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  • CLASSES

    Antipsoriatic Monoclonal Antibodies and Others
    Anti-Rheumtic Monoclonal Antibodies
    Tumor Necrosis Factor (TNF)-Alpha Inhibitors

    BOXED WARNING

    Bone marrow suppression, corticosteroid therapy, diabetes mellitus, fungal infection, herpes infection, immunosuppression, infection, mycobacterial infection, sepsis, tuberculosis, viral infection

    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.[27994] [61891]

    Cervical cancer, lymphoma, Merkel cell carcinoma, new primary malignancy, skin cancer

    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. Caution should be exercised in considering infliximab treatment in patients with a history of neoplastic disease or in continuing treatment in patients who develop malignancy while receiving infliximab.[27994] [61891]

    DEA CLASS

    Rx

    DESCRIPTION

    TNF blocker; given as an intravenous infusion
    Used for Crohn's disease and ulcerative colitis in adult and pediatric patients 6 years and older; also used in adults with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis
    Boxed warnings for increased risk of serious infections and potential risk of malignancy

    COMMON BRAND NAMES

    AVSOLA, INFLECTRA, IXIFI, Remicade, RENFLEXIS

    HOW SUPPLIED

    AVSOLA/INFLECTRA/Infliximab (Murine)/IXIFI/Remicade/RENFLEXIS Intravenous Inj Pwd F/Sol: 100mg

    DOSAGE & INDICATIONS

    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 patients who have an inadequate response to conventional therapy.
    Intravenous dosage
    Adults

    5 mg/kg IV infusion at weeks 0, 2, and 6 as induction therapy. Thereafter, a maintenance regimen of 5 mg/kg IV infusion every 8 weeks. For patients who initially respond and then lose response, consider an increase in dose to 10 mg/kg IV infusion every 8 weeks. The median time to response is 7 days. Maximum response is usually observed within 2 to 4 weeks. Patients who do not respond by week 14 are unlikely to respond with continued treatment; consider discontinuing therapy. The American College of Gastroenterology strongly recommends 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 patients receiving placebo (25%). In addition, 25% of patients in remission and receiving maintenance therapy were able to discontinue corticosteroid therapy as opposed to 11% of placebo patients. 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 years and older

    5 mg/kg IV infusion at weeks 0, 2 and 6 weeks as induction therapy. After that, a maintenance regimen of 5 mg/kg IV infusion 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 infusion at weeks 0, 2, and 6 as induction therapy. Thereafter, a maintenance regimen of 5 mg/kg IV infusion is given every 8 weeks. For patients who initially respond and then lose their response, consider an increase in dose to 10 mg/kg IV infusion every 8 weeks. Patients 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 patients treated with infliximab and 26% of patients treated with 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.[27994] [60724] [61891] [62698] The American College of Gastroenterology states that infliximab is effective and should be considered in treating perianal fistulas due to CD; 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.[64397]

    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.[27994] [60724] [61891]

    For the treatment of moderate to severe rheumatoid arthritis in combination with methotrexate.
    Intravenous dosage
    Adults

    3 mg/kg IV infusion at 0, 2, and 6 weeks for induction. Thereafter, give a maintenance regimen of 3 mg/kg IV infusion every 8 weeks. Infliximab is given in combination with methotrexate. For patients with an incomplete response, may consider increasing dose up to 10 mg/kg or treating as often as every 4 weeks. In clinical trials, maximal doses were 6 mg/kg or 10 mg/kg IV infusion 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 (i.e., extensive and/or disabling) plaque psoriasis.
    Intravenous dosage
    Adults

    For induction, 5 mg/kg IV infusion given at weeks 0, 2, and 6. Thereafter, give a maintenance dose of 5 mg/kg IV infusion every 8 weeks. The British Association of Dermatologist guidelines suggest a maintenance dose of 5 mg/kg via IV infusion every 6 weeks when an inadequate primary response may be due to insufficient drug exposure (e.g., known subtherapeutic drug concentrations, obese patients, relapse during treatment); however, the guidelines warn that consideration should be given to an increased risk for infection and adverse reactions. Appropriate candidates for treatment are those patients with severe or recalcitrant disease who are candidates for systemic therapies when other systemic therapies are medically less appropriate and the patient can be closely monitored with regular visits to the prescriber. Infliximab is often a second or third-line choice in treatment in guidelines for plaque psoriasis; however, in some patients, biologic therapies may be considered as first-line therapies due to improvement in clinical signs, symptoms, and quality of life. In phase III clinical trials, 80% of patients achieved at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) at week 10, and nearly half of the treated patients achieved PASI 90. Improvements in PASI scores are associated with significantly improved Dermatological Life Quality Index scores. Results have been maintained for up to 50 weeks with infliximab monotherapy.

    For the treatment of active psoriatic arthritis (PsA) with or without methotrexate.
    Intravenous dosage
    Adults

    5 mg/kg IV infusion given at 0, 2 and 6 weeks for induction. After that, give a maintenance dose of 5 mg/kg IV infusion every 8 weeks. Infliximab reduces signs and symptoms, inhibits progression of joint structural damage, and improves physical functioning. The response to treatment occurs regardless of concomitant use of methotrexate (25 mg/week PO or less). Improvement in symptoms was noted using American College of Rheumatology (ACR) response criteria and observed as early as week 2 of treatment. At 6 months, the ACR 20/50/70 responses were achieved by 54%, 41%, and 27%, respectively, of patients receiving infliximab vs. 16%, 4%, and 2%, respectively, of patients receiving placebo. Improvements in the Psoriasis Area and Severity Index (PASI) are also noted.

    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 mg/kg IV infusion as a single dose given over 2 hours may be considered as an alternative to a second infusion of IVIG or corticosteroids for IVIG-resistant patients.[61950]

    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).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    10 mg/kg/dose IV.

    Geriatric

    10 mg/kg/dose IV.

    Adolescents

    5 mg/kg/dose IV for Crohn's disease and ulcerative colitis.

    Children

    6 to 12 years: 5 mg/kg/dose IV for Crohn's disease and ulcerative colitis.
    1 to 5 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    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.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Infliximab is administered as an intravenous infusion only.
    Prior to initiating infliximab therapy, patients must be evaluated for latent tuberculosis infection.[27994] [60724] [61891] [62698]
     
    Reconstitution of infliximab vials
    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.
    Reconstitute each vial (100 mg) with 10 mL of Sterile Water for Injection. 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.[27994] [60724] [61891] [62698]
     
    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 mix.
    The final infusion concentration should be 0.4 mg/mL to 4 mg/mL. 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.[27994] [60724] [61891] [62698]
     
    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.[27994] [60724] [61891] [62698]
     
    If Infusion Reactions Occur During Administration [27994] [60724] [61891] [62698]
    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.

    STORAGE

    AVSOLA:
    - Avoid direct heat and sunlight
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - May be stored at temperatures up to 86 degrees F for up to 6 months
    - Product stored at controlled room temperature should not be returned to a refrigerator
    - Store diluted product in accordance with package insert instructions
    - Store in a cool, well ventilated, dry place
    - Store in original container
    - Store reconstituted product in accordance with package insert instructions
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    INFLECTRA:
    - Avoid direct heat and sunlight
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - May be stored at temperatures up to 86 degrees F for up to 6 months
    - Product stored at controlled room temperature should not be returned to a refrigerator
    - Store diluted product in accordance with package insert instructions
    - Store in a cool, well ventilated, dry place
    - Store in original container
    - Store reconstituted product in accordance with package insert instructions
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    IXIFI:
    - Avoid direct heat and sunlight
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - May be stored at temperatures up to 86 degrees F for up to 6 months
    - Product stored at controlled room temperature should not be returned to a refrigerator
    - Store diluted product in accordance with package insert instructions
    - Store in a cool, well ventilated, dry place
    - Store in original container
    - Store reconstituted product in accordance with package insert instructions
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    Remicade:
    - Avoid direct heat and sunlight
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - May be stored at temperatures up to 86 degrees F for up to 6 months
    - Product stored at controlled room temperature should not be returned to a refrigerator
    - Store diluted product in accordance with package insert instructions
    - Store in a cool, well ventilated, dry place
    - Store in original container
    - Store reconstituted product in accordance with package insert instructions
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    RENFLEXIS:
    - Avoid direct heat and sunlight
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - May be stored at temperatures up to 86 degrees F for up to 6 months
    - Product stored at controlled room temperature should not be returned to a refrigerator
    - Store diluted product in accordance with package insert instructions
    - Store in a cool, well ventilated, dry place
    - Store in original container
    - Store reconstituted product in accordance with package insert instructions
    - Store unopened containers in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.

    Human anti-chimeric antibody (HACA), infusion-related reactions, murine protein hypersensitivity

    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. 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.[27994] 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.[27994][61891]

    Hepatitis, hepatitis B exacerbation

    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.

    Bone marrow suppression, corticosteroid therapy, diabetes mellitus, fungal infection, herpes infection, immunosuppression, infection, mycobacterial infection, sepsis, tuberculosis, viral infection

    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.[27994] [61891]

    Heart failure

    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.[27994]

    Cervical cancer, lymphoma, Merkel cell carcinoma, new primary malignancy, skin cancer

    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. Caution should be exercised in considering infliximab treatment in patients with a history of neoplastic disease or in continuing treatment in patients who develop malignancy while receiving infliximab.[27994] [61891]

    Chronic obstructive pulmonary disease (COPD), tobacco smoking

    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; mostdevelopedlung 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.

    Guillain-Barre syndrome, multiple sclerosis, neurological disease, optic neuritis, seizure disorder, seizures, vasculitis

    Prescribers should exercise caution when considering the use of infliximab in patients with pre-existing or recent onset neurological disease or seizure disorder. Infliximab has been associated with optic neuritis, 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.

    Hematological disease, leukopenia, neutropenia, thrombocytopenia

    Cases of leukopenia, neutropenia, 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 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.

    Hepatotoxicity, jaundice

    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, mild or moderate elevations of ALT and AST were observed in patients receiving infliximab without progression to severe hepatic injury.

    Autoimmune disease

    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.

    Vaccination

    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.[27994]

    Infants, neonates, pregnancy

    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 and the available data from various studies and prospective pregnancy registries suggest low risk for use during early pregnancy as monotherapy.[61808] [30556] [61892] [61893] [62180] 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.[61893] 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.[61808] Other experts state that infliximab can be continued up to gestational week 20, and in select patients, longer if clinically indicated.[62180] 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.[27994] [48842] [60724] [61891] [62698]

    Breast-feeding

    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).

    Children

    Infliximab has not been studied in children less than 6 years of age. 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.

    Hepatitis C infection, HIV serum status

    Before starting 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. Similarily, 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.

    Surgery

    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.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / 0-1.0
    serum sickness / Delayed / 0.2-1.0
    GI obstruction / Delayed / 0.2
    pulmonary edema / Early / 0.2
    bradycardia / Rapid / 0.2
    hemolytic anemia / Delayed / 0.2
    hepatic encephalopathy / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    stroke / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    Guillain-Barre syndrome / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    seizures / Delayed / Incidence not known
    myelitis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    cervical cancer / Delayed / Incidence not known
    lymphoma / Delayed / Incidence not known
    skin cancer / Delayed / Incidence not known
    Merkel cell carcinoma / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 7.0-62.0
    elevated hepatic enzymes / Delayed / 17.0-51.0
    infusion-related reactions / Rapid / 18.0-20.0
    hypertension / Early / 0-7.0
    neutropenia / Delayed / 7.0-7.0
    candidiasis / Delayed / 5.0-5.0
    hypotension / Rapid / 0.2-1.0
    chest pain (unspecified) / Early / 1.0-1.0
    dyspnea / Early / 1.0-1.0
    dehydration / Delayed / 0.2
    constipation / Delayed / 0.2
    edema / Delayed / 0.2
    thrombocytopenia / Delayed / 0.2
    anemia / Delayed / 0.2
    phlebitis / Rapid / 0.2
    leukopenia / Delayed / 0.2
    lymphadenopathy / Delayed / 0.2
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    angina / Early / Incidence not known
    dysphagia / Delayed / Incidence not known
    psoriaform rash / Delayed / Incidence not known
    skin ulcer / Delayed / Incidence not known

    Mild

    infection / Delayed / 5.3-56.0
    abdominal pain / Early / 12.0-26.0
    nausea / Early / 21.0-21.0
    headache / Early / 5.0-18.0
    sinusitis / Delayed / 14.0-14.0
    diarrhea / Early / 12.0-12.0
    cough / Delayed / 12.0-12.0
    pharyngitis / Delayed / 12.0-12.0
    dyspepsia / Early / 10.0-10.0
    fatigue / Early / 9.0-9.0
    flushing / Rapid / 9.0-9.0
    arthralgia / Delayed / 1.0-8.0
    fever / Early / 3.0-7.0
    rash / Early / 3.0-3.0
    chills / Rapid / 3.0-3.0
    pruritus / Rapid / 0-1.0
    urticaria / Rapid / 0-1.0
    myalgia / Early / 0-1.0
    dizziness / Early / 0.2
    hyperhidrosis / Delayed / 0.2
    lichen planus-like eruption / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known

    DRUG INTERACTIONS

    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.
    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.
    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.
    Daclizumab: (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.
    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.
    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.
    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.
    Nanoparticle Albumin-Bound Sirolimus: (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.
    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.
    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.
    Sirolimus: (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.
    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. his suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of infliximab therapy.
    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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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).

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    Infliximab is administered intravenously. 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 infliximab is 7.7 to 9.5 days.
     
    Currently, therapeutic monitoring of 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.

    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.