor-alpha (TNFalpha). Infliximab binds to high affinity soluble and transmembrane forms of TNFalpha and inhibits the binding of TNFalpha with its receptors. Infliximab does not neutralize TNFbeta, a related cytokine that utilizes the same receptors as TNFalpha. Biological activities attributed to TNFalpha include induction of pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6; enhancement of leukocyte migration by increasing endothelial layer permeability; expression of adhesion molecules by endothelial cells and leukocytes; activation of neutrophil and eosinophil functional activity; fibroblast proliferation; synthesis of prostaglandins; and induction of acute phase and other liver proteins. Infliximab inhibits the functional activity of TNFalpha in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils, B and T lymphocytes, and epithelial cells. Cells expressing transmembrane bound TNFalpha bound by infliximab can be lysed in vitro by complement or effector cells. In vitro models show that anti-TNFalpha antibodies reduce disease activity in colitis models and decrease synovitis and joint erosions in animal models. Infliximab prevents disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFalpha, and, when administered after disease onset, allows eroded joints to heal.
In patients with Crohn's disease, infliximab reduces infiltration of inflammatory cells and TNFalpha production in inflamed areas of the intestine. In addition, the proportion of mononuclear cells from the lamina propria able to express TNFalpha and interferon gamma is reduced. In patients with rheumatoid arthritis, infliximab treatment reduces inflammatory cell infiltration into inflamed areas of the joint and reduces the expression of molecules mediating adhesion [E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vacular adhesion molecule-1 (VCAM-1)], chemoattraction (monocyte chemotactic protein (MCP-1 and IL-8), and tissue degradation (matrix metalloproteinase (MMP) 1 and 3). After treatment with infliximab, patients with Crohn's disease or rheumatoid arthritis have decreased concentrations of IL-6 and C-reactive protein as compared to baseline.
In patients with plaque psoriasis, infliximab reduces infiltration of inflammatory cells within the plaques. In addition, infliximab may reduce epidermal thickness. The relationship between these pharmacodynamic effects and the mechanism of action of infliximab for the treatment of plaque psoriasis is unknown.
Infliximab is administered both intravenously and subcutaneously. Infliximab is predominantly distributed within the vascular compartment. No evidence of accumulation of infliximab has been observed after repeated dosing 3 mg/kg or 10 mg/kg IV at 4 or 8-week intervals. The median terminal half-life of intravenous infliximab is 7.7 to 9.5 days, and the mean half-life for a single subcutaneous dose of infliximab 120 mg is 332 hours.
Currently, therapeutic monitoring of intravenous infliximab is not recommended. The relationship between the serum trough concentration of infliximab and clinical response has been studied in 105 patients with rheumatoid arthritis (RA) who received infliximab 3 mg/kg IV at baseline and at 2, 6, and 14 weeks; 86 patients also received concurrent methotrexate. The DAS28 (28 joint disease activity score) before each infliximab infusion was compared with the corresponding trough serum infliximab concentration. Response was based on European League Against Rheumatism (EULAR) criteria and was determined at week 14. Nonresponse was defined either as a DAS28 decrease of up to 0.6 or a decrease greater than 0.6 and up to 1.2 with an attained DAS of greater than 5.1. The clinical response to infliximab correlated with serum trough concentrations. Specifically, 88 to 90% of patients with a serum trough infliximab of at least 1.3 mg/L were EULAR responders whereas only 50% of RA patients with a lower serum trough infliximab concentration were EULAR responders. Correction for potential confounders such as baseline C-reactive protein concentrations, baseline DAS28 scores, and rheumatoid factor presence did not affect the observed relationship.
-Route-Specific Pharmacokinetics
Intravenous Route
When single IV infusions of infliximab 3 to 20 mg/kg are given, a linear relationship exists between the dose administered and the maximal concentration (Cmax) observed.
Subcutaneous Route
Following a single subcutaneous dose of infliximab, the mean Cmax and AUCinf were 10 (+/-3.2) mcg/mL and 6945.6 (+/- 2830.2) mcg * hour/mL. Following single and multiple subcutaneous doses, AUC is proportionally increased over the dose range from 120 mg to 240 mg. Tmax was 7 days in healthy subjects after a single subcutaneous dose of infliximab 120 mg. Volume of distribution of subcutaneous infliximab is 3.36 L. Steady state in subcutaneous infliximab maintenance dosing was achieved in Ulcerative colitis (UC) patients and Crohn's disease (CD) patients by week 22 after intravenous induction at week 10. The mean trough serum concentration at steady state was 14.6 (+/- 7.8) mcg/mL in UC patients, and 14.6 (+/- 8.9) mcg/mL in CD patients. In healthy patients, AUCinf of a single subcutaneous dose of infliximab 120 mg was approximately 23% relative to a single intravenous dose of infliximab 5 mg/kg. Following subcutaneous dosing every 2 weeks, steady state AUC for an 8-week interval was 25% to 35% higher compared to intravenous dose of infliximab 5 mg/kg given every 8 weeks in subjects with UC and CD.
-Special Populations
Hepatic Impairment
It is not known if there are differences in clearance or other pharmacokinetic parameters in patients with marked hepatic impairment.
Renal Impairment
It is not known if there are differences in clearance or other pharmacokinetic parameters in patients with marked renal impairment.
Pediatrics
The pharmacokinetics of IV infliximab are similar in pediatric patients and adults. The median half-life in pediatric patients (age 4 to 17 years) with juvenile idiopathic arthritis receiving doses of 3 and 6 mg/kg IV was 6.9 and 9.5 days, respectively. As compared to the 6 mg/kg dose, the 3 mg/kg dose had lower median serum concentrations. After week 36 of treatment, more than half of the patients receiving 3 mg/kg/dose lacked measurable infliximab concentrations by the end of the 8-week interval between doses. A progressive increase in the number of patients who achieved American College of Rheumatology Pediatric 30 (ACR Pedi 30) was observed as serum infliximab trough concentrations increased. Infliximab pharmacokinetic characteristics (including peak and trough concentrations and terminal half-life) were similar in pediatric (age 6 to 17 years) and adult patients with Crohn's disease or ulcerative colitis after the administration of 5 mg/kg/dose IV.
Geriatric
No major differences of infliximab clearance or volume of distribution were observed in patient subgroups defined by age.
Gender Differences
No major differences of infliximab clearance or volume of distribution were observed in patient subgroups defined by gender.
Obesity
No major differences of intravenous infliximab clearance or volume of distribution were observed in patient subgroups defined by weight. Subcutaneous infliximab exposure may be inversely related to body weight. The magnitude of body weight on systemic exposure was not clinically meaningful in adult subjects with ulcerative colitis and Crohn's disease weighing 39 to 130kg.
Other
Anti-Drug Antibodies
Patients who were positive for anti-drug antibodies while treated with subcutaneous infliximab showed a lower trough serum concentration by approximately 30 to 40% compared to patients who were negative for anti-drug antibodies. Some patients with higher titers of anti-drug antibodies and positive neutralizing antibodies had trough serum concentrations below the lower limit of quantitation (less than 0.1 mcg/mL).