Infliximab

[Section Outline]

Crohn Disease
Ulcerative Colitis
Rheumatoid Arthritis
Ankylosing Spondylitis
Psoriatic Arthritis
Plaque Psoriasis
Other Uses

Several infliximab biosimilars are available.167,194,195 Biosimilarity of these products has been demonstrated for the indications described in the table below (see Table 1).167,172,194,195

Biosimilarity to originator infliximab is additionally supported by comparative clinical studies in patients with rheumatoid arthritis (infliximab-abda, infliximab-axxq, infliximab-dyyb), Crohn disease (infliximab-dyyb), and/or ankylosing spondylitis (infliximab-dyyb).173,174,175,176,177,192,196,197,198,199,200

A subcutaneous version of infliximab-dyyb (Zymfentra®) is also available for the maintenance treatment of ulcerative colitis and Crohn disease in adults following treatment with IV infliximab.225

Table 1: Infliximab Biosimilar Products and FDA-licensed Indications167,194,195

FDA-labeled indication	Infliximab-axxq (Avsola®)	Infliximab-dyyb (Inflectra®)	Infliximab-abda (Renflexis®)
Crohn disease	X	X	X
Pediatric Crohn disease	X	X	X
Ulcerative colitis	X	X	X
Pediatric ulcerative colitis	X	X	X
Rheumatoid arthritis	X	X	X
Ankylosing spondylitis	X	X	X
Psoriatic arthritis	X	X	X
Plaque psoriasis	X	X	X

Crohn Disease

Crohn Disease in Adults

Infliximab and its biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) are used to reduce the signs and symptoms of Crohn disease and to induce and maintain clinical remission in adults with moderately to severely active disease who have had an inadequate response to conventional therapies.1,167,194,195 Infliximab and its biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) also are used to reduce the number of draining enterocutaneous and rectovaginal fistulas and to maintain fistula closure in adults with fistulizing Crohn disease.1,167,194,195 Infliximab has been designated an orphan drug by FDA for these uses.191

The subcutaneous formulation of infliximab-dyyb is used for the maintenance treatment of moderately to severely active Crohn disease in adults following IV treatment with an infliximab product.225

Safety and efficacy of infliximab for these uses are based principally on the results of randomized controlled trials.1,5,38,64,136,140,141,225 Guidelines generally support the use of infliximab for induction and maintenance therapy in adults with moderate to severe Crohn disease or fistulizing Crohn disease.2000,2001

Clinical Experience

Safety and efficacy of infliximab in the management of active Crohn disease were evaluated in a double-blind, placebo-controlled, dose-ranging study that included 108 adults with moderately to severely active Crohn disease who had an inadequate response to conventional therapies (e.g., corticosteroids, mesalamine, azathioprine, or mercaptopurine).1,5 To be included in the study, patients had to have had Crohn disease for a minimum of 6 months and a Crohn Disease Activity Index (CDAI) of 220-400 at the time of study entry.5 The CDAI score is based on the daily number of liquid or very soft stools, severity of abdominal pain or cramping, general well-being, presence or absence of extraintestinal manifestations, presence or absence of an abdominal mass, use or nonuse of antidiarrheal drugs, the hematocrit, and body weight; scores below 150 indicate clinical remission and scores above 450 indicate severe illness.5,64 Patients were randomized to receive placebo or a single dose of 5, 10, or 20 mg/kg of infliximab given by IV infusion over 2 hours.5 Those who were receiving fixed dosages of oral corticosteroids, oral mesalamine, and/or azathioprine or mercaptopurine continued to receive these drugs during the study (92% continued to receive one or more of these drugs).5 A clinical response (defined as a reduction from baseline CDAI of 70 points or more at 4 weeks after the dose without an increased need for other Crohn drugs or surgical intervention) was observed in 81, 50, or 64% of patients receiving 5, 10, or 20 mg/kg of infliximab, respectively, compared with 16% of patients receiving placebo.1,5,38 At 4 weeks after the dose, 33% of those who received infliximab and 4% of those who received placebo were in clinical remission based on the CDAI.5 There was no evidence of a dose-response relationship (doses exceeding 5 mg/kg did not result in a greater response rate) and, at all 3 infliximab dosages, the maximum response was observed within 2-4 weeks after the IV infusion.5 At 12 weeks after the dose, the overall rate of clinical response or clinical remission based on the CDAI was 41 or 24%, respectively, in those who received infliximab compared with 12 or 8%, respectively, in those who received placebo.5

To determine whether patients with moderately or severely active Crohn disease who do not respond to a single dose of infliximab would respond to an additional dose of the drug, the subset of patients in the above study who did not have a clinical response 4 weeks after the initial infliximab or placebo dose were enrolled in an open-label follow-up study and given a single 10-mg/kg dose of infliximab.5 In those who had received placebo in the original study, the rate of clinical response or remission was 58 or 47%, respectively, 4 weeks following this 10-mg/kg infliximab dose.5 However, in those who had already received a dose of infliximab in the first phase of the study, the rate of clinical response or remission was only 34 or 17%, respectively, 4 weeks following the second dose of the drug.5 These results indicate that patients who do not respond to an initial infliximab dose may be less likely to respond to a second dose of the drug.5

Safety and efficacy of infliximab for maintenance therapy in patients with moderately or severely active Crohn disease were evaluated in a preliminary study and in a double-blind, multidose, multicenter study (ACCENT I) that included more than 500 adults.1,38,136 The duration of response to infliximab usually ranges from 4-12 weeks in patients who experience a clinical benefit after a single dose of the drug.38,47,89 In one preliminary study, a subset of 73 adults from a double-blind, placebo-controlled study who had maintained a clinical response 8 weeks after an initial placebo or infliximab dose were re-randomized at week 12 to receive 4 doses of placebo or infliximab (10 mg/kg) given by IV infusion at 8-week intervals (i.e., weeks 12, 20, 28, 36).1,38 Those who were receiving fixed dosages of oral corticosteroids, oral mesalamine or sulfasalazine, and/or azathioprine or mercaptopurine continued to receive these drugs during the study; patients receiving oral corticosteroids where allowed to taper dosage if they responded to treatment.38 Patients were assessed every 4 weeks through week 48.38 The clinical response was maintained through week 44 (8 weeks after the fourth infusion) in 62 or 37% of patients receiving infliximab or placebo, respectively.38 In those randomized to receive infliximab for maintenance therapy, 37.8% were in clinical remission at week 12 and 52.9% were in clinical remission at week 44.38 In contrast, 44.4% of those randomized to receive placebo for maintenance therapy were in clinical remission at week 12 and only 20% were in clinical remission at week 44.38 Although further study is needed to determine the relative benefits of concomitant use of infliximab and azathioprine or mercaptopurine for maintenance of remission, 75% of patients receiving one of these drugs concomitantly with infliximab had a clinical response at 44 weeks compared with 50% of those not receiving one of these drugs concomitantly.38

In a double-blind study of 573 adults with moderately to severely active Crohn disease that was designed to compare the safety and efficacy of a maintenance regimen of infliximab to a single dose of the drug (ACCENT I), all patients received an initial 5-mg/kg dose of infliximab; following assessment of clinical response at week 2 (defined as a CDAI decrease of at least 70 points and at least a 25% decrease from baseline CDAI), patients were randomized to receive placebo or an infliximab induction regimen (5-mg/kg doses given at weeks 2 and 6 followed by either 5- or 10-mg/kg maintenance doses given once every 8 weeks) for up to 1 year.72,136 Those who were receiving fixed dosages of oral corticosteroids (prednisone 40 mg or less daily or equivalent), oral mesalamine, sulfasalazine, anti-infective agents, azathioprine, mercaptopurine, or methotrexate continued to receive these drugs during the study; patients receiving oral corticosteroids were allowed to taper the dosage after week 6 if they responded to treatment.136 Among adults who responded to the initial dose of infliximab, 39 or 46% of those receiving 5- or 10-mg maintenance doses of infliximab, respectively, were in clinical remission at week 30 compared with 25% of those receiving maintenance doses of placebo.1,136 In addition, among patients receiving corticosteroids at baseline, 25 or 34% of those receiving 5- or 10-mg maintenance doses of infliximab, respectively, were in clinical remission and were able to discontinue corticosteroid use at week 54 compared with 11% of those receiving maintenance doses of placebo.1 The median time to loss of response in those receiving maintenance doses of infliximab or placebo was 46 or 19 weeks, respectively.136

Although the relative benefits of concomitant use of infliximab and an immunosuppressant agent (e.g., methotrexate, azathioprine) for maintenance therapy remain to be determined, 50% of those receiving immunosuppressive therapy at baseline maintained clinical response at week 54 compared with 41% of those not receiving such therapy.136

Patients in this study who responded initially but subsequently lost response were eligible to receive infliximab at a higher dose than the dose they had been receiving; these patients were eligible to receive infliximab on an episodic basis at a dose 5 mg/kg higher than the dose they had been receiving in the study.1 Most patients responded to the higher dose.1

Among adults who did not respond to the initial dose of infliximab, 59% of those receiving maintenance doses of infliximab responded by week 14 compared with 51% of those receiving maintenance doses of placebo.1 In patients who did not respond to infliximab by week 14, additional doses of infliximab did not result in a clinically important response.1

In a subset of patients with mucosal ulceration at baseline who participated in an endoscopic study, 13 of 43 patients receiving maintenance doses of infliximab had endoscopic evidence of mucosal healing at week 10 compared with 1 of 28 patients receiving placebo for maintenance therapy.1 Nine of 12 patients receiving maintenance doses of infliximab with mucosal healing at week 10 also had mucosal healing at week 54.1

Safety and efficacy of infliximab in the management of fistulizing Crohn disease have been evaluated in a double-blind, placebo-controlled study involving 94 adults with one or more cutaneously draining fistulas of at least 3 months' duration (90% had perianal fistulas, 10% had abdominal fistulas, 55% had multiple cutaneously draining fistulas).1,64 Patients were randomized to receive placebo or infliximab (5 or 10 mg/kg) given by IV infusion over 2 hours at weeks 0, 2, and 6 and were followed for up to 26 weeks.1,64 Those who were receiving fixed dosages of oral corticosteroids, oral mesalamine or sulfasalazine, anti-infectives, and/or methotrexate, azathioprine, or mercaptopurine continued to receive these drugs during the study (83% continued to receive one or more of these drugs).1,64 A clinical response (defined as a 50% or greater reduction from baseline in the number of fistulas draining after gentle compression during at least 2 consecutive visits without an increased need for other drugs used for the treatment of Crohn disease or surgical intervention) occurred in 68 or 56% of patients receiving infliximab in a dosage of 5 or 10 mg/kg, respectively, versus 26% of those receiving placebo.1,64 Closure of all fistulas was attained in 52% of patients receiving infliximab versus 13% of those receiving placebo.1,64 In patients receiving infliximab, the median time to onset of response was 2 weeks and the median duration of response was 12 weeks; there was no evidence of a dose-response relationship.1,64 New fistula(s) occurred in approximately 15% of patients receiving infliximab or placebo.1,64

Long-term safety and efficacy of infliximab in the management of fistulizing Crohn disease have been evaluated in a multicenter, double-blind, randomized, placebo-controlled trial (ACCENT II) in adults with at least one draining fistula (e.g., perianal, enterocutaneous, or rectovaginal fistulas) for at least 3 months.1,140,141 In the initial phase of this study, all patients received infliximab (5 mg/kg) at weeks 0, 2, and 6; those with a clinical response (defined as a 50% or greater reduction from baseline in the number of fistulas draining after gentle compression during at least 2 consecutive visits without an increased need for other drugs or surgical intervention) at weeks 10 and 14 were randomized to receive placebo or infliximab 5 mg/kg at week 14 and then every 8 weeks through week 46 (maintenance treatment).1,140 Patients who were receiving stable dosages of 5-aminosalicylates, oral corticosteroids, methotrexate, azathioprine, mercaptopurine, mycophenolate mofetil, or anti-infective agents continued to receive these drugs during the study.1,140 At week 14, 65% of patients had a clinical response to the initial 3 doses of infliximab; in this group, 87% had perianal fistulas, 14% had abdominal fistulas, and 8% had rectovaginal fistulas.1 During the maintenance phase of the study, time to loss of clinical response was longer in patients who received infliximab every 8 weeks than those who received placebo (40 versus 14 weeks, respectively).1,140,141 At 54 weeks, 46 or 23% of patients receiving infliximab or placebo, respectively, had a response,140 while 36 or 19% of patients receiving infliximab or placebo, respectively, had complete response (defined as absence of draining fistulas).140 There was a trend toward fewer hospitalizations in those receiving infliximab maintenance compared with those receiving placebo.1 Patients who initially had a clinical response but lost response (defined as recrudescence of draining fistulas, need for a change in a drug, need for additional therapy for persistent or worsening luminal disease activity, need for surgery, or discontinuance of infliximab because of perceived lack of efficacy) were eligible to receive infliximab maintenance treatment using a dosage 5 mg/kg higher than the dosage they originally received; 66% of patients who were originally randomized to placebo responded to infliximab 5 mg/kg and 57% of patients who were originally randomized to infliximab 5 mg/kg responded to infliximab 10 mg/kg.1,140 Patients who did not respond to infliximab therapy by week 14 of the study were unlikely to respond to additional doses of the drug.1,140 In patients who did not have an initial response to infliximab, 16 (7 out of 44 patients) or 21% (9 out of 43 patients) of those receiving placebo or infliximab, respectively, had a response.140 At week 22, patients who were receiving placebo and who had a loss of response were eligible to cross over to maintenance therapy with infliximab 5 mg/kg while those who were receiving infliximab 5 mg/kg could cross over to receive infliximab 10 mg/kg.140 In patients who crossed over from placebo to infliximab, response was reestablished in 61% of individuals.140 Overall, a similar number of patients in the infliximab or placebo groups developed new fistulas (17%) and new abscesses (15%).1

The efficacy and safety of subcutaneous infliximab-dyyb as a maintenance therapy in moderately to severely active Crohn disease following treatment with an IV infliximab product were evaluated in a randomized, double-blind, placebo-controlled trial.225 All patients were intially administered 3 IV induction doses of 5 mg/kg infliximab-dyyb at weeks 0, 2, and 6.225 Patients who experienced a clinical response, defined as a decrease from baseline in CDAI of at least 100 points at week 10, were randomly assigned to infliximab-dyyb 120 mg subcutaneously or placebo every 2 weeks.225 The co-primary endpoints were clinical remission (based on CDAI) and endoscopic response at week 54.225 Results revealed that maintenance subcutaneous infliximab-dyyb therapy was associated with an improvement in both clinical remission (63% vs. 30%) and endoscopic response (50% vs. 18%) as compared to placebo in the total population.225

Clinical Perspective

The American College of Gastroenterology (ACG) and the American Gastroenterological Association (AGA) have issued guidelines for the medical treatment of Crohn disease.2000,2001,2002 Treatment of Crohn disease is typically divided into 2 phases: induction therapy (where control of inflammation is rapidly achieved) and maintenance therapy (where control of inflammation is sustained for a prolonged period of time).2000 Specific treatments for Crohn disease are selected according to the patient's risk profile and disease severity.2000 Drug classes used to treat Crohn disease include 5-aminosalicylates, antibiotics, corticosteroids, immunomodulators (e.g., thiopurines, immunomodulators), and biologic agents, including tumor necrosis factor (TNF; TNF-α) blocking agents, ustekinumab, vedolizumab, and natalizumab.2000

TNF blocking agents used in the treatment of Crohn disease include infliximab, adalimumab, and certolizumab pegol.2000,2001 The TNF blocking agents are generally recommended for use as induction and maintenance therapy in adults with moderate to severe Crohn disease.2000,2001 The ACG states that TNF blocking agents should be used to treat moderate to severe and/or moderate to high risk Crohn disease that is resistant to treatment with corticosteroids and/or refractory to thiopurines or methotrexate.2000 Combining TNF blocking agents with a thiopurine in the induction setting may be more effective than TNF blocking agent monotherapy in patients who are naïve to these therapies.2000 The AGA suggests combining infliximab or adalimumab with a thiopurine over infliximab or adalimumab monotherapy for induction and maintenance of remission in patients with moderate to severe Crohn disease who are naïve to biologics and immunomodulators.2001 The TNF blocking agents can also be considered to treat severely active Crohn disease, and infliximab may be used to treat fulminant Crohn disease.2000

Patients with perianal fistulas should be considered for TNF blocking therapy; however, guideline recommendations regarding agent selection differ in this setting.2000,2001 The ACG states that infliximab is effective in this setting, while adalimumab and certolizumab pegol may be effective.2000 The AGA recommends infliximab and suggests adalimumab, ustekinumab, or vedolizumab over no treatment in this setting, and notes that certolizumab pegol may not be effective for induction of fistula remission.2001 In patients with enterocutaneous or rectovaginal fistulas, infliximab may be effective and should be considered.2000 If a patient with Crohn disease achieves remission with a TNF blocking agent, TNF blocking therapy should be continued to maintain remission; monotherapy with a TNF blocking agent is effective for maintaining remission, but combination with azathioprine/6-mercaptopurine or methotrexate should be considered due to the potential for immunogenicity and loss of response.2000 For patients with surgically induced remission of Crohn disease, the AGA suggests TNF blocking agents and/or thiopurines over other agents to prevent recurrence.2002 Similarly, the ACG recommends that patients who undergo surgery for Crohn disease and remain at high risk for recurrence should begin therapy with a TNF blocking agent within 4 weeks of surgery to prevent postoperative recurrence.2000

Crohn Disease in Pediatric Patients

Infliximab and its biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) are used to reduce the signs and symptoms of Crohn disease and to induce and maintain clinical remission in pediatric patients 6 years of age and older with moderately to severely active disease who have had an inadequate response to conventional therapy.1,167,194,195 Infliximab has been designated an orphan drug by FDA for this use.191 Safety and efficacy of infliximab in the treatment of Crohn disease in pediatric patients are based principally on the results of a randomized controlled trial (REACH), with supporting evidence from an open-label extension study and small open-label trials.1,86,87,201,202

Clinical Experience

The REACH study was a randomized, open-label study in 112 pediatric patients 6-17 years of age (median age 13 years) with moderately to severely active Crohn disease who had a median Pediatric Crohn Disease Activity Index (PCDAI) of 40 (on a scale of 0-100) and an inadequate response to conventional therapy.1,201 Prior to enrollment in the study, patients were required to be on a stable dosage of mercaptopurine, azathioprine, or methotrexate; 35% of the patients also were receiving corticosteroids at baseline.1 All patients received infliximab induction therapy with 5 mg/kg administered at weeks 0, 2, and 6.1,201 At week 10, 103 patients were randomized to receive maintenance therapy of 5 mg/kg of infliximab every 8 or 12 weeks.1,201 At week 10, 88% of patients had clinical response (defined as a decrease in PCDAI score of 15 or more points from baseline and a total PCDAI score of 30 points or less), and 59% of patients were in clinical remission (defined as a PCDAI score of 10 points or less).1 The proportion of pediatric patients achieving a clinical response at week 10 compared favorably with the rate of clinical response reported in adults with active Crohn disease who received infliximab in a clinical trial.1 The clinical response rate both at week 30 (73 versus 47%) and week 54 (64 versus 33%) was higher in pediatric patients receiving infliximab every 8 weeks than in those receiving the drug every 12 weeks.1 In addition, the clinical remission rate both at week 30 (60 versus 35%) and week 54 (56 versus 24%) was higher in patients receiving infliximab every 8 weeks than in those receiving the drug every 12 weeks.1 Among patients receiving corticosteroids at baseline, 46 or 33% of those receiving maintenance doses of infliximab every 8 or 12 weeks, respectively, were in clinical remission and were able to discontinue corticosteroid use at week 30, while at week 54, 46 or 17% of those receiving maintenance doses of infliximab every 8 or 12 weeks, respectively, were in clinical remission and were able to discontinue corticosteroid use.1 Patients who completed REACH were eligible to enter an open-label extension study.202 Patients in the extension study received infliximab 5 mg/kg every 8 or 12 weeks or infliximab 10 mg/kg every 8 weeks, depending on the maintenance regimen they were receiving at the completion of the REACH study.202 In this study, clinical benefit of infliximab was maintained for up to 3 additional years of treatment.202

In another open-label study in 15 pediatric patients 6-18 years of age with medically refractory Crohn disease (unable to tolerate corticosteroid taper; PCDAI score of 30 or greater; no improvement despite use of mercaptopurine, methotrexate, and/or cyclosporine for 4 months or longer), a single 5-mg/kg dose of infliximab was administered by IV infusion.87 At 4 weeks after the dose, 14/15 (94%) had responded to infliximab with a decrease in the PCDAI score of 25 points or greater; at 10 weeks, 10/15 (67%) were in clinical remission (PCDAI score of 15 or less).87 All patients continued mercaptopurine or methotrexate therapy during and after the infliximab infusion, but oral corticosteroid dosage was tapered in most patients.87 During the 52-week follow-up of the 14 responders, 11 (78%) had clinical relapse that required additional drug therapy or surgical intervention.87 When these children were subdivided based on disease duration, the relapse rate was 50% in those who had been diagnosed with Crohn disease less than 2 years previously; however, the relapse rate was 100% in those who had been diagnosed more than 2 years previously.87

In an open-label study in 19 pediatric patients 9-19 years of age with moderately or severely active Crohn disease, 1-3 doses of infliximab (5 mg/kg) were given by IV infusion usually at 4-week intervals.86 At 4 weeks after the initial dose, all 19 pediatric patients had a clinical response documented by physician global assessment and PCDAI score; at 12 weeks after the initial dose, only 4 patients maintained a clinical response to the drug.86

Clinical Perspective

Many of the agents used to treat Crohn disease in adults are also used to treat Crohn disease in pediatric patients; these agents include 5-aminosalicylates, corticosteroids, immunomodulators (e.g., azathioprine, methotrexate), and biologic agents (e.g., TNF blocking agents).2015,2016 A “treat-to-target” approach is used in pediatric patients, with targets including clinical response, clinical remission, restoration of normal growth, endoscopic healing, and normalization of biomarkers (e.g., C-reactive protein [CRP], fecal calprotectin).2017 In pediatric patients, exclusive enteral nutrition is recommended as first-line induction therapy, with corticosteroids as an alternative.2015,2016 Immunomodulators are typically used first-line for maintenance therapy.2016 TNF blocking agents used in the treatment of pediatric Crohn disease include infliximab and adalimumab; these agents are generally used for induction and maintenance therapy in pediatric patients who fail an adequate trial of steroids and exclusive enteral nutrition and/or immunomodulators, unless the patient has a complex perianal fistula at diagnosis.2016

Ulcerative Colitis

Ulcerative Colitis in Adults

Infliximab and its biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) are used to reduce signs and symptoms, to induce and maintain clinical remission and mucosal healing, and to eliminate use of corticosteroids in adults with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapies.1,167,194,195

The subcutaneous formulation of infliximab-dyyb is used for the maintenance treatment of moderately to severely active ulcerative colitis in adults following IV treatment with an infliximab product.225

Safety and efficacy of infliximab for this use are based principally on the results of 2 randomized controlled trials.1,147 Guidelines generally support the first-line use of TNF blocking agents for induction and maintenance of remission in patients with moderate to severe ulcerative colitis.2019,2020,2019

Clinical Experience

Safety and efficacy of infliximab in the management of ulcerative colitis in adults were evaluated in 2 randomized, double-blind, placebo-controlled studies (the Active Ulcerative Colitis Trials 1 and 2; ACT 1 and ACT 2, respectively)1,147 in 728 patients with moderately to severely active ulcerative colitis who had an inadequate response to conventional therapies.1,147 In the ACT 1 study, patients had an inadequate response to or were intolerant of corticosteroids alone or in combination with azathioprine or mercaptopurine, while in the ACT 2 study, patients had an inadequate response to or were intolerant of corticosteroids alone or in combination with azathioprine or mercaptopurine and/or to preparations containing 5-aminosalicylates.1,147 Patients were randomized to receive placebo or a 5- or 10-mg/kg dose of infliximab at weeks 0, 2, and 6 and then every 8 weeks through week 22 in the ACT 2 study or week 46 in the ACT 1 study.1,147 Patients in the ACT 2 study were allowed to continue blinded therapy to week 46 at the investigator's discretion.1 Those who were receiving fixed dosages of azathioprine or mercaptopurine, and/or 5-aminosalicylates, continued to receive these drugs during the study.147 Corticosteroids were tapered gradually until discontinuance.147 In both studies, the proportions of patients who had a clinical response or remission at weeks 8 and 30, and at week 54 in the ACT 1 study, were higher by a factor of 1.7 to more than 2 in patients receiving infliximab than in those receiving placebo.147 Clinical response (defined as a reduction from baseline Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1) at week 30 in the ACT 1 study was reported in 52 or 51% of patients receiving 5 or 10 mg of infliximab, respectively, compared with 30% patients receiving placebo, while in the ACT 2 study such response was observed in 47 or 60% of patients receiving 5 or 10 mg of infliximab, respectively, compared with 26% of patients receiving placebo.1,147 At week 54 in the ACT 1 study, clinical response was reported in 46 or 44% of patients receiving 5 or 10 mg of infliximab, respectively, compared with 20% of patients receiving placebo.147 The rates of clinical response were similar between the subpopulations of patients who were refractory to corticosteroids and those who were not refractory to corticosteroids.147 In the ACT 1 study, in patients refractory to corticosteroids, clinical response at week 8 was reported in 77 or 68% of those receiving 5 or 10 mg of infliximab, respectively, and in 35% of those receiving placebo, while in patients not refractory to corticosteroids, such response was reported in 67 or 59% of those receiving 5 or 10 mg of infliximab, respectively, and in 38% of those receiving placebo.147 In the ACT 2 study, in patients refractory to corticosteroids, clinical response at week 8 was reported in 63 or 66% of those receiving 5 or 10 mg of infliximab, respectively, and in 38% of those receiving placebo, while in patients not refractory to corticosteroids, such response was reported in 65 or 70% of those receiving 5 or 10 mg of infliximab, respectively, and in 26% of those receiving placebo.147 At week 30, clinical remission was reported in 34 and 37% of patients receiving 5 or 10 mg of infliximab, respectively, compared with 16% of those receiving placebo in the ACT 1 study, while such remission was observed in 26 or 36% of patients receiving 5 or 10 mg of infliximab, respectively, compared with 11% of patients receiving placebo.1,147 At week 54 in the ACT 1 study, clinical remission was reported in 35 or 34% of patients receiving 5 or 10 mg of infliximab, respectively, compared with 17% of patients receiving placebo.1,147 The proportions of patients with a sustained clinical response or sustained remission were significantly higher in patients receiving infliximab than in those receiving placebo. 1,147 In addition, mucosal healing at weeks 8 and 30 in both studies (ACT 1 and ACT 2) and at week 54 in ACT 1 occurred in significantly more patients receiving infliximab than in those receiving placebo.1,147 At baseline, 61 and 51% of patients were receiving corticosteroids in the ACT 1 and ACT 2 studies, respectively.147 The proportions of patients who were in clinical remission and had discontinued corticosteroids at week 30 in both studies and at week 54 in the ACT 1 study, were higher in those receiving infliximab that in those receiving placebo.147

The efficacy and safety of subcutaneous infliximab-dyyb as a maintenance therapy in moderately to severely active ulcerative colitis following treatment with an IV infliximab product were evaluated in a randomized, double-blind, placebo-controlled trial.225 All patients were intially administered 3 IV induction doses of 5 mg/kg infliximab-dyyb at weeks 0, 2, and 6.225 Patients who experienced a clinical response, defined as a decrease from baseline in the modified Mayo score of at least 2 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 point at week 10, were randomly assigned to infliximab-dyyb 120 mg subcutaneously or placebo every 2 weeks.225 The primary endpoint was the proportion of patients in clinical remission at week 54.225 Results revealed that maintenance subcutaneous infliximab-dyyb therapy was associated with an improvement in clinical remission as compared to placebo (43% vs. 21%) in the total population.225

Clinical Perspective

The American College of Gastroenterology (ACG) and the American Gastroenterological Association (AGA) issued guidelines for the medical treatment of ulcerative colitis in adults in 2019 and 2020.2018,2019,2020 Goals of therapy in ulcerative colitis include achieving and maintaining corticosteroid-free remission and promoting mucosal healing.2020 Specific treatments are selected according to disease severity, as well as disease location/extent, disease prognosis, and previous therapies used.2018,2019,2020 Drug classes used to treat ulcerative colitis include oral and rectal 5-aminosalicylates, oral and rectal corticosteroids, immunomodulators (e.g., thiopurines, methotrexate), tofacitinib, and biologic agents, including TNF blocking agents, vedolizumab, and ustekinumab.2018,2019 In most cases, if a drug used for induction therapy is effective, it is continued for maintenance of remission.2019

TNF blocking agents used in the treatment of ulcerative colitis include infliximab, golimumab, and adalimumab; the primary role for these agents is in the treatment of moderate to severe ulcerative colitis.2019,2020 For adult outpatients with moderate to severe ulcerative colitis, the AGA recommends TNF blocking therapies, vedolizumab, tofacitinib, or ustekinumab over no treatment.2019 AGA conditionally recommends the use of infliximab or vedolizumab over adalimumab for induction of remission in biologic-naïve patients based on evidence from a comparative randomized controlled trial (vedolizumab) and a network meta-analysis (infliximab).2019 ACG recommends the use of oral corticosteroids, TNF blocking agents, vedolizumab, or tofacitinib for induction of remission in patients with moderately to severely active ulcerative colitis.2020

Early use of biologic agents with or without immunomodulator therapy is conditionally recommended over gradual step up therapy after failure of 5-aminosalicylates.2019 Combination therapy with a TNF blocking agent and a thiopurine or methotrexate is conditionally recommended over biologic monotherapy.2019 Combination therapy with a thiopurine is specifically recommended for patients who receive induction therapy with infliximab.2020 Patients who achieve remission with TNF blocking therapy should continue on TNF blocking therapy to maintain remission after induction.2020 Patients with primary nonresponse to one TNF blocking therapy should be switched to a biologic from a different class; patients who initially respond to TNF blocking therapy and later lose response can be switched to a different TNF blocking agent.2020 Patients with mildly active ulcerative colitis and multiple prognostic factors associated with an increased risk of hospitalization or surgery should be treated with therapies for moderately to severely active disease.2020 Consult the ACG guideline for additional details on prognostic factors that may be considered.2020

Hospitalized patients with acute severe ulcerative colitis should receive IV corticosteroids to induce remission; if the response to IV corticosteroids is inadequate after 3 to 5 days of therapy, infliximab or cyclosporine should be used as rescue therapy.2019,2020 The choice between infliximab or cyclosporine should be based on provider experience with the agent, history of previous failure of immunomodulator or TNF blocking therapy, and serum albumin.2020

Ulcerative Colitis in Pediatric Patients

Infliximab and its biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) are used to reduce the signs and symptoms of ulcerative colitis and to induce and maintain clinical remission in pediatric patients 6 years of age and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.1,167,194,195 Infliximab has been designated as an orphan drug by FDA for the treatment of ulcerative colitis in pediatric patients.191

Clinical Experience

Efficacy and safety of infliximab for this indication are supported by evidence from controlled clinical studies in adults and by an uncontrolled study in 60 pediatric patients 6-17 years of age with moderately to severely active ulcerative colitis (Mayo score of 6-12, endoscopic subscore of 2 or greater) and an inadequate response to conventional therapies.1,203 At the start of the study in pediatric patients, 53% of patients were receiving immunosuppressive therapy with mercaptopurine, azathioprine, or methotrexate, and 62% were receiving corticosteroids; discontinuance of immunosuppressive agents and tapering of corticosteroid dosage was permitted after week 0.1 All patients received induction therapy with infliximab (5 mg/kg at weeks 0, 2, and 6); those who exhibited a response at week 8 were randomized to receive a maintenance regimen of 5 mg/kg every 8 weeks through week 46 or 5 mg/kg every 12 weeks through week 42.1,203 Patients who experienced loss of response during maintenance therapy were allowed to receive higher and/or more frequent doses of the drug.1,203

At week 8 of the pediatric study, approximately 73% of patients exhibited a clinical response (defined as a reduction from baseline Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or achievement of an absolute rectal-bleeding subscore of 0 or 1); 40% of patients were in clinical remission as defined by Mayo score (2 points or less, with no individual subscore exceeding 1), and approximately 33% of patients were in clinical remission as measured by the Pediatric Ulcerative Colitis Activity Index (PUCAI) (score less than 10 points).1,203 Clinical response at 8 weeks was observed in 23 of 32 patients (72%) receiving concomitant immunosuppressive therapy at baseline and in 21 of 28 patients (75%) not receiving such therapy at baseline.1

At week 54 of the pediatric study, clinical remission (as measured by PUCAI score) was observed in 8 of 21 patients receiving infliximab every 8 weeks and 4 of 22 patients receiving the drug every 12 weeks.1,203 Of the 45 patients randomized to receive maintenance therapy, 23 patients (including 9 patients receiving infliximab every 8 weeks and 14 patients receiving the drug every 12 weeks) required higher and/or more frequent doses of the drug because of loss of response, and 9 of those patients (including 7 patients who received the drug every 8 weeks) achieved remission at week 54.1 Efficacy of infliximab in inducing and maintaining mucosal healing could not be established because the study was uncontrolled and few patients underwent endoscopy at week 54.1

Clinical Perspective

Many of the agents used to treat ulcerative colitis in adults are also used to treat ulcerative colitis in pediatric patients; these agents include 5-aminosalicylates, corticosteroids, immunomodulators (e.g., azathioprine), and biologic agents (e.g., TNF blocking agents).2015,2016 Choice of agent is generally guided by severity of presentation.2015 A “treat-to-target” approach is used in pediatric patients, with targets including clinical response, clinical remission, restoration of normal growth, endoscopic healing, and normalization of biomarkers (e.g., CRP, fecal calprotectin).2017

In pediatric patients, 5-aminosalicylates are used first-line for induction and maintenance of remission in mild to moderate ulcerative colitis; corticosteroids are used first-line for induction of remission in severe disease and in patients who fail to respond to 5-aminosalicylates.2016 Azathioprine is typically used first-line for maintenance therapy in patients who attain remission on corticosteroids.2016 Long-term corticosteroid treatment should be avoided if possible.2016 TNF blocking agents used in the treatment of pediatric ulcerative colitis include infliximab and adalimumab; these agents are generally used in patients with moderate to severe disease who fail therapy with 5-aminosalicylates/azathioprine and/or who are unable to wean from corticosteroids on 5-aminosalicylate/azathioprine therapy.2015,2016 Hospitalized patients with acute severe colitis are typically treated with corticosteroids first-line, but if adequate response is not attained after 3 to 5 days, infliximab therapy can be used to induce remission.2016

Rheumatoid Arthritis

Infliximab and its biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) are used in conjunction with methotrexate to manage signs and symptoms, improve physical function, and inhibit progression of structural damage in adults with moderately to severely active rheumatoid arthritis.1,167,194,195 Safety and efficacy of infliximab for this use are based principally on the results of several randomized controlled trials.1,14,15,17,18,41,41,145 Guidelines generally support the use of TNF blocking agents as add-on therapy to methotrexate in patients who do not meet treatment goals with methotrexate alone.2003

Clinical Experience

Safety and efficacy of infliximab used in conjunction with methotrexate for the management of rheumatoid arthritis in adults have been evaluated in several open-label and double-blind, placebo-controlled studies in adults with active disease as defined by the American College of Rheumatology (ACR) who had not responded adequately to methotrexate.1,14,15,17,18,41 Infliximab in conjunction with methotrexate also has been evaluated in a controlled study in adults with early active rheumatoid arthritis (i.e., duration of 3 years or less) who had not previously received therapy with methotrexate.1,145 Results indicate that addition of infliximab to a methotrexate regimen can result in decreases in the signs and symptoms of rheumatoid arthritis.1,14,15,41 For patients with early active rheumatoid arthritis, concomitant use of infliximab and methotrexate is more effective than methotrexate (as the sole disease-modifying antirheumatic drug [DMARD]) for the management of rheumatoid arthritis in adults.1,145 In addition, infliximab used concomitantly with methotrexate can improve physical function and inhibit the progression of structural damage in patients with rheumatoid arthritis.1,15,145

Concomitant use of infliximab and methotrexate for the management of rheumatoid arthritis was evaluated in a large double-blind, placebo-controlled, phase III, international study that involved 428 patients (Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy [ATTRACT]).1,14 At study entry, patients had active rheumatoid arthritis (defined as 6 or more swollen or tender joints and at least 2 additional manifestations, including morning stiffness for 45 minutes or longer, erythrocyte sedimentation rate [ESR] of 28 mm/hour or greater, or CRP level of 2 mg/dL or greater) despite having received methotrexate (oral or parenteral) and folic acid consistently for at least 3 months.14 Study patients were a median age of 51 years old, had a median disease duration of 11 years, and previously received treatment with 2.5-2.8 DMARDs other than methotrexate.14,15 These patients had median swollen and tender joint counts of 21 and 31, respectively; 77% were rheumatoid factor positive; 37% had undergone a joint surgery; 25% had joint replacement surgery; and approximately 40% were classified as ACR functional class III.1,14,15

Patients were randomized to receive placebo or 3 or 10 mg/kg of infliximab by IV infusion at weeks 0, 2 and 6, followed by additional doses given once every 4 or 8 weeks.1,14 Patients continued to receive stable weekly dosages of methotrexate (median dosage 16 mg once weekly) beginning 4 weeks before and throughout the study.1,14,15 Those who were receiving stable dosages of nonsteroidal anti-inflammatory agents (NSAIAs) and/or oral corticosteroids (oral prednisone 10 mg or less daily or equivalent) for at least 4 weeks prior to study entry were permitted to continue these drugs; patients who had not received such therapy were not permitted to initiate these drugs after entering the study.1,14 Patient evaluations were performed every 4 weeks and assessed according to ACR criteria for improvement (ACR response); the primary end point was the proportion of patients at week 30 who experienced a 20% improvement in rheumatoid disease activity (ACR 20 response).14 The ACR 20 response is achieved if the patient experiences a 20% or greater improvement in both tender and swollen joint counts and a 20% or greater improvement in at least 3 of the following criteria: patient pain assessment, patient global assessment, physician global assessment, patient self-assessed disability, or laboratory indicators of disease activity (i.e., ESR or CRP level).1,13,14 Patients also were evaluated for ACR 50 and 70 responses (these are defined using the same criteria as ACR 20 with a level of improvement of 50 or 70%, respectively); reductions in individual measures of disease activity; and a general health assessment.14

At 30 weeks, an ACR 20 response was attained in 50% of patients who received 3 mg/kg of infliximab every 8 weeks concomitantly with weekly methotrexate compared with 20% of patients who received placebo and weekly methotrexate.1,14 Similar response rates were observed in patients receiving the higher infliximab dosage (10 mg/kg) and/or more frequent doses (every 4 weeks).1,14 At 30 weeks, an ACR 50 response was attained in 26-31% and an ACR 70 response was attained in 8-18% of patients who received infliximab in a dosage of 3 or 10 mg/kg every 4 or 8 weeks concomitantly with once weekly methotrexate;1 an ACR 50 or 70 response was attained at week 30 in only 5 or 0%, respectively, of patients who received placebo with once weekly methotrexate.1,14

At 54 weeks, 42-59% of those who received 3 or 10 mg/kg of infliximab once every 4 or 8 weeks concomitantly with once weekly methotrexate maintained an ACR 20 response compared with 17% of patients who received placebo concomitantly with once weekly methotrexate.15 At 54 weeks, an ACR 50 or 70 response was maintained in 21-40% or 11-26%, respectively, of those receiving infliximab concomitantly with once weekly methotrexate compared with only 9 or 2%, respectively, of patients receiving placebo concomitantly with once weekly methotrexate.1,15

Physical function and disability were assessed using the Health Assessment Questionnaire (HAQ) and the general health-related quality-of-life questionnaire SF-36.1 All 4 dosage regimens of infliximab and weekly methotrexate were associated with greater improvement from baseline in the HAQ and SF-36 physical component summary score averaged over time through week 54 compared with the placebo plus methotrexate regimen; in addition, the infliximab regimens were not associated with deterioration in the SF-36 mental component summary score.1 Improvements in HAQ and SF-36 were maintained through week 102.1

Structural damage in the hands and feet of patients in this study was assessed radiographically at baseline and at weeks 54 and 102 using the van der Heijde-modified Sharp score (a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing in hands/wrists and feet).1 At 54 weeks, there was more progression of joint damage from baseline in the group of patients who received placebo with once weekly methotrexate compared with those who received infliximab with once weekly methotrexate.1,15 The inhibition of progression of structural damage reported in patients receiving infliximab at week 54 was maintained through week 102.1 There also was evidence that infliximab had a benefit on both erosions and joint-space narrowing when these scores were examined independently and when the hands and feet were examined separately.1,15

Efficacy of infliximab in conjunction with methotrexate has been evaluated in a study that included 1004 adults with early active rheumatoid arthritis (i.e., duration of 3 years or less) who had not previously received methotrexate.1,145 The median age of study patients was 51 years, and the median disease duration was 0.6 years.1,145 These patients had median swollen and tender joint counts of 19 and 31, respectively; greater than 80% of these individuals had joint damage at baseline.1,145 Patients were randomized to receive placebo or 3 or 6 mg/kg of infliximab by IV infusion at weeks 0, 2, and 6, followed by additional doses given once every 8 weeks.1,145 All patients received methotrexate (optimized to a dosage of 20 mg each week by week 8 of the study); patients receiving stable dosages of NSAIAs and/or oral corticosteroids (oral prednisone 10 mg or less daily or equivalent) at study entry were permitted to continue these drugs.1,145 Reduction in the signs and symptoms of rheumatoid arthritis were evaluated using ACR criteria, physical function and disability was assessed using HAQ scores, and joint damage was assessed using the van der Heijde-modified Sharp score.1,145 At 54 weeks, 62-66% of patients receiving 3 or 6 mg/kg of infliximab with once-weekly methotrexate attained an ACR 20 response compared with 54% of those who received placebo concomitantly with once weekly methotrexate.1,145 At 54 weeks, an ACR 50 or 70 response was attained by 46-50 or 33-37%, respectively, of patients receiving infliximab concomitantly with weekly methotrexate compared with 32 or 21%, respectively, of those receiving placebo with once-weekly methotrexate.1,145 Both dosage regimens of infliximab and weekly methotrexate were associated with greater improvement from baseline in the HAQ averaged over time through week 54 compared with the placebo plus methotrexate regimen.1,145 Radiographic analysis at week 54 indicates that infliximab in conjunction with methotrexate is more effective than methotrexate alone in delaying joint damage.1,145

There are limited data available regarding efficacy of infliximab without concurrent methotrexate for the management of rheumatoid arthritis in adults†.1,17,18,20,21,23,72

Results of early open-label and placebo-controlled studies using infliximab as the only DMARD in adults with rheumatoid arthritis indicated that the drug could result in clinical improvement in patients who had not responded adequately to other DMARDs.17,18,20,21,23 In one multicenter, placebo-controlled, double-blind study, 73 adults with rheumatoid arthritis were randomized to receive a single dose of placebo or 1 or 10 mg/kg of infliximab given by IV infusion.21 Patients were not allowed to receive any other DMARDs beginning 4 weeks before the study; however, those receiving stable dosages of oral corticosteroids or NSAIAs were allowed to continue these drugs.21 At 4 weeks after the dose, a clinical response (defined as a Paulus 20% response) was reported in 44 or 79% of patients who received a 1- or 10-mg/kg infliximab dose, respectively, compared with 8% of those who received placebo.21 A Paulus 50% response was reported at 4 weeks in 28 or 58% of patients who received 1 or 10 mg/kg of the drug, respectively, compared with 8% of those who received placebo.21 Although there was no evidence of a dose-response relationship based on results at 2 weeks, the higher dose (10 mg/kg) was associated with significantly higher response rates and greater responses (e.g., improvements in pain score, grip strength, CRP, ESR) than the lower dose (1 mg/kg) at week 4.21 There also was some evidence that the higher dose resulted in a more prolonged response than the lower dose.21

Clinical Perspective

The American College of Rheumatology issued guidelines for the treatment of rheumatoid arthritis in 2021.2003 Disease-modifying treatments for rheumatoid arthritis include conventional DMARDs (e.g., hydroxychloroquine, leflunomide, methotrexate, sulfasalazine), biologic DMARDs (e.g., TNF blocking agents, abatacept, tocilizumab, sarilumab, rituximab), and/or targeted synthetic DMARDs (e.g., Janus kinase inhibitors).2003 Specific agents for rheumatoid arthritis treatment are selected according to current disease activity, prior therapies used, and the presence of comorbidities.2003 A “treat-to-target” approach is typically employed, with the goal of achieving a predefined target of low disease activity or remission.2003

TNF blocking agents used in the treatment of rheumatoid arthritis include adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab.2003 Methotrexate monotherapy is strongly recommended over biologic DMARD monotherapy and conditionally recommended over the combination of methotrexate and a TNF blocking agent for DMARD-naïve patients with moderate to high disease activity, because many patients will achieve their treatment goal with methotrexate alone, and combination therapy with TNF blocking agents may be associated with additional risks and costs.2003 Biologic DMARDs (including TNF blocking agents) and targeted synthetic DMARDs are conditionally recommended as add-on therapy for patients who are taking maximally tolerated doses of methotrexate and are not at target.2003 Recommendations for the use and selection of biologic DMARDs in rheumatoid arthritis vary based on the presence of certain comorbidities (e.g., heart failure, previous serious infection, nontuberculous mycobacterial lung disease).2003 Consult the American College of Rheumatology guidelines for additional details.2003

Ankylosing Spondylitis

Infliximab and its biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) are used to reduce the signs and symptoms of ankylosing spondylitis in patients with active disease.1,167,194,195 Safety and efficacy of infliximab for this use are based principally on the results of randomized controlled trials in addition to other supporting studies.1,137,204 ,205,206 Guidelines generally support the use of TNF blocking agents for the treatment of ankylosing spondylitis in patients with active disease despite treatment with nonsteroidal antiinflammatory agents (NSAIAs).2004

Clinical Experience

Safety and efficacy of infliximab for the management of ankylosing spondylitis were assessed in the randomized, double-blind, placebo-controlled ASSERT study.1,204 In this study, 279 adults with active ankylosing spondylitis were randomized in a 3:8 ratio to receive placebo or infliximab 5 mg/kg IV at weeks 0, 2, 6, 12, and 18.1,204 Patients were not allowed to receive DMARDs or systemic corticosteroids during the study period, but stable dosages of NSAIAs, acetaminophen, and tramadol were permitted.1,204 The primary end point was a 20% improvement according to the Assessment in Ankylosing Spondylitis criteria (ASAS 20) at week 24.204 The ASAS 20 response is achieved if the patient experiences a 20% or greater improvement from baseline and an absolute improvement of at least 1 unit in at least 3 of the following assessment domains: patient global assessment, spinal pain, function according to the Bath Ankylosing Spondylitis Functional Index (BASFI), and morning stiffness.204 Patients also were evaluated for ASAS 50 and 70 responses (these are defined using the same criteria as ASAS 20 with a level of improvement of 50 or 70%, respectively).1

At week 24, the ASAS 20 responder rates were 60 and 18% in the infliximab and placebo groups, respectively.1 Symptomatic improvements in the infliximab group were observed as early as week 2 and maintained through week 24 of treatment.1 The ASAS 50 and ASAS 70 responder rates at week 24 were 44 and 28%, respectively, in the infliximab group and 9 and 4%, respectively, in the placebo group.1 Patients in the infliximab group also experienced improvements in health-related quality of life (measured by the physical component of the Short Form 36 [SF 36]) at week 24.1,204 Efficacy and safety of infliximab were maintained for up to 2 years.205

In an additional placebo-controlled study in adults with ankylosing spondylitis, 53% of those receiving infliximab (5-mg/kg doses given at 0, 2, and 6 weeks) experienced at least a 50% reduction in disease activity (assessed using the Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]) compared with 9% of those receiving placebo.137 In addition, infliximab therapy was associated with improvements in physical function and quality of life.137 Efficacy and safety of infliximab were maintained for up to 5 years of treatment.206

An open-label, randomized study compared infliximab to etanercept in 50 DMARD- and biologic-naïve patients with ankylosing spondylitis refractory to oral NSAIAs.207 Patients were randomized to receive etanercept 50 mg subcutaneously weekly or infliximab 5 mg/kg at weeks 0, 2, and 6, then every 6 weeks thereafter for a period of 102 weeks.207 At week 12, 75 and 60% of patients receiving infliximab and etanercept, respectively, demonstrated an ASAS 20 response, and 55 and 43% of patients receiving infliximab and etanercept, respectively, demonstrated an ASAS 40 response.207 For both groups, efficacy was generally maintained up to the end of the observation period (week 104).207

Clinical Perspective

The American College of Rheumatology, the Spondylitis Association of America, and the Spondyloarthritis Research and Treatment Network issued a joint guideline for the treatment of ankylosing spondylitis in 2019.2004 Treatments for ankylosing spondylitis include NSAIAs, conventional DMARDs (e.g., methotrexate, sulfasalazine), biologic DMARDs (e.g., TNF blocking agents, secukinumab, ixekizumab), and/or targeted synthetic DMARDs (e.g., tofacitinib).2004 Continuous NSAIA treatment is typically considered first-line for active ankylosing spondylitis, with other agents used in the treatment of NSAIA-refractory disease.2004 Specific agents for ankylosing spondylitis treatment are selected according to current disease activity, prior therapies, and the presence of comorbidities.2004 Goals of therapy in ankylosing spondylitis are to alleviate symptoms, improve functioning, maintain the ability to work, decrease complications, and prevent or slow skeletal damage.2004

TNF blocking agents used in the treatment of ankylosing spondylitis include adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab.2004 For adults with active ankylosing spondylitis despite treatment with NSAIAs, treatment with a TNF blocking agent is strongly recommended over no treatment with a TNF blocking agent and conditionally recommended over treatment with tofacitinib, secukinumab, or ixekizumab.2004 No specific TNF blocking agent is recommended over others.2004 In patients with active ankylosing spondylitis despite treatment with a first TNF blocking agent, guidelines conditionally recommend secukinumab or ixekizumab for patients with primary nonresponse to TNF blocking therapy and treatment with a different TNF blocking therapy for patients with secondary nonresponse to TNF blocking therapy.2004 In adults with stable ankylosing spondylitis, continuation of biologic monotherapy is conditionally recommended over discontinuation of the biologic or continuation of combination therapy with NSAIAs or conventional DMARDs.2004 Recommendations for treatment selection in ankylosing spondylitis may be influenced by the presence of certain comorbidities (e.g., iritis, inflammatory bowel disease).2004 Consult the joint guideline issued by the American College of Rheumatology, the Spondylitis Association of America, and the Spondyloarthritis Research and Treatment Network for additional details.2004

Psoriatic Arthritis

Infliximab and its biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) are used to reduce the signs and symptoms of active arthritis, inhibit the progression of structural damage, and improve physical function in adults with psoriatic arthritis.1,167,194,195 Safety and efficacy of infliximab for this use are based principally on the results from a randomized controlled trial, with supporting data from an additional randomized controlled trial and an open-label extension study.1,208,209,210,211,212,213,214 Guidelines generally support the use of TNF blocking agents as first-line treatment in patients with active psoriatic arthritis.2005

Clinical Experience

Safety and efficacy of infliximab in the management of active psoriatic arthritis (i.e., at least 5 swollen joints and at least 5 tender joints, with one or more of the following subtypes: arthritis involving DIP joints, arthritis mutilans, asymmetric peripheral arthritis, polyarticular arthritis, spondylitis with peripheral arthritis) were evaluated in a multicenter, double-blind, placebo-controlled study in 200 adult patients who had an inadequate response to therapy with DMARDs or NSAIAs (IMPACT 2).1,208 Patients also had plaque psoriasis with qualifying target lesion of at least 2 cm in diameter.1,208 During the 24-week double-blind phase, patients were randomized to receive infliximab 5 mg/kg by IV infusion (100 patients) or placebo (100 patients) at weeks 0, 2, 6, 14, and 22.1,208 Forty-six percent of patients continued to receive stable doses of methotrexate (up to 25 mg weekly).1 Patient evaluations were assessed according to ACR criteria for improvement (ACR response).1 Patients receiving placebo, who achieved less than 10% improvement from baseline at week 16, were switched to induction therapy with infliximab (early escape).1 At week 24, all patients receiving placebo were switched to induction therapy with infliximab.1 Infliximab therapy was continued through week 46 for all patients.1 At 14 weeks, an ACR 20 response was attained in 58% of patients who received infliximab compared with 11% of patients who received placebo.1,208 The response was similar regardless of concomitant use with methotrexate.1 Improvement has been observed in some patients as early as week 2.1 At 6 months, ACR 20, 50, or 70 response was attained in 54, 41, or 27% of patients, respectively, who received infliximab, compared with 16, 4, or 2% of patients receiving placebo.1 Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with arthritis mutilans and spondylitis with peripheral arthritis subtypes.1 Infliximab therapy resulted in improvements in the components of the ACR response criteria and in dactylitis and enthesopathy compared with placebo.1 The clinical response was maintained through week 54.1,209

Among the 170 patients who had baseline affected body surface area (BSA) of 3% or more, improvement in the Psoriasis Area and Severity Index (PASI) of at least 75% (PASI 75) from baseline was achieved at week 14 (regardless of concomitant methotrexate use) in 64% of patients receiving infliximab and in 2% of patients receiving placebo.1,208 Improvement was observed in some patients as early as week 2.1 At 6 months, PASI 75 and PASI 90 responses were achieved in 60 and 39%, respectively, of patients receiving infliximab and in 1 and 0%, respectively, of patients receiving placebo.1 The PASI response generally was maintained through week 54.1,209

Structural damage in the hands and feet was assessed radiographically by the change from baseline in the van der Heijde-Sharp (vdH-S) score, modified by the addition of hand distal interphalangeal (DIP) joints.1 The total modified vdH-S score was a composite score of structural damage measuring the number and size of joint erosions and the degree of joint space narrowing (JSN) in the hands and feet.1 At week 24, less radiographic progression (mean change of -0.7 versus 0.82), less progression in erosion scores (-0.56 versus 0.51), and less progression in JSN scores (-0.14 versus 0.31) were observed in patients receiving infliximab compared with those receiving placebo.1 Continued inhibition of structural damage at week 54 was reported in patients receiving infliximab.1,210 A median change of 0 in the vdH-S score was reported during the 12-month study in patients initially randomized to either infliximab or placebo.1 Readily apparent radiographic progression was observed in a higher percentage of patients receiving placebo than in those receiving infliximab (12 versus 3%).1

Patients receiving infliximab experienced substantial improvement in physical function as assessed by the HAQ Disability Index (HAQ-DI), with median improvement of 43% from baseline to week 14 and week 24 in patients receiving infliximab compared with 0% in those receiving placebo.1,211 During the 24-week placebo-controlled portion of the trial, a clinically meaningful improvement in HAQ-DI (decrease of at least 0.3 units) was reported in 54% of patients receiving infliximab and in 22% of those receiving placebo.1 Patients receiving infliximab also achieved a greater improvement in the physical and mental component summary scores of the SF-36 Health Survey compared with patients receiving placebo.1,211 These responses were maintained for up to 2 years in an open-label extension study.1

An earlier randomized, placebo-controlled study (IMPACT) in 104 adults with psoriatic arthritis and previous failure of at least 1 DMARD therapy additionally evaluated the efficacy and safety of infliximab.1,212 Patients were randomized to receive placebo or infliximab 5 mg/kg IV at weeks 0, 2, 6, and 14.212 Patients who were initially randomized to placebo were crossed over to infliximab beginning at week 16 and received infliximab infusions at weeks 16, 18, 22, 30, 38, and 46.212 At weeks 16 and 18, patients who were initially randomized to infliximab received placebo infusions to maintain blinding; infliximab infusions were continued in this group at weeks 22, 30, 38, and 46.212 Concomitant therapy with stable doses of oral corticosteroids, NSAIAs, and/or 1 DMARD (methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, intramuscular gold, penicillamine, or azathioprine) was permitted during the study.212

At week 16, an ACR 20 response was achieved in 65 and 10% of patients receiving infliximab and placebo, respectively.212 Response to infliximab was observed as early as week 2.212 At week 16, a PASI 75 response was achieved in 68 and 0% of patients who received infliximab and placebo, respectively.212 Clinical response was maintained for up to 98 weeks of continued infliximab treatment in an open-label extension study.1,213 Radiographic progression was inhibited in patients receiving infliximab, with most patients demonstrating no worsening in modified vdH-S scores from baseline at weeks 50 and 98.213,214

Clinical Perspective

The American College of Rheumatology and the National Psoriasis Foundation issued a joint guideline for the treatment of psoriatic arthritis in 2018.2005 Various drugs and drug classes are used to treat psoriatic arthritis, with some classes used for symptom management (e.g., NSAIAs and corticosteroids) and others used as immunomodulatory disease-modifying therapy.2005 Disease-modifying treatments for psoriatic arthritis include oral small molecules (e.g., methotrexate, sulfasalazine, cyclosporine, leflunomide, apremilast), biologic DMARDs (e.g., TNF blocking agents, secukinumab, ixekizumab, ustekinumab, brodalumab, abatacept), and/or targeted synthetic DMARDs (e.g., tofacitinib).2005 Specific agents for psoriatic arthritis treatment are selected according to disease characteristics, including disease severity, as well as patient preferences/values and comorbidities.2005 A “treat-to-target” approach is typically employed, with the goal of achieving low/minimal disease activity or remission.2005,2006

TNF blocking agents used in the treatment of psoriatic arthritis include adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab.2005 For patients with treatment-naïve psoriatic arthritis, treatment with a TNF blocking agent is conditionally recommended over treatment with an oral small molecule or an interleukin (IL) 17 inhibitor (secukinumab, ixekizumab, brodalumab) or IL12/23 inhibitor (ustekinumab).2005 For patients with active psoriatic arthritis despite treatment with an oral small molecule, switching to monotherapy with a TNF blocking agent is conditionally recommended over combination therapy with a TNF blocking agent plus methotrexate or switching to another oral small molecule, ustekinumab, secukinumab, ixekizumab, brodalumab, abatacept, or tofacitinib.2005 For patients with active psoriatic arthritis despite treatment with TNF blocking agent monotherapy, switching to monotherapy with a different TNF blocking agent is conditionally recommended over switching to ustekinumab, secukinumab, ixekizumab, brodalumab, abatacept, or tofacitinib.2005 For patients with active psoriatic arthritis despite treatment with a combination of a TNF blocking agent and methotrexate, switching to a different TNF blocking agent plus methotrexate is conditionally recommended over switching to a different TNF blocking agent as monotherapy.2005 Switching to a TNF blocking agent is conditionally recommended for patients with active psoriatic arthritis despite treatment with secukinumab, ixekizumab, brodalumab, or ustekinumab.2005 Recommendations for the use and selection of disease-modifying therapies in psoriatic arthritis vary based on the presence of certain disease characteristics (e.g., psoriatic spondylitis/axial disease, enthesitis) and comorbidities (e.g., inflammatory bowel disease, diabetes)2005 Consult the American College of Rheumatology/National Psoriasis Foundation guideline for additional details.2005

Plaque Psoriasis

Infliximab and its biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) are used for the treatment of chronic, severe (i.e., extensive and/or disabling) plaque psoriasis in adults who are candidates for systemic therapy when other systemic therapies are medically less appropriate.1,167 Infliximab products should only be used in patients who will be closely monitored and will have regular follow-up visits with a clinician.1,167,194,195 Safety and efficacy of infliximab for this use are based principally on the results from 3 randomized controlled trials.1,215,216,217,218,219,220 Guidelines generally support the use of TNF blocking agents in moderate to severe psoriasis, either as monotherapy or in combination with topical, oral, or phototherapy.2007

Clinical Experience

Safety and efficacy of infliximab were assessed in 3 randomized, double-blind, placebo-controlled studies (EXPRESS, EXPRESS II, SPIRIT) in adults (18 years of age or older) with chronic, stable plaque psoriasis involving at least 10% of body surface area (BSA), who had a Psoriasis Area and Severity Index (PASI) score of at least 12, and who were candidates for systemic therapy or phototherapy.1,215,216,217 Patients with guttate, pustular, or erythrodermic psoriasis were excluded from the studies.1 With the exception of low-dependency topical corticosteroids on the face and groin after week 10, no concomitant psoriasis treatments were allowed during the studies.1 The primary end point in all 3 studies was the proportion of patients who achieved a reduction in PASI score of at least 75% from baseline to week 10 (PASI 75).1,215,216,217 Efficacy and safety of infliximab treatment beyond 50 weeks have not been evaluated in patients with plaque psoriasis.1

In the EXPRESS study, 378 patients were randomized to receive placebo or a 5-mg/kg dose of infliximab by IV infusion at weeks 0, 2, and 6 (induction therapy) and then every 8 weeks through week 46 (maintenance therapy).1,215 At week 24, patients who were randomized to receive placebo were crossed over to receive 5 mg/kg dose of infliximab (induction therapy) by IV infusion and then maintenance therapy (every 8 weeks).1,215 Patients had a median baseline PASI score of 21 and a baseline static Physician Global Assessment (sPGA) score ranging from moderate (52% of patients) to marked (36%) to severe (2%).1 Chronic, stable plaque psoriasis involving at least 20% of BSA was present in 75% of patients.1 71 or 82% of patients had received prior systemic therapy or phototherapy, respectively.1 PASI 75 was achieved in 80 or 3% of patients receiving infliximab or placebo, respectively.1,215 Patients also were evaluated by the sPGA score (a 6-category scale ranging from “5=severe” to “0=cleared”) according to the physician's overall assessment of the psoriasis severity focusing on induration, erythema, and scaling.1 “Cleared” or “minimal” score (consisting of none or minimal elevation in plaque, up to faint red coloration in erythema, and none or minimal fine scale over less than 5% of the plaque) was achieved in 80 or 4% of patients receiving the drug or placebo, respectively.1 In the subgroup of patients with more extensive psoriasis who previously had received phototherapy, PASI 75 was achieved at week 10 in 85% of patients receiving infliximab compared with 4% of those receiving placebo.1 Health-related quality of life, as measured by Dermatology Life Quality Index (DLQI) and SF 36 scores, was improved with infliximab compared to placebo at weeks 10 and 24.218

In the EXPRESS II study, 835 patients (having a median baseline PASI score of 18, 63% having psoriasis involving at least 20% of BSA, and 55 or 64% having received prior systemic or phototherapy, respectively) were randomized to receive placebo or a 3- or 5-mg/kg dose of infliximab at weeks 0, 2, or 6 (induction therapy).1,216 At week 14, patients randomized to receive a 3- or 5-mg/kg dose of infliximab were randomized to receive either scheduled (every 8 weeks) or “as needed” maintenance treatment through week 46.1,216 At week 16, patients who were randomized to receive placebo were crossed over to receive a 5-mg/kg dose of infliximab induction therapy followed by maintenance therapy every 8 weeks.1,216 PASI 75 was achieved in 2, 70, or 75%, respectively, of patients receiving placebo or a dose of 3 or 5 mg/kg of infliximab.1 Patients also were evaluated by the rPGA score (a 6-category scale ranging from “6=severe” to “1=clear”) assessed relative to baseline in which overall lesions were graded with consideration to the percent of body involvement as well as overall induration, scaling, and erythema.1 “Clear” or “excellent” score (consisting of some residual pinkness or pigmentation to marked improvement [nearly normal skin texture; some erythema may have been present]) was achieved in 1, 69, or 75% of patients receiving placebo or a dose of 3 or 5 mg/kg of infliximab, respectively.1 In the subgroup of patients with more extensive psoriasis who previously had received phototherapy, PASI 75 was achieved at week 10 in 1, 72, or 77% of patients receiving placebo or a dose of 3 or 5 mg/kg of infliximab, respectively.1 In the subgroup of patients with more extensive psoriasis who had failed or were intolerant to phototherapy, PASI 75 was achieved at week 10 in 2, 70, or 78% of patients receiving placebo or a dose of 3 or 5 mg/kg of infliximab, respectively.1 Maintenance of response was studied in 292 (out of 313) patients randomized to receive infliximab 3 mg/kg and in 297 (out of the 314) patients randomized to receive infliximab 5 mg/kg.1 At week 14, patients were stratified by PASI response at week 10 and by investigational site and were then randomized to receive either scheduled or as needed maintenance therapy.1 A higher percentage of patients receiving scheduled maintenance therapy (every 8 weeks) appeared to maintain a PASI 75 through week 50 compared with patients receiving as needed maintenance therapy, with the best response maintained with a dosage of 5 mg/kg every 8 weeks.1,216 In a subset of patients who had achieved a response at week 10, maintenance of response appeared to be greater in patients receiving infliximab 5 mg/kg every 8 weeks.1 A decline in response in a subpopulation of patients in each group over time was observed in patients receiving either as needed or scheduled maintenance therapy.1

In the SPIRIT study, 249 patients who previously had received either psoralen plus ultraviolet A treatment (PUVA) or other systemic psoriasis therapy were randomized to receive placebo or a 3- or 5-mg/kg dose of infliximab at weeks 0, 2, and 6 (induction therapy).1,217 At week 26, patients with an sPGA score of “moderate” or “worse” (a score of at least 3 on a scale of 0-5) received an additional dose of the randomized treatment.1,217 Patients had a median baseline PASI score of 19 and a baseline sPGA score of moderate (62% of patients), marked (22%), or severe (3%);1 BSA of at least 20% was present in 75% of patients.1 At week 26, 46% of enrolled patients received an additional infliximab dose.1 At week 10, PASI 75 was achieved in 6, 72, or 88% of patients receiving placebo or a dose of 3 or 5 mg/kg of infliximab, respectively.1,217 In addition, a score of “cleared” or “minimal” by the sPGA score was achieved in 10, 72, or 90% of patients receiving placebo or a dose of 3 or 5 mg/kg of infliximab, respectively.1 Health-related quality of life, as measured by DLQI score, was improved with infliximab compared to placebo at week 10.219

A single-blind randomized controlled trial compared infliximab to etanercept for the treatment of moderate to severe plaque psoriasis.220 In this study, adults were randomized to receive etanercept 50 mg subcutaneously twice weekly or infliximab 5 mg/kg IV at weeks 0, 2, 6, and every 8 weeks thereafter for up to 48 weeks.220 The primary outcome was PASI 75 response rate at week 24.220 The PASI 75 response rate at week 24 was significantly higher among patients receiving infliximab compared to patients receiving etanercept.220 PASI 75 response rates were 72 and 35% in the infliximab and etanercept groups, respectively.220

Clinical Perspective

The American Academy of Dermatology and the National Psoriasis Foundation issued joint guidelines for the treatment of psoriasis in adult and pediatric patients between 2019 and 2021.2007,2008,2009,2010,2011 Various drugs and drug classes are used to treat psoriasis.2007,2008,2009,2012 Phototherapy and topical treatments (e.g., vitamin D analogues, calcineurin inhibitors, keratolytics, and corticosteroids) are frequently used to treat mild psoriasis present on limited areas of the body, but these therapies may be inadequate to obtain skin clearance in patients with more extensive or severe disease.2007,2008,2009,2012 Systemic biologic and nonbiologic therapies are mainstays of treatment for moderate to severe psoriasis, and may also be useful for treating psoriasis on parts of the body that are difficult to treat with topical therapy (e.g., the scalp, palms and soles of the feet, genitals).2007,2009,2012 Topical therapies can be used adjunctively in moderate to severe disease.2012 Nonbiologic oral therapies used in the treatment of psoriasis include methotrexate, apremilast, cyclosporine, acitretin, and dimethyl fumarate.2009,2012 Biologics used in the treatment of psoriasis include TNF blocking agents, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab.2007,2012 Treatment selection in psoriasis is primarily based on disease characteristics (e.g., severity, location, presence of psoriatic arthritis), with additional consideration being given to patient age and comorbidities.2010,2011,2012

TNF blocking agents used in the treatment of psoriasis include adalimumab, certolizumab pegol, etanercept, and infliximab.2007,2012 These TNF blocking agents are recommended for the treatment of adult patients with moderate to severe plaque psoriasis, with or without concomitant topical, oral, or phototherapy.2007 Recommendations for the use and selection of psoriasis therapies vary based on patient age, disease characteristics (e.g., severity, location, presence of psoriatic arthritis), and comorbidities (e.g., inflammatory bowel disease).2007,2008,2009,2010,2011,2012 Consult the American Academy of Dermatology/National Psoriasis Foundation guidelines for additional details.2007,2008,2009,2010,2011

Other Uses

Juvenile Arthritis

Infliximab has been used in a limited number of pediatric patients with juvenile rheumatoid arthritis† (also known as juvenile idiopathic arthritis); however, further study is needed to evaluate the safety and efficacy of the drug for juvenile rheumatoid arthritis.1,72,103,104,153,167

Safety and efficacy of infliximab for the management of juvenile rheumatoid arthritis† have been evaluated in children 4-17 years of age with juvenile arthritis who had not responded adequately to methotrexate.1,153 Pediatric patients were randomized to receive placebo or 3 mg/kg of infliximab by IV infusion at weeks 0, 2, 6, and 14.1,153 Patients continued to receive oral or parenteral methotrexate (10-15 mg/m² per week);1,153 study participants also could receive folic acid prophylaxis (required for methotrexate), oral corticosteroids, NSAIAs, and/or other analgesics.153 At week 14, those who received placebo crossed over to all active treatment; these individuals received 6 mg/kg of infliximab by IV infusion at weeks 14, 16, and 20, followed by additional doses given once every 8 weeks concomitantly with weekly methotrexate through week 44 .1,153 Children who received infliximab during the initial 14 weeks of the study continued to receive 3 mg/kg of infliximab once every 8 weeks concomitantly with weekly methotrexate through week 44.1,153

The primary end point of this study was the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement (i.e., 30% or greater improvement in at least 3 of 6 and 30% or greater deterioration in no more than 1 of 6 core set criteria that include physician and patient/parent global assessments, active joint count, limitation of motion, functional assessment, and ESR) at week 14.153 An ACR Pedi 30 was achieved by 63.8% of patients who received infliximab concomitantly with methotrexate compared with 49.2% of patients who received placebo and methotrexate at week 14.153 Achievement of the primary end point did not differ significantly between infliximab-treated children and placebo-treated children.153 At week 16 when all study participants were receiving infliximab, an ACR Pedi 30 was achieved by 73.2% of patients.153 At week 52, an ACR Pedi 50 or 70 (defined using the same criteria as Pedi 30 with a level of improvement of 50 or 70%, respectively) was achieved by 69.6 or 51.8%, respectively, of study participants.153 Other observations from this study include a higher rate of immunogenic reactions in study participants than has been observed in infliximab-treated adults.1,153

Behcet Syndrome

Infliximab has been used in a limited number of patients with Behcet syndrome†;93,102,115,116 however, further study is needed to evaluate safety and efficacy of the drug in this disease.93 Behcet syndrome is a chronic inflammatory disorder of unknown etiology characterized by recurrent orogenital ulceration, skin lesions, and arthritic symptoms that may be complicated by GI, ocular, and neurologic involvement.93 Proinflammatory cytokines, including TNF, are produced by monocytes as part of the inflammatory cascade in Behcet disease.93 Use of infliximab in an adult with Behcet disease who was receiving maintenance therapy with oral prednisone resulted in improvement in GI symptoms and discontinuance of the corticosteroid.93 In addition, use of infliximab (5-mg/kg doses given at 0, 2, and 6 weeks) resulted in improvements in both oral and genital lesions in an adult with Behçet disease who had recalcitrant orogenital ulceration 115 and a single 5-mg/kg dose of infliximab decreased acute ocular inflammation and improved visual acuity in several adults with panuveitis associated with Behçet disease.116

Congestive Heart Failure

Because of evidence that TNF may play a role in progression of heart failure, infliximab has been investigated for the management of congestive heart failure† in patients with moderate to severe (New York Heart Association [NYHA] class III or IV) congestive heart failure.1,139 In a phase II, double-blind, placebo-controlled study, patients with stable NYHA class III or IV congestive heart failure (left ventricular ejection fraction 35% or less) were randomized to receive placebo, infliximab 5 mg/kg, or infliximab 10 mg/kg at 0, 2, and 6 weeks.1,139 However, there was no evidence that infliximab improved clinical status of these patients and those receiving infliximab (especially those receiving 10 mg/kg) had a higher incidence of mortality and hospitalization for worsening heart failure compared with those receiving placebo.1,139

Pyoderma Gangrenosum

Infliximab has been used in a limited number of patients with pyoderma gangrenosum†.221 In a single randomized controlled trial, 30 adults with pyoderma gangrenosum were randomized to receive placebo or infliximab 5 mg/kg IV once at week 0; patients were reassessed at week 2 and offered open-label infliximab treatment if no clinical improvement was observed.221 At week 2, clinical improvement (defined by patient and clinician global assessments) was observed in 46 and 6% of patients who received infliximab and placebo, respectively.221

Dosage and Administration ⬆ ⬇

[Section Outline]

General
Administration
Dosage
Special Populations

General

Pretreatment Screening

Evaluate all patients for active and inactive tuberculosis prior to initiating therapy.1,167,194,195,225
Screen patients for hepatitis B virus (HBV) infection before initiation of therapy.1,167,194,195,225
Do not initiate therapy in patients with an active infection, including clinically important localized infections.1,167,194,195,225

Patient Monitoring

Monitor patients for infusion reactions during and for at least 30 minutes after IV infusion.1,167,194,195,72,142 Ensure that appropriate personnel and medications are available to treat infusion reactions.1,167,194,195 For patients without a history of acute infusion reactions with prior doses of the drug, monitor vital signs every 30 minutes; for patients with a history of such reactions, monitor every 15 minutes.72
Monitor closely for signs or symptoms of infection (e.g., fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, serious systemic illness including shock), including the possible development of tuberculosis in patients who tested negative for latent tuberculosis prior to initiating therapy, during and after treatment with tumor necrosis factor (TNF; TNF-α) blocking agents.1,155,159,167,194,195,225
Evaluate and monitor chronic carriers of HBV prior to the initiation of infliximab therapy, during treatment, and for several months following treatment.1,167,194,195,225
Perform periodic dermatologic evaluations in all patients, particularly those with risk factors for skin cancer.1,167,194,195,225
Monitor patients with psoriasis, particularly those who received prior prolonged phototherapy for their disease, for nonmelanoma skin cancer.1,167,194,195
Perform periodic screening for cervical cancer in females.1,167,194,195,225
Closely monitor patients during therapy for new or worsening symptoms of heart failure.1,167,194,195,225
Monitor hepatic enzymes and liver function tests every 3 to 4 months during subcutaneous maintenance therapy with infliximab-dyyb (Zymfentra®).225

Premedication and Prophylaxis

May premedicate patients with histamine-1 receptor antagonists, histamine-2 receptor antagonists, acetaminophen, and/or corticosteroids to prevent IV infusion reactions.1,167,194,195

Dispensing and Administration Precautions

To avoid medication errors, the Institute for Safe Medication Practices (ISMP) recommends that prescribers communicate both the brand and generic names for infliximab products on the prescription order form.222

Other General Considerations

May continue treatment with agents used for the management of Crohn disease or ulcerative colitis (e.g., corticosteroids, mesalamine, sulfasalazine, azathioprine, mercaptopurine, methotrexate, anti-infective agents) in patients receiving infliximab products.1,5,38,167 However, consider increased risks of hepatosplenic T-cell lymphoma with combination therapy and the observed (in infliximab studies) increase in immunogenicity and hypersensitivity reactions associated with infliximab products given as monotherapy.1,167,194,195 225
Infliximab products are used in conjunction with methotrexate for the management of rheumatoid arthritis.1,167,194,195 Other nonbiologic agents used for the management of rheumatoid arthritis (e.g., corticosteroids, nonsteroidal anti-inflammatory agents [NSAIAs]) may be continued in patients receiving infliximab products.1,167,194,195
Infliximab products can be used with or without methotrexate for the management of psoriatic arthritis.1,167,194,195

Administration

IV Admininstration

Infliximab products may be administered by IV infusion.1,167,194,195 Use an in-line, sterile, nonpyrogenic, low-protein-binding filter with a pore diameter of 1.2 µm or less for administration.1,167,194,195 Do not admix infliximab products with other drugs or infuse in the same IV line with other drugs.1,167,194,195

Store commercially available infliximab lyophilized powders at 2-8°C.1,167,194,195 Vials of infliximab-axxq should be protected from light.195 Unopened vials of infliximab or infliximab-abda may be stored at temperatures up to 30°C for a single period of up to 6 months; following removal from refrigerated storage, the drug cannot be returned to refrigerated storage.1,194

Reconstitution

Infliximab products for IV administration are supplied as lyophilized powders that must be reconstituted and diluted prior to administration using proper aseptic technique.1,167,194,195

Reconstitute the lyophilized powder by adding 10 mL of sterile water for injection to a vial labeled as containing 100 mg of the infliximab product to provide a solution containing 10 mg/mL.1,167,194,195 Based on the indicated dosage of the infliximab product, reconstitute the appropriate number of vials of the drug.1,167,194,195 During reconstitution, direct the sterile water diluent toward the side of the vial using a sterile syringe with a 21-gauge or smaller needle and gently swirl the contents to minimize foaming during dissolution; some foaming will occur.1,167,194,195 To avoid excessive foaming, do not shake or vigorously agitate the vial.1,167,194,195 Inspect the reconstituted solution visually for particulate matter.1,167,194,195 The solution should be colorless to light yellow and opalescent and should not be used if discolored or opaque or if foreign particles other than a few translucent proteinaceous particles are present.1,167,194,195 Allow the reconstituted solution to stand for 5 minutes before further dilution.1,167,194,195

Dilution

Further dilute the reconstituted infliximab solution in 0.9% sodium chloride injection to provide a total volume of 250 mL (i.e., if a 250-mL bottle or bag of 0.9% sodium chloride injection is used, remove a volume of the diluent equal to the total required volume of reconstituted infliximab product solution from the bag or bottle prior to addition of the infliximab product).1,167,194,195 Add the total required volume of reconstituted infliximab solution slowly to the diluent and gently mix the diluted solution.1,167,194,195

The final concentration of the reconstituted and diluted infliximab solution should be 0.4-4 mg/mL.1,167,194,195 For volumes greater than 250 mL, use a larger infusion bag (e.g., 500 mL) or multiple 250 mL infusion bags to ensure that the concentration of the infusion solution does not exceed 4 mg/mL.1,167,195 Begin the infliximab infusion within 3 hours of reconstitution and dilution of the drug.1,167,194,195 Discard any unused portions of the reconstituted or diluted solution since the drug does not contain any preservatives or bacteriostatic agents.1,167,194,195

Rate of Administration

Infuse diluted infliximab solutions IV over a period of at least 2 hours.1,167,194,195

The manufacturer of infliximab states that IV infusions can be given at a rate of 2 mL/minute or, alternatively, a rate titration schedule may be used in an attempt to prevent or ameliorate acute infusion reactions.72 If a rate titration schedule is used in patients who are receiving an initial infliximab dose or in patients with or without a history of acute infusion reactions to prior doses of the drug, the manufacturer recommends initiating the IV infusion at a rate of 10 mL/hour for the first 15 minutes followed by 20 mL/hour for 15 minutes, 40 mL/hour for 15 minutes, 80 mL/hour for 15 minutes, 150 mL/hour for 30 minutes, and then 250 mL/hour for 30 minutes.72

Subcutaneous Administration

Infliximab-dyyb (Zymfentra®) is approved for subcutaneous administration and is intended for use under the supervision of a healthcare provider.225 After proper training, a patient or a caregiver may be able to administer subcutaneously.225

Prior to administration, visually inspect the formulation for particulate matter and discoloration.225 The formulation should be a clear, colorless to pale brown solution.225

Inject infliximab-dyyb (Zymfentra®) into the front of the thighs, the abdomen (except for the 2 inches around the navel), or the outer area of the upper arms (caregiver only).225 Rotate the injection site each time an injection is administered with at least 1.2 inches between the new and prior injection sites.225 Do not inject into red, bruised, tender, or indurated skin areas.225

If a subcutaneous dose is missed, inject the next dose as soon as possible and then every 2 weeks thereafter.225

Store at 2-8ºC.225 Do not freeze.225 Keep the product in its outer carton until time of administration in order to protect from light.225

Dosage

Adult Dosage

Crohn Disease

The usual adult dosage of infliximab or biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) for the management of moderately or severely active Crohn disease or fistulizing Crohn disease is 5 mg/kg given by IV infusion over a period of at least 2 hours.1,167,194,195

The manufacturers recommend that adults with moderately to severely active Crohn disease or with fistulizing Crohn disease receive the initial 3 doses of infliximab at 0, 2, and 6 weeks (induction regimen) and that additional doses be given once every 8 weeks thereafter (maintenance regimen).1,167,194,195 An increase in infliximab dosage to 10 mg/kg every 8 weeks may be considered in patients who respond initially but subsequently lose response.1,167,194,195 Patients who do not respond to infliximab by week 14 are unlikely to respond with continued administration; discontinuance of the drug should be considered in these patients.1,167,194,195

The usual maintenance dose of infliximab-dyyb (Zymfentra®) in adults with moderately to severely active Crohn disease following treatment with an IV induction regimen with an infliximab product is 120 mg subcutaneously once every 2 weeks.225 The maintenance dosage should be initiated at week 10.225

To switch patients who are responding to maintenance therapy with an infliximab product given IV, administer the initial subcutaneous dose in place of the next scheduled IV infusion and every 2 weeks thereafter.225

Ulcerative Colitis

The usual adult dosage of infliximab or biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) for the management of moderately or severely active ulcerative colitis is 5 mg/kg given by IV infusion over a period of at least 2 hours.1,167,194,195

The manufacturers recommend that adults with moderately to severely active ulcerative colitis receive the initial 3 doses of infliximab at 0, 2, and 6 weeks (induction regimen) and that additional doses be given once every 8 weeks thereafter (maintenance regimen).1,167,194,195

The usual maintenance dose of infliximab-dyyb (Zymfentra®) in adults with moderately to severely active ulcerative colitis following treatment with an IV induction regimen with an infliximab product is 120 mg subcutaneously once every 2 weeks.225 The maintenance dosage should be initiated at week 10.225

Rheumatoid Arthritis

For the management of moderately to severely active rheumatoid arthritis in adults, the usual dosage of infliximab or biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) is 3 mg/kg given by IV infusion over a period of at least 2 hours.1,167,194,195 The manufacturers recommend that adults with rheumatoid arthritis receive the initial 3 doses of infliximab at 0, 2, and 6 weeks (induction regimen) and that additional doses be given once every 8 weeks thereafter (maintenance regimen).1,167,194,195 Infliximab should be given in combination with methotrexate.1,167,194,195 For patients who have an incomplete response to this 3-mg/kg regimen, consideration can be given to increasing the infliximab dosage up to 10 mg/kg every 8 weeks and/or administering infliximab doses as often as once every 4 weeks.1,167,194,195

Ankylosing Spondylitis

For the management of ankylosing spondylitis in adults, the usual dosage of infliximab or biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) is 5 mg/kg given by IV infusion over a period of at least 2 hours.1,167,194,195 The manufacturers recommend that adults with ankylosing spondylitis receive the initial 3 doses of infliximab at 0, 2, and 6 weeks (induction regimen) and that additional doses of 5 mg/kg be given once every 6 weeks thereafter (maintenance regimen).1,167,194,195

Psoriatic Arthritis

For the management of psoriatic arthritis in adults, the usual dosage of infliximab or biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) is 5 mg/kg given by IV infusion over a period of at least 2 hours.1,167,194,195 The manufacturers recommend that adults with psoriatic arthritis receive the initial 3 doses of infliximab at 0, 2, and 6 weeks (induction regimen) and that additional doses of 5 mg/kg be given once every 8 weeks thereafter (maintenance regimen).1,167,194,195

Plaque Psoriasis

For the management of chronic severe plaque psoriasis in adults, the usual dosage of infliximab or biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) is 5 mg/kg given by IV infusion over a period of at least 2 hours.1,167,194,195 The manufacturers recommend that adults with plaque psoriasis receive the initial 3 doses of infliximab at 0, 2, and 6 weeks (induction regimen) and that additional doses of 5 mg/kg be given once every 8 weeks thereafter (maintenance regimen).1,167,194,195 If maintenance therapy with infliximab for the management of psoriasis is interrupted, itherapy should be reinitiated as a single dose followed by maintenance therapy.1,167,194,195

Pediatric Dosage

Crohn Disease

The recommended dosage of infliximab or biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) in pediatric patients 6 years of age or older with moderately to severely active Crohn disease is 5 mg/kg given by IV infusion over a period of at least 2 hours at 0, 2, and 6 weeks (induction therapy) followed by a maintenance regimen of 5 mg/kg every 8 weeks.1,167,194,195

Ulcerative Colitis

The recommended dosage of infliximab or biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) in pediatric patients 6 years of age or older with moderately to severely active ulcerative colitis is 5 mg/kg given by IV infusion over a period of at least 2 hours at 0, 2, and 6 weeks (induction regimen) followed by a maintenance regimen of 5 mg/kg every 8 weeks.1,167,194,195

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1,167,194,195,225

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1,167,194,195,225

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1,167,194,195,225

Cautions ⬆ ⬇

[Section Outline]

Contraindications
Warnings/Precautions
Common Adverse Effects

Contraindications

Prior hypersensitivity reaction to infliximab products or any inactive ingredients in the formulations or any murine proteins.1,167,194,195,225
Doses greater than 5 mg/kg are contraindicated in patients with moderate or severe heart failure.1,167,194,195

Warnings/Precautions

Warnings

Serious Infections

A boxed warning about the risk of serious infections is included in the prescribing information for infliximab products.1,167,194,195,225 Patients receiving tumor necrosis factor (TNF) blocking agents, including infliximab products, are at increased risk of developing serious infections involving various organ systems and sites that may require hospitalization or result in death.1,167,194,195,225 Opportunistic infections caused by bacterial, mycobacterial, invasive fungal, viral, or parasitic, or other opportunistic pathogens—including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, salmonellosis, and tuberculosis—have been reported in patients receiving TNF blocking agents.1,72,155,159 Infections frequently have been disseminated rather than localized.1 Closely monitor patients during and after treatment with TNF blocking agents for the development of signs or symptoms of infection (e.g., fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, serious systemic illness including shock), including the possible development of tuberculosis in patients who tested negative for latent tuberculosis prior to initiating therapy.1,72,155,159,167,194,195,225 Most patients who developed serious infections were receiving concomitant therapy with immunosuppressive agents such as corticosteroids or methotrexate.1

In clinical studies evaluating infliximab in patients with rheumatoid arthritis, serious infection was reported in 5.3% of patients who received infliximab in conjunction with methotrexate and in 3.4% of those who received methotrexate and placebo (follow-up: 52 weeks for both groups).1 Serious infections reported in patients receiving infliximab have included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection.1 Extrapulmonary and disseminated tuberculosis, including fatal miliary tuberculosis, have been reported in patients receiving infliximab products.1,72,118,159,167,194,195 During clinical trials, tuberculosis was reported in 14 patients receiving infliximab, and there were 4 fatalities related to miliary tuberculosis.1 During postmarketing surveillance, other cases of tuberculosis have been reported.1,118,123,146 Reactivation of latent tuberculosis and new tuberculosis infections have been reported in patients receiving infliximab products, including in patients who previously received antimycobacterial therapy for latent or active tuberculosis.1 Cases of active tuberculosis also have been reported in patients receiving infliximab products while they were receiving antimycobacterial therapy for latent tuberculosis.1 As of September 2002, FDA had received 335 reports of infliximab-associated tuberculosis.146 Most of the cases of tuberculosis occurred within the first 2 months following initiation of infliximab therapy; these cases may reflect recrudescence of latent tuberculosis infection.1 As of September 2011, FDA had identified 103 reports of Legionella pneumonia associated with TNF blocking agents, including infliximab.159 The 103 cases of Legionella pneumonia occurred in patients 25-85 years of age, many of whom received concomitant therapy with immunosuppressive agents (e.g., corticosteroids and/or methotrexate); 17 deaths were reported.159 In 78% of the cases of Legionella pneumonia, the median duration of TNF blocker therapy prior to the onset of Legionella pneumonia was 10.4 months (range: less than 1 month to 73 months).159 As of September 2011, FDA also had identified 26 published reports of Listeria infections, including meningitis, bacteremia, endophthalmitis, and sepsis, in patients who received TNF blocking agents; 7 deaths were reported.159 Many of the Listeria infections occurred in patients who had received concomitant therapy with immunosuppressive agents.159 In addition, FDA identified fatal Listeria infections during a review of data regarding laboratory-confirmed infections that occurred in premarketing clinical studies and during postmarketing surveillance.159 Invasive fungal infections have occurred in patients receiving TNF blocking agents.1,155,167 Failure to recognize fungal infections has led to delays in appropriate treatment.155

An increased incidence of serious infections also was observed in clinical studies in patients with rheumatoid arthritis when a TNF blocking agent was used concomitantly with anakinra or abatacept .1 Concomitant use of infliximab products and anakinra, abatacept, or other biological products used to treat the same conditions as infliximab is not recommended.1,167,194,195

Do not initiate therapy with infliximab products in patients with active infections, including clinically important localized infections.1,167,194,195 225 Patients older than 65 years of age, patients with comorbid conditions, and/or patients receiving concomitant therapy with immunosuppressive agents such as corticosteroids or methotrexate may be at increased risk of infection.1,159,167,194,195,225 Consider the potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic, recurring, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who reside or have traveled in regions where tuberculosis or mycoses such as histoplasmosis, coccidioidomycosis, and blastomycosis are endemic.1,159,167,194,195,225 If a patient develops a new infection while receiving an infliximab product, perform a thorough diagnostic evaluation (appropriate for an immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor the patient.1,155,167,194,195,225 Discontinue therapy with infliximab products in patients who develop a serious infection or sepsis.1,34,34,35,44,118,167,194,195,225

Because tuberculosis has been reported in patients receiving infliximab products, including in patients who received infliximab products during treatment for latent tuberculosis or following treatment for active or latent tuberculosis, evaluate all patients for active or latent tuberculosis and for risk factors for tuberculosis prior to and periodically during therapy with the drug.1,72,118,159,167,194,195 225 When indicated, initiate an appropriate antimycobacterial regimen for the treatment of latent tuberculosis prior to therapy with infliximab products.1,72,118,167,194,195 225 Antimycobacterial treatment lowers the risk of latent tuberculosis infection progressing to active disease (i.e., reactivation) in patients receiving TNF blocking agents.1,167,194,195 Antimycobacterial therapy also should be considered prior to initiation of infliximab product therapy in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and in individuals with a negative tuberculin skin test who have risk factors for tuberculosis.1,167,194,195 225 Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.1,167,194,195,225 Monitor patients receiving infliximab products, including individuals with a negative tuberculin skin test, for signs and symptoms of active tuberculosis.1,167,194,195,225 If active tuberculosis is diagnosed during therapy with infliximab products, discontinue the drug and initiate an appropriate antimycobacterial regimen.1,167,118,167,225 The possibility of tuberculosis should be strongly considered in patients who develop new infections while receiving infliximab products, especially if they previously have traveled to countries where tuberculosis is highly prevalent or have been in close contact with an individual with active tuberculosis.1,167,194,195,225

Infection with Histoplasma capsulatum , Coccidioides immitis , Legionella , Listeria , Pneumocystis jiroveci (formerly Pneumocystis carinii ) and other bacterial, mycobacterial, or fungal infections have been reported in patients receiving infliximab products.1,159,167 Carefully evaluate the potential risks and benefits of therapy with infliximab products before the drug is initiated in individuals who reside or have traveled in areas where mycoses are endemic.1,167,194,195,225 Ascertain if patients receiving TNF blocking agents who present with signs and symptoms suggestive of systemic fungal infection reside or have traveled in regions where mycoses are endemic.155 Consider empiric antifungal therapy in patients at risk of histoplasmosis or other invasive fungal infections who develop severe systemic illness, taking into account both the risk for severe fungal infection and the risks associated with antifungal therapy.1,155,159,167,194,195,225 Serologic tests for histoplasmosis may be negative in some patients with active infection.1,167,194,195,225 When deciding whether TNF blocking agent therapy should be reinitiated following resolution of an invasive fungal infection, reevaluate the risks and benefits of such therapy, particularly in patients who reside in regions where mycoses are endemic.155 Whenever feasible, decisions regarding initiation and duration of antifungal therapy and reinitiation of TNF blocking agent therapy should be made in consultation with a specialist in fungal infections.1,155,167,194,195,225

Malignancies

A boxed warning about the risk of malignancy is included in the prescribing information for infliximab products.1,167,194,195,225 Malignancies, some fatal, have been reported in children, adolescents, and young adults who received treatment with TNF blocking agents beginning when they were 18 years of age or younger.1,154,167,194,195,225 In August 2009, FDA reported the results of an analysis of reports of lymphoma and other malignancies in children and adolescents who had received TNF blocking agents.154 These cases were reported postmarketing and were derived from various sources, including registries and spontaneous postmarketing reports.1,167,194,195 FDA identified 48 cases of malignancies in children and adolescents in the analysis.154

Of the 48 cases reviewed by FDA, approximately 50% were lymphomas, including Hodgkin's disease and non-Hodgkin's lymphoma.1,154 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.1 Other malignancies reported included leukemia, melanoma, and solid organ tumors; malignancies such as leiomyosarcoma, hepatic malignancies, and renal cell carcinoma, which rarely occur in children, also were reported.154 The malignancies occurred after a median of 30 months (range: 1-84 months) following the first dose of therapy with TNF blocking agents.1 Of the 48 cases of malignancies, 11 deaths were reported; causes of death included hepatosplenic T-cell lymphoma (9 cases), T-cell lymphoma (1 case), and sepsis following remission of lymphoma (1 case).154 The observed US reporting rates for cases of malignancy with infliximab were consistently higher compared with expected background rates for lymphomas and all malignancies.154 The observed reporting rates offer limited inference into the potential differences in risk of malignancy among TNF blocking agents because of uncertainties about actual patient exposure to treatment and the possibility of underreporting of cases of malignancy.154 Most of the 48 patients (88%) also were receiving other immunosuppressive drugs such as azathioprine and methotrexate, which also are associated with an increased risk of lymphoma.1,154 Although there were other contributory factors, the role of TNF blocking agents in the development of malignancies in children and adolescents could not be excluded.154 Therefore, FDA has concluded that there is an increased risk of malignancy with TNF blocking agents.154 However, due to the relatively rare occurrence of these cancers, the limited number of pediatric patients who received TNF blocking agents, and the possible role of other immunosuppressive drugs used concomitantly with TNF blocking agents, FDA was unable to fully characterize the strength of the association between use of TNF blocking agents and the development of a malignancy.154

Hepatosplenic T-cell lymphoma, a rare, aggressive, usually fatal type of T-cell lymphoma, has been reported during postmarketing experience mainly in adolescent and young adult males with Crohn disease or ulcerative colitis who received treatment with TNF blocking agents and/or thiopurine analogs (mercaptopurine or azathioprine).1,154,160,167,194,195,225 Most of the reported cases of hepatosplenic T-cell lymphoma occurred in patients who had received a combination of immunosuppressive agents, including TNF blocking agents and thiopurine analogs (azathioprine or mercaptopurine).1,160,167,194,195,225 In some cases, potential confounding factors could not be excluded because complete medical histories were not available.160 As of December 31, 2010, FDA had identified 25 cases of hepatosplenic T-cell lymphoma in patients with Crohn disease or ulcerative colitis who had received infliximab (20 cases) or both infliximab and adalimumab (5 cases); in 22 of these cases, a thiopurine analog (mercaptopurine or azathioprine) was used concomitantly.160 These 25 cases of hepatosplenic T-cell lymphoma occurred in patients 12-74 years of age (median age: 29-30 years) following infliximab therapy for periods ranging from 1 dose to 8 years of intermittent therapy; 22 of the patients were males and 21 of the cases were fatal.160 It is not clear whether the occurrence of hepatosplenic T-cell lymphoma is related to use of TNF blocking agents or use of TNF blocking agents in conjunction with other immunosuppressive agents.1,167,194,195 Since patients with certain conditions (e.g., rheumatoid arthritis, Crohn disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis) may be at increased risk for lymphoma, it may be difficult to measure the added risk of treatment with TNF blocking agents, azathioprine, and/or mercaptopurine.160

In clinical studies, lymphoma occurred more frequently in patients receiving TNF blocking agents than in controls.1 Lymphoproliferative disorders, including lymphoma (e.g., non-Hodgkin's lymphoma, Hodgkin's disease) and myeloma, have been reported in patients receiving infliximab.1,28,30,38,42,154 In the controlled and open-label portions of infliximab clinical trials, 5 out of 5707 patients receiving infliximab (median duration of follow-up: 1 year) developed lymphomas compared with no cases of lymphoma in 1600 control patients (median duration of follow-up: 0.4 years).1 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 threefold higher than expected in the general population.1 In the combined clinical trial population for rheumatoid arthritis, Crohn disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were observed for a rate of 0.1 cases per 100 patient-years of follow-up, which is approximately fourfold higher than expected in the general population.1 Patients with rheumatoid arthritis, Crohn disease, or plaque psoriasis (especially those with highly active disease and/or chronic exposure to immunosuppressive therapies) may be at increased risk of lymphoma (even in the absence of TNF blocking agent therapy); the role of TNF blocking agents in the development of lymphoma or other malignancies has not been fully determined.1,154,167,194,195,225

Cases of acute and chronic leukemia have been reported during postmarketing surveillance of TNF blocking agents used in the management of rheumatoid arthritis and other conditions.1,154,167,194,195,225 In August 2009, FDA reported the results of a review of 147 cases of leukemia in adults and pediatric patients who received TNF blocking agents; these cases had been identified during postmarketing surveillance.154 Of the 147 cases, acute myeloid leukemia (44 cases), chronic lymphocytic leukemia (31 cases), and chronic myeloid leukemia (23 cases) were the most frequent types of leukemia reported.154 Four cases of leukemia were reported in children.154 Most patients (61%) also were receiving other immunosuppressive drugs.154 There were a total of 30 deaths reported; leukemia was reported as the cause of 26 of the 30 deaths, and the event was associated with the use of TNF blocking agents.154 Leukemia generally occurred during the first 2 years of therapy.154 The interpretation of these findings was complicated by the fact that published epidemiologic studies suggest that patients with rheumatoid arthritis may be at increased risk of leukemia, independent of any treatment with TNF blocking agents.1,154 However, based on the available data, FDA has concluded that there is a possible association between treatment with TNF blocking agents and the development of leukemia in patients receiving these drugs.154

Melanoma and Merkel cell carcinoma have been reported in patients receiving TNF blocking agents, including infliximab products. 1,167,194,195,225

In a population-based retrospective cohort study using Swedish national health registry data, the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with infliximab was two- to threefold higher compared to biologic-naïve patients or the general population, particularly those over 60 years of age.1,167,194,195 A causal relationship between infliximab and cervical cancer cannot be excluded.1,167,194,195,225

Other malignancies (basal cell carcinoma, breast cancer, colorectal cancer, rectal adenocarcinoma, squamous cell carcinoma) have also been reported during clinical studies in patients receiving infliximab.1,14,17,141 In the controlled portions of clinical trials of some TNF blocking agents, including infliximab products, more malignancies (excluding lymphoma and nonmelanoma skin cancer [NMSC]) have been observed in patients receiving TNF blocking agents compared with control patients.1,167,194,195,225 During the controlled portions of infliximab trials in patients with moderately to severely active rheumatoid arthritis, Crohn disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis receiving infliximab, 14 of 4019 patients were diagnosed with malignancies (excluding lymphoma and NMSC) compared with 1 patient among 1597 control patients (a rate of 0.52/100 patient-years among patients receiving infliximab compared with a rate of 0.11/100 patient-years among control patients), with a median duration of follow-up of 0.5 years for patients receiving the drug and 0.4 years for control patients.1 The most common malignancies reported were breast and colorectal cancer and melanoma.1 The rate of malignancies in patients receiving infliximab was similar to that expected in the general population, while the rate in the control patients was lower than expected in the general population.1 The role of TNF blocking agents in the development of malignancies has not been fully determined.1,42,154,167,194,195 225 Rates of malignancy in clinical trials for infliximab cannot be compared with rates in clinical trials of other TNF blocking agents and such rates may not predict rates in a broader population of patients receiving the drug.1

In a randomized, controlled clinical trial investigating the use of infliximab in patients with moderate to severechronic obstructive pulmonary disease† (COPD) who were or had been heavy smokers, patients received infliximab at dosages similar to those used in rheumatoid arthritis and Crohn disease.1,157 Nine (out of 157) patients receiving the drug developed a malignancy, including 1 case of lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years).1,157 One malignancy was reported in 77 control patients, for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years).1,157 The most frequent malignancies were lung or head and neck cancer.1,157

In the maintenance portion of clinical trials evaluating infliximab for treatment of psoriasis, NMSC was more common in patients who had received prior phototherapy.1

Consider the possibility of and monitor for the occurrence of malignancies during and following treatment with TNF blocking agents.154,160 Exercise caution when considering therapy with infliximab products in patients with a history of malignancy or when deciding whether to continue therapy in patients who develop a malignancy while receiving infliximab.1,34,35,44,59,64,167 Because therapy with TNF blocking agents and/or thiopurine analogs (azathioprine or mercaptopurine) may increase the risk of malignancies, including hepatosplenic T-cell lymphoma, carefully consider the risks and benefits of these agents, especially in adolescent and young adult males and in the treatment of Crohn disease or ulcerative colitis.1,160,167,194,195,225 When deciding whether infliximab products should be used alone or in combination with other immunosuppressive agents, consider both the possibility of an increased risk of hepatosplenic T-cell lymphoma with combination therapy and the observed (in infliximab studies) increase in immunogenicity and hypersensitivity reactions associated with infliximab given as monotherapy.1,167,194,195,225 Because melanoma and Merkel cell carcinoma have been reported in patients receiving infliximab products, periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.1,167,194,195,225 Because nonmelanoma skin cancer has been reported in patients with psoriasis receiving infliximab, monitor patients with psoriasis who are receiving infliximab products, particularly those who received prior prolonged phototherapy for nonmelanoma skin cancer.1,167,194,195 Periodically screen women treated with infliximab products for cervical cancer.1,167,194,195,225 Because malignancies (mainly lung cancer or head and neck malignancies) were reported more frequently in infliximab-treated than placebo-treated patients with moderate to severe COPD, exercise caution when considering therapy with infliximab in such patients.1,167,194,195

Sensitivity Reactions

Acute Sensitivity Reactions

Hypersensitivity reactions have been reported in patients receiving infliximab products; these reactions vary in their time to onset and have required hospitalization in some patients.1,167,194,195,225 Most hypersensitivity reactions have occurred during or within 2 hours of infusion; reactions have included anaphylaxis, urticaria, dyspnea, and hypotension.1,167,194,195

In clinical studies, infusion reactions were reported in approximately 20% of patients receiving infliximab compared with 10% of patients receiving placebo.1 In these studies, 27% of patients who experienced an infusion reaction during infliximab induction therapy also experienced an infusion reaction during maintenance therapy with the drug, whereas 9% of patients who had no infusion reactions during infliximab induction therapy experienced an infusion reaction during maintenance therapy.1 Infusion reaction rates remained stable through 1 year in patients receiving infliximab in the psoriasis EXPRESS study.1 Infusion reaction rates in the psoriasis EXPRESS II study were variable over time and were somewhat higher following the final infusion than after the initial infusion.1 In the 3 psoriasis studies, acute infusion reactions were reported in 7, 4, or 1%, respectively, of patients receiving a 3- or 5-mg/kg dose of infliximab or placebo.1

Infusion reaction symptoms may include fever, chills, chest pain, hypotension, hypertension, dyspnea, urticaria, and/or pruritis.1 Most acute infusion reactions have been mild and transient, and symptoms have been controlled by slowing the infusion rate, discontinuing the infusion, or treatment (e.g., with antihistamines).1,5,10,14,18,23,28,38,42,47,72,92 Serious infusion reactions, including anaphylaxis, seizures, erythematous rash, and/or hypotension have been reported in less than 1% of patients receiving infliximab.1,36,128 Anaphylactic reactions, including anaphylactic shock, laryngeal/pharyngeal edema and severe bronchospasm, and seizure have occurred during postmarketing experience in patients receiving infliximab products.1,167,194,195

Infusion reactions that were not serious (including nonserious anaphylactoid reactions) were reported in 18% of pediatric patients receiving infliximab for the treatment of Crohn disease.1 About 13% of pediatric patients receiving infliximab for the treatment of ulcerative colitis experienced one or more nonserious infusion reactions, including 18% of pediatric patients receiving the recommended maintenance regimen of 5 mg/kg every 8 weeks.1 Infusion reactions were reported in 35 or 18%, respectively, of children receiving 3- or 6-mg/kg doses of infliximab for the treatment of juvenile rheumatoid arthritis.1 The most frequently reported infusion-related events were vomiting, fever, headache, and hypotension.1,153 Serious infusion reactions occurred in a few patients.1,153

In clinical studies in patients with rheumatoid arthritis, Crohn disease, or psoriasis, readministration of infliximab after a period without treatment resulted in a higher incidence of infusion reactions as compared to regular maintenance treatment.1 In a clinical trial evaluating 2 long-term treatment strategies (i.e., long-term maintenance therapy with infliximab versus retreatment with an induction regimen of infliximab following disease flare) in patients with moderate to severe psoriasis, serious infusion reactions were reported in 4% of patients receiving retreatment following disease flare compared with less than 1% of those receiving long-term maintenance therapy.1 Patients in this study did not receive other immunosuppressive agents concomitantly with infliximab.1 Most of the serious infusion reactions occurred during the second infusion at week 2 and manifestations included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension.1 In all cases, infliximab therapy was discontinued and/or other treatment was instituted with complete resolution of signs and symptoms.1

There is some evidence indicating that the incidence of acute infusion reactions to infliximab products is lower in patients who are receiving concomitant therapy with immunosuppressive agents (e.g., azathioprine, mercaptopurine, methotrexate) than in those not receiving such therapy.1,47 The manufacturers and some clinicians suggest considering the use of a pretreatment regimen (e.g., acetaminophen, antihistamines, prednisone) prior to each infusion of the drug to prevent or ameliorate these acute infusion reactions.1,47,72,167 In addition, clinicians may consider the use of a rate titration schedule to administer IV infusions of infliximab.72 Although safety and efficacy of the procedure have not been established, at least 2 Crohn disease patients with a history of anaphylactic/anaphylactoid reactions to infliximab have received a subsequent dose of the drug using a desensitization procedure that involved dose escalation in an intensive care setting.92

Monitor patients closely (including measurement of vital signs) during and for at least 30 minutes after each IV infusion of the drug.72 Drugs for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids, and/or epinephrine) should be immediately available.1,72,167,194,195 To prevent or ameliorate acute infusion reactions, clinicians can consider the use of a pretreatment regimen (e.g., acetaminophen, antihistamines, prednisone) prior to each infliximab product dose and use of a rate titration schedule to administer IV infusions of the drug.1,47,72,167,194,195 If a patient experiences a clinically important change in vital signs (e.g., diastolic blood pressure drops 15-20 mm Hg) or any symptoms of hypersensitivity (e.g., urticaria, shortness of breath) while receiving an IV infusion of an infliximab product, stop the infusion immediately, evaluate manifestations, and initiate appropriate therapy.72 The manufacturer of infliximab states that if the infusion is stopped because of an acute infusion reaction but the reaction is not severe and can be controlled with the use of drugs other than epinephrine (e.g., diphenhydramine, acetaminophen, prednisone), then the infusion may be restarted with caution using a rate titration schedule.72 If the infusion can be completed in these patients, then they may receive additional indicated doses of the infliximab product with caution and in the presence of appropriately trained medical personnel.72 However, if the acute infusion reaction is more serious and requires treatment with epinephrine or if symptoms increase in severity, then the infusion of the infliximab product should be discontinued.72

Delayed Sensitivity Reactions

Infusion reactions that appear to be delayed hypersensitivity or serum sickness-like reactions have occurred after initial therapy with infliximab products (i.e., as early as after the second dose) and when therapy with infliximab products was reinstituted following an extended period without such treatment.1,10,42,136,167 Symptoms associated with these reactions included fever, rash, headache, sore throat, myalgia, polyarthralgia, hand/facial edema, and/or dysphagia.1 These reactions were associated with marked increases in antibodies to infliximab, loss of detectable infliximab concentrations in the serum, and possible loss of drug efficacy.1

Delayed infusion reactions to infliximab were first reported in a study in adults with moderately to severely active Crohn disease or fistulizing Crohn disease who were receiving retreatment with infliximab after an interval of 2-4 years.10,42 Delayed hypersensitivity reactions (generally reported as serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash) have been reported in about 1% of patients with plaque psoriasis receiving infliximab in clinical studies; these reactions generally occurred within 2 weeks after repeat infusion of the drug.1

There is some evidence that patients who have received at least 3 months of therapy with an immunosuppressive agent (e.g., azathioprine, mercaptopurine, methotrexate) prior to administration of infliximab have a lower rate of development of human antichimeric antibodies (HACA) and a lower rate of infusion reactions than patients not receiving such therapy.1,18,47,72

Because delayed infusion reactions have occurred 3-12 days after an infliximab dose in patients who received retreatment with the drug after a period of 2-4 years, exercise caution when retreating patients with infliximab products following an extended period of time (e.g., after 1 year or longer).10,42

Carefully consider the risks and benefits of readministration of infliximab products after a period without treatment (especially readministration as a reinduction regimen at 0, 2, and 6 weeks), since such retreatment regimens have resulted in a higher incidence of infusion reactions as compared to regular maintenance treatment.1,167,194,195 If maintenance therapy with an infliximab product for the management of psoriasis is interrupted, reinitiate the drug as a single dose followed by maintenance therapy.1,167,194,195

Other Warnings and Precautions

HBV Reactivation

Use of TNF blocking agents, including infliximab products, has been associated with reactivation of hepatitis B virus (HBV) infection in patients who are chronic carriers of this virus (i.e., hepatitis B surface antigen-positive [HBsAg-positive]).1,167,194,195,225 HBV reactivation has resulted in death in a few individuals receiving a TNF blocking agent.1,167,194,195,225 Most patients experiencing HBV reactivation were receiving concomitant therapy with other immunosuppressive agents; use of multiple immunosuppressive agents may have contributed to HBV reactivation.1,167,194,195,225

Screen all patients before initiating therapy with infliximab products.1,167,194,195,225 Consultation with an expert in the treatment of hepatitis B is recommended for patients who test positive for hepatitis B surface antigen.1,167,194,195,225 Appropriately evaluate and monitor chronic carriers of HBV prior to the initiation of therapy, during treatment, and for up to several months following therapy with infliximab products.1,167,194,195,225 Safety and efficacy of antiviral therapy for prevention of viral reactivation in HBV carriers receiving a TNF blocking agent have not been established.1,167,194,195,225 Discontinue therapy with the infliximab product if HBV reactivation occurs, and initiate appropriate treatment, including antiviral therapy.1,167,194,195,225 It has not been established whether an infliximab product can be safely readministered once control of the reactivated HBV infection has been achieved; caution is advised if infliximab products are resumed in such a situation.1,167,194,195,225

Hepatotoxicity

Severe hepatic reactions (e.g., acute liver failure, jaundice, hepatitis, cholestasis) have been reported rarely during postmarketing surveillance in patients receiving infliximab products.1,167,194,195,225 These reactions occurred between 2 weeks to longer than 1 year after initiation of therapy with the drug; hepatic aminotransferase elevations were not observed prior to discovery of the liver injury in many of these cases.1,167,194,195,225 Some of these cases were fatal or needed liver transplantation.1,167,194,195,225

In clinical trials in patients with rheumatoid arthritis, Crohn disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis, increases in serum AST (SGOT) and/or ALT (SGPT) concentrations were observed in a greater proportion of patients receiving infliximab than in controls, both when infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents.1 In these patient populations, increases in serum ALT concentrations of 5 or more times the upper limit of normal (ULN) were observed in less than 1 to 4% of patients receiving infliximab.1 In general, patients who developed hepatic aminotransferase elevations were asymptomatic, and such increases either decreased or resolved with either continuation or discontinuance of infliximab or modification of concomitant drug therapy.1

In clinical trials in adults with rheumatoid arthritis, mild (less than 2 times the ULN) or moderate (2-3 times the ULN) transient increases in serum ALT concentrations have occurred in 34% of patients receiving infliximab in conjunction with methotrexate and in 24% of patients receiving placebo in conjunction with methotrexate.1 Increases in serum ALT concentrations of 3 or more times the ULN were observed in 4 or 3% of patients receiving infliximab in conjunction with methotrexate or methotrexate without infliximab, respectively (median follow-up 58 weeks).1

In clinical trials in patients with Crohn disease (median follow-up 54 weeks), mild to moderate increases in serum ALT concentrations have been observed in 39 or 34% of patients receiving maintenance therapy with infliximab or placebo, respectively.1 In addition, increases in serum ALT concentrations of 3 or more times the ULN were observed in 5 or 4% of patients receiving maintenance therapy with infliximab or placebo, respectively.1

In a clinical trial in pediatric patients with Crohn disease (median follow-up 53 weeks), mild to moderate increases in serum ALT concentrations have been observed in 18% of patients receiving infliximab.1 In addition, increases in serum ALT concentrations of 3 or more and 5 or more times the ULN were observed in 4 and 1% of patients receiving infliximab, respectively.1

In a clinical trial in patients with ankylosing spondylitis, mild to moderate increases in ALT concentrations occurred in 51 or 15% of patients receiving infliximab or placebo, respectively.1 In addition, increases in serum ALT concentrations of 3 or more times the ULN were observed in 10 or 0% of patients receiving infliximab or placebo, respectively.1

In a clinical trial in patients with ulcerative colitis, mild to moderate increases in ALT concentrations have occurred in 17 or 12% of patients receiving infliximab or placebo, respectively.1 In addition, increases in serum ALT concentrations of 3 or more times the ULN were observed in 2 or 1% of patients receiving infliximab or placebo, respectively.1

In a clinical trial in pediatric patients with ulcerative colitis (median follow-up of 49 weeks), increases in serum ALT concentrations of up to 3 times the ULN occurred in 17% of patients receiving infliximab, while increases of 3 or more times the ULN or 5 or more times the ULN occurred in 7 or 2%, respectively, of patients receiving the drug.1

In a clinical trial in patients with psoriatic arthritis, mild to moderate increases in ALT concentrations occurred in 50 or 16% of patients receiving infliximab or placebo, respectively.1 In addition, increases in serum ALT concentrations of 3 or more times the ULN were observed in 7 or 0% of patients receiving infliximab or placebo, respectively.1

In clinical trials in patients with plaque psoriasis, mild to moderate increases in ALT concentrations have occurred in 49 or 24% of patients receiving infliximab or placebo, respectively.1 In addition, increases in serum ALT concentrations of 3 or more times the ULN were observed in 8 or less than 1% of patients receiving infliximab or placebo, respectively.1

Evaluate patients with signs or symptoms of hepatic dysfunction for evidence of liver injury.1,167,194,195 If jaundice and/or marked hepatic aminotransferase elevations (5 or more times the ULN) develop, discontinue infliximab and investigate the hepatic abnormality.1,167,194,195

Monitor hepatic enzymes and liver function tests every 3 to 4 months during subcutaneous maintenance treatment with infliximab-dyyb (Zymfentra®).225 Interrupt this treatment if drug-induced liver injury is suspected, until the diagnosis is excluded.225

Heart Failure

Use of infliximab in patients with moderate to severe (New York Heart Association [NYHA] class III or IV) congestive heart failure was associated with higher incidences of mortality and hospitalization for worsening heart failure compared with similar patients receiving placebo.1,135,139 In a phase II study involving use of infliximab (5 or 10 mg/kg given at 0, 2, and 6 weeks) in patients with NYHA class III or IV congestive heart failure, at week 28, 4 of 101 patients receiving infliximab had died versus 0 of 49 patients receiving placebo.139 At week 28, 14 of 101 patients receiving infliximab had been hospitalized for worsening congestive heart failure versus 5 of 49 patients receiving placebo.139 Results of this study suggest that infliximab dosages of 10 mg/kg are associated with higher rates of mortality and dosages of 5 and 10 mg/kg are associated with higher rates of adverse cardiovascular effects.1 There have been postmarketing reports of worsening heart failure, with or without identifiable precipitating factors, in patients receiving infliximab.1

If infliximab is used in patients with heart failure, caution and careful monitoring are recommended; if new or worsening symptoms of heart failure occur, discontinue the drug.1,167,194,195,225

Hematologic Reactions

Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with fatal outcome, and idiopathic or thrombotic thrombocytopenic purpura have been reported in patients receiving infliximab products.1,167,194,195,225 Although a high-risk group for these adverse effects has not been identified, caution is advised if infliximab products are used in patients with a history of substantial hematologic abnormalities.1,167,194,195,225 Advise patients receiving infliximab products to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor).1,167,194,195,225 If substantial hematologic abnormalities are confirmed, consider discontinuance of the infliximab product.1,167,194,195,225

Cardiovascular and Cerebrovascular Reactions

Serious cerebrovascular accidents, myocardial ischemia/infarction (sometimes fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of infliximab product infusion.1,167,194,195 Cases of transient visual loss have also been reported during and within 2 hours of infliximab product infusion.1,167,194,195 Monitor patients for such events during infusion; if a serious reaction occurs, discontinue the infusion and manage the reaction as dictated by signs and symptoms.1,167,194,195

Neurologic Reactions

CNS manifestations of systemic vasculitis, seizure, and new onset or exacerbation of clinical manifestations and/or radiographic evidence of central or peripheral nervous system demyelinating disorders (e.g., multiple sclerosis, optic neuritis, Guillain-Barré syndrome) have been reported rarely in patients receiving infliximab products or other TNF blocking agents.1,167,194,195,225

Exercise caution when considering use of infliximab products in patients with these neurologic disorders and consider discontinuance of infliximab if these disorders develop.1,167,194,195,225

Concurrent Administration with Other Biological Products

Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNF blocker, etanercept, with no added clinical benefit compared to etanercept alone.1,167,194,195,225 Because of the nature of the adverse reactions seen with the concurrent use of etanercept and anakinra therapy, similar toxicities may also result from the concurrent use of anakinra and other TNF blockers.1,167,194,195 Therefore, the concurrent use of infliximab and anakinra is not recommended.1,167,194,195

In clinical studies, concurrent administration of TNF blockers and abatacept have been associated with an increased risk of infections including serious infections compared with TNF blockers alone, without increased clinical benefit.1,167,194,195 Therefore, concurrent use of infliximab and abatacept is not recommended.1

There is insufficient information regarding the concurrent use of infliximab with other biological products used to treat the same conditions as infliximab.1,167,194,195 Concurrent use of infliximab with these biological products is not recommended because of the possibility of an increased risk of infection.1,167,194,195

Switching Between Biological Disease-Modifying Antirheumatic Drugs (DMARDs)

Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.1,167,194,195

Immunologic Reactions and Antibody Formation

Infliximab therapy may result in the formation of antibodies to infliximab.1,167,194,195,225 The presence of infliximab in the serum sample may interfere with enzyme immunoassay (EIA) methods used to measure antibodies to infliximab and result in underestimation of the prevalence of antibody development to the drug.1 EIA methods were used to assess antibody development in the following studies; however, in pediatric patients with ulcerative colitis, a second assay method, an electrochemiluminescence immunoassay (ECLIA) method (which is 60-fold more sensitive than the original EIA method and permits classification of patient samples as either positive or negative for antibodies to the drug without the need for an inconclusive category) also was used.1 In patients receiving a 3-dose infliximab induction regimen followed by maintenance therapy who were evaluated over 1-2 years of treatment, 10% of patients were antibody-positive by EIA; most patients had low antibody titers.1 Patients with Crohn disease who had a drug-free interval longer than 16 weeks were more likely to be antibody-positive than patients who received the usually recommended maintenance regimen of infliximab (i.e., doses every 8 weeks).1 EIA antibody test results were inconclusive (because infliximab was present in the serum sample) in approximately 77% of pediatric patients receiving infliximab in conjunction with stable dosages of mercaptopurine, azathioprine, or methotrexate for the treatment of Crohn disease; following exclusion of these inconclusive samples, 3 of 24 patients (12.5%) had antibodies to infliximab.1 Antibodies to infliximab were detected by EIA in 38 or 12%, respectively, of children receiving 3- or 6-mg/kg doses of infliximab for the treatment of juvenile rheumatoid arthritis.1,153 In pediatric patients with ulcerative colitis, antibodies to the drug were detected by EIA or ECLIA in 7 or 52%, respectively, of patients.1 Patients who were antibody-positive were more likely to have higher rates of clearance, have reduced efficacy, and/or experience infusion reactions.1

Patients with Crohn disease or rheumatoid arthritis receiving concomitant immunosuppressive therapy (e.g., methotrexate, azathioprine, mercaptopurine) were less likely to be antibody-positive.1 In patients who received infliximab in a dosage of 1, 3, or 10 mg/kg without concomitant methotrexate, infliximab antibodies were detected by EIA in 53, 21, or 7%, respectively; in those who received the same dosages of infliximab with concomitant methotrexate therapy (7.5 mg once weekly), infliximab antibodies were present in 15, 7, or 0%, respectively.18 Although further study is needed, it has been suggested that these data indicate that higher infliximab dosages and concomitant methotrexate therapy may induce a degree of immunologic tolerance to infliximab.13,17,18,23,25,84,85

In one study, development of antibodies to infliximab was detected by EIA in 15% of 191 patients with psoriatic arthritis receiving infliximab 5 mg/kg with or without methotrexate.1 In the psoriasis EXPRESS II study in patients who received infliximab for 1 year at a dosage of 5 or 3 mg/kg, antibodies to infliximab were detected by EIA in 36 or 51% of patients, respectively, while in the psoriasis SPIRIT study in patients who received infliximab induction therapy at a dosage of 5 or 3 mg/kg, antibodies to infliximab were detected by EIA in 20 or 27%, respectively.1 Despite the increase in antibody formation, serious infusion reaction rates in patients receiving infliximab induction therapy at a dosage of 5 mg/kg followed by maintenance therapy every 8 weeks in the psoriasis EXPRESS and EXPRESS II studies and in patients receiving induction therapy at a dosage of 5 mg/kg in the psoriasis SPIRIT study were similar to those observed in other study populations (less than 1%).1 The effects of the apparent increased immunogenicity in patients with psoriasis on efficacy and infusion reaction rates with chronic infliximab therapy compared with patients with other disease states receiving infliximab products are not known.1,167

No clinically meaningful differences have been found between infliximab biosimilars and infliximab with respect to antidrug antibody response resulting from administration of these drugs.168,223,224 Small numerical differences in antidrug antibody response were noted between infliximab-abda and infliximab; however, these differences were not felt to be clinically meaningful.223

Therapy with infliximab products may induce formation of autoantibodies and rarely may result in development of a lupus-like syndrome.1,167,194,195,225

When patients receiving infliximab in clinical studies were evaluated for the presence of antinuclear antibodies (ANA) and antibodies to double stranded DNA (anti-dsDNA), about 50 or 20 % had developed ANA or anti-dsDNA antibodies, respectively, between study entry and final evaluation.1 In these studies, about 20 or 0% of patients receiving placebo developed ANA or anti-dsDNA antibodies, respectively.1 When data from several studies in adults with rheumatoid arthritis were combined, approximately 30% of the study population had ANA at the time of study entry and 0% had anti-dsDNA.90 After infliximab treatment, 53% had ANA and 14% had anti-dsDNA.90 The mean time to detection of anti-dsDNA following initiation of infliximab therapy was 6.3 weeks (range: 4-10 weeks); in most patients, anti-dsDNA antibodies resolved within 4-6 weeks after induction.90 With the exception of one patient who had immunoglobulin G (IgG), IgA, and IgM class anti-dsDNA antibodies and who had clinical manifestations suggestive of a drug-induced lupus syndrome, anti-dsDNA antibodies in all other patients were of the IgM class only.90

Children receiving infliximab for the treatment of juvenile arthritis have been tested for the presence of ANA and anti-dsDNA antibodies.153 The 3-mg/kg dose of infliximab was associated with a substantially higher risk of ANAs and anti-dsDNA antibodies than the 6-mg/kg dose.153 Approximately 14.8 or 13% of children receiving the 3-mg/kg dose of infliximab developed ANA or anti-dsDNA antibodies, respectively, between study entry and final evaluation.153 Only 2.2% of children receiving the 6-mg/kg dose of infliximab developed ANA antibodies during the study; 0% of children receiving this dose developed anti-dsDNA antibodies.153

Clinical symptoms consistent with a lupus-like syndrome (e.g., rash on face, hands, or forearms, exacerbation of joint pains, fever, dyspnea, pleuropericarditis) have occurred rarely in patients receiving infliximab products;1,14,18,38,41,136,167 these manifestations improved or resolved following discontinuance of the drug and appropriate medical therapy.14,18,38,41,136 One rheumatoid arthritis patient receiving infliximab in a clinical study developed a vasculitic rash and became positive for anti-dsDNA antibodies after the second infliximab dose; however, the rash and antibodies resolved spontaneously 11 weeks later.41 Current data are insufficient to determine whether induction of anti-dsDNA antibodies is associated with an increased risk of developing a lupus-like syndrome if infliximab therapy is continued for prolonged periods.90 Discontinue infliximab products in patients who develop a lupus-like syndrome.1,167,194,195

Vaccinations and Use of Live Vaccines/Therapeutic Infectious Agents

Avoid live vaccines during therapy with infliximab products.1,167,194,195,225 Information is not available regarding whether infliximab would affect the rate of secondary transmission of infection following administration of a live vaccine.1,167,194,195

When considering infliximab therapy, review the vaccination status of the patient and administer all age-appropriate vaccines included in current immunization guidelines, if possible, prior to initiation of therapy.1,167,194,195,225

Fatal outcome due to disseminated bacille Calmette-Guérin (BCG) infection has been reported in an infant who received a BCG vaccine after in utero exposure to infliximab.1,167,194,195,225 Do not administer live vaccines to infants exposed to infliximab in utero for at least 6 months after birth, as infliximab is known to cross the placenta and has been detected up to 6 months following birth.1,167,194,195,225

Use of therapeutic infectious agents (e.g., BCG bladder instillation for the treatment of cancer) is not recommended with concurrent administration of infliximab products.1,167,194,195,225

Specific Populations

Pregnancy

Available observational studies in pregnant women exposed to infliximab products showed no increased risk of major malformations among live births as compared to those exposed to non-biologics.1,167,194,195,225 In a study using data from an inflammatory bowel disease pregnancy registry, infliximab exposure was not associated with increased rates of major congenital malformations, miscarriage/stillbirth, infants of low birth weight, small for gestational age, or infection in the first year of life.1,167 195 In a second study of inflammatory bowel disease patients conducted in Sweden, Finland, and Denmark, exposure to infliximab was not associated with increased rates of congenital anomalies or infant death; however, when infliximab was given in combination with immunosuppressants (e.g., systemic corticosteroids, azathioprine), the combination therapy was associated with increased rates of preterm birth, small for gestational age, low birth weight, and infant hospitalization for infection compared to non-biologic systemic treatment.1,167,194,195 Methodological limitations may hinder interpretation of these study results.1,167,194,195 Women with inflammatory bowel disease or rheumatoid arthritis may have an increased risk of adverse pregnancy outcomes (e.g., preterm delivery, low birth weight, small for gestational age at birth) with increased disease activity.1,167,194,195

Infliximab crosses the placenta during the third trimester of pregnancy and may affect immune responses in infants who were exposed in utero.1,167,194,195,225 Infliximab has been detected for up to 6 months in the serum of infants whose mothers received infliximab products during pregnancy.1,167,194,195,225

Reproduction studies using infliximab products in animals have not been conducted since the drug only binds TNF from humans and other primates and does not cross-react with TNF from other species.1 In a developmental toxicity study conducted in mice using a murine anti-TNF antibody that selectively inhibits murine TNF, no evidence of maternal toxicity, fetal mortality, or structural abnormalities was observed.1 In pharmacodynamic animal models using an analogous anti-TNF antibody, doses of 10-15 mg/kg produced maximal pharmacologic effectiveness; in animal reproduction studies, doses up to 40 mg/kg produced no adverse effects.1

Lactation

Clinical studies indicate that IV infliximab is present in human milk at low levels.1,167,194,195 Systemic exposure in a breastfed infant is expected to be low, as infliximab is largely degraded in the GI tract.1,167,194,195,225 In a study of 168 women with inflammatory bowel disease treated with infliximab, infants exposed to infliximab through breast milk had no increase in infection rates and demonstrated normal development.1,167,194,195 There are no data on the effects of infliximab on milk production.1 167,194,195,225 Consider the developmental and health benefits of breastfeeding, along with the mother's clinical need for the infliximab product and any potential adverse effects on the breastfed infant from the infliximab product or from the underlying maternal condition.1,167,194,195 225

Pediatric Use

Safety and efficacy of IV infliximab and its biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) have been established in pediatric patients 6 years of age and older with Crohn disease.1,167,194,195 The manufacturer states that infliximab has been studied in this population only in conjunction with conventional immunosuppressive therapy.1,167,194,195 Safety and efficacy of long-term therapy (exceeding 1 year) with infliximab products in pediatric patients with Crohn disease have not been established.1,167,194,195 Use of infliximab products for the management of Crohn disease in pediatric patients 6 years of age or older is supported by the results of a randomized, open-label study in 112 pediatric patients 6 years of age or older.1 Safety and efficacy for the management of Crohn disease have not been established in pediatric patients younger than 6 years of age.1

Safety and efficacy of IV infliximab and its biosimilars (infliximab-abda, infliximab-axxq, infliximab-dyyb) have been established in pediatric patients 6 years of age and older with ulcerative colitis.1,167,194,195 Safety and efficacy of long-term infliximab therapy (exceeding 1 year) in pediatric patients with ulcerative colitis have not been established.1 Use of infliximab products for the management of ulcerative colitis in pediatric patients 6 years of age or older is supported by the results of adequate and well-controlled studies in adults with additional safety and pharmacokinetic data from an open-label study in 60 pediatric patients 6 years of age or older.1 Safety and efficacy for the management of ulcerative colitis have not been established in pediatric patients younger than 6 years of age.1

Safety and efficacy of infliximab products in pediatric patients with plaque psoriasis have not been established.1,167

Safety and efficacy of infliximab for the management of juvenile rheumatoid arthritis† have been evaluated in children 4-17 years of age with juvenile arthritis who had not responded adequately to methotrexate.1,153 While infliximab in combination with methotrexate produced important and durable clinical effects in children, the primary efficacy end point (i.e., the American College of Rheumatology [ACR] Pediatric 30 [Pedi 30] criteria for improvement) measured at week 14 did not differ between infliximab-treated children and placebo recipients.1,153 A 3-mg/kg dose of infliximab was associated with a higher risk of serious adverse events, infusion reactions, and development of antibodies to infliximab, antinuclear antibodies (ANAs), and antibodies to double stranded DNA (anti-ds DNA) compared with a 6-mg/kg dose.153 Further study is needed to evaluate the safety and efficacy of the drug for juvenile rheumatoid arthritis.1,72,104,153

Malignancies, some fatal, have been reported in children and adolescents who received treatment with TNF blocking agents.1,154,160,167 It is unclear whether reported cases of hepatosplenic T-cell lymphoma in patients receiving infliximab products have been related to use of the TNF blocking agent or use of the TNF blocking agent in conjunction with other immunosuppressive agents.1,167,194,195 Therefore, carefully assess risks and benefits when deciding whether to use infliximab products alone or in combination with other immunosuppressive agents.1,167,194,195

Pharmacokinetic values for infliximab in pediatric patients 6-17 years of age with Crohn disease or ulcerative colitis are similar to values in adults with these diseases.1

All pediatric patients should be up to date with their vaccinations prior to initiating therapy with infliximab products.1,167,194,195

Infliximab has been detected for up to 6 months in the serum of infants whose mothers received infliximab products during pregnancy.1,167,194,195 Infants who were exposed to infliximab products in utero may be at increased risk of infection.1,167,194,195 Fatal disseminated BCG infection has been reported in an infant who received BCG vaccine after having been exposed to infliximab in utero.1,167,194,195 Do not administer live vaccines to infants exposed to infliximab products in utero for at least 6 months following birth.1,167,194,195

The safety and efficacy of infliximab-dyyb (Zymfentra®) in pediatric patients have not been established.225

Geriatric Use

Clinical studies evaluating infliximab for the management of Crohn disease, ulcerative colitis, ankylosing spondylitis, and psoriatic arthritis have included an insufficient number of patients 65 years of age and older to make a valid comparison of the drug's safety and efficacy in geriatric patients compared with younger adults.1,167,194,195 In clinical studies in adults with rheumatoid arthritis or plaque psoriasis, there were no overall differences in the safety and efficacy of infliximab in those 65 years of age or older compared with younger adults; however, the incidence of serious adverse effects was higher in infliximab-treated and control patients 65 years of age or older compared with younger adults.1,167,194,195 Because serious infectious complications have been reported in some patients receiving infliximab products and because the overall incidence of infection is higher in geriatric adults than in younger individuals, monitor geriatric patients who receive infliximab products closely for the development of serious infections..1,167,194,195

Hepatic Impairment

The pharmacokinetics of infliximab have not been formally studied in patients with hepatic impairment.1,167,194,195,225

Renal Impairment

The pharmacokinetics of infliximab have not been formally studied in patients with renal impairment.1,167,194,195,225

Common Adverse Effects

Adverse effects reported in greater than 10% of patients receiving IV infliximab products include infections (e.g., upper respiratory, sinusitis, pharyngitis), infusion-related reactions, headache, and abdominal pain.1,167,194,195

Adverse effects reported in ≥3% of patients receiving subcutaneous infliximab-dyyb for ulcerative colitis include COVID-19, anemia, arthralgia, injection site reaction, increased alanine aminotransferase, and abdominal pain.225

Adverse effects reported in ≥3% of patients receiving subcutaneous infliximab-dyyb for Crohn disease include COVID-19, headache, upper respiratory tract infection, injection site reaction, diarrhea, increased blood creatine phosphokinase, arthralgia, increased alanine aminotransferase, hypertension, urinary tract infection, neutropenia, dizziness, and leukopenia.225

Drug Interactions ⬆ ⬇

[Section Outline]

Drugs Metabolized by Hepatic Microsomal Enzymes
Biologic Agents
Methotrexate
Vaccines and Therapeutic Infectious Agents

Although specific drug interaction studies evaluating concomitant use of infliximab or its biosimilars and other drugs have not been conducted to date,1,167,194,195,225 most patients in clinical studies evaluating infliximab received one or more concomitant drugs.1,14,15,17,18,39,41 Patients with Crohn disease usually received infliximab concomitantly with corticosteroids, mesalamine or sulfasalazine, azathioprine or mercaptopurine, and/or anti-infective agents;1,5,6,38,64,69 patients with rheumatoid arthritis usually received infliximab concomitantly with methotrexate1,14,15,17,18,41 and may also have received corticosteroids, nonsteroidal anti-inflammatory agents (NSAIAs), folic acid, or narcotics.1

In patients with Crohn disease, serum concentrations of infliximab do not appear to be affected by baseline use of corticosteroids, 5-aminosalicylates, or anti-infectives (ciprofloxacin, metronidazole).1 There is some evidence from studies of infliximab that the incidence of some adverse immunologic reactions to infliximab products (e.g., infusion reactions, formation of antibodies to infliximab) is lower in patients receiving infliximab products concomitantly with immunosuppressive agents (e.g., corticosteroids, azathioprine, mercaptopurine, methotrexate) compared with those receiving infliximab products without such agents.1,18,167

When deciding whether infliximab products should be used alone or in combination with other immunosuppressive agents, clinicians should consider both the possibility of an increased risk of hepatosplenic T-cell lymphoma with combination therapy and the observed (in infliximab studies) increase in immunogenicity and hypersensitivity reactions associated with infliximab products given as monotherapy.1,167,194,195

Drugs Metabolized by Hepatic Microsomal Enzymes

Because increased levels of cytokines (e.g., tumor necrosis factor [TNF]-α, interferon, interleukin-1, interleukin-6, interleukin-10) during chronic inflammation may suppress the formation of cytochrome P-450 (CYP) isoenzymes, it is expected that a drug that antagonizes cytokine activity, such as an infliximab product, could normalize the formation of CYP enzymes.1,167,194,195,225 Following initiation or discontinuance of therapy with infliximab products, monitor patients receiving certain drugs metabolized by CYP isoenzymes (i.e., those with a low therapeutic index [e.g., cyclosporine, theophylline, warfarin]) for therapeutic effect and/or changes in serum concentrations, and adjust dosages of these drugs as needed.1,167,194,195,225

Biologic Agents

Exercise caution when switching from one biologic disease-modifying antirheumatic drug (DMARD) to another, since overlapping biologic activity may further increase the risk of infection.1,167,194,195

Insufficient data are available regarding concomitant use of infliximab products with other biologic agents used to treat the same conditions.1,167,194,195 Concomitant use of infliximab products with these agents is not recommended because of an increased risk of infection.1,167,194,195,225

Abatacept

When abatacept and a TNF blocking agent were used concomitantly, an increased incidence of infection and serious infection was observed, with no substantial improvement in efficacy over that observed with a TNF blocking agent alone.1,167,194,195 Similar toxicities would be expected with concomitant use of abatacept and infliximab products.1,167,194,195 Concomitant use of infliximab products and abatacept is not recommended.1,167,194,195

Anakinra

When anakinra and etanercept were used concomitantly in patients with rheumatoid arthritis, an increased incidence of serious infection and neutropenia was observed, with no substantial improvement in efficacy over that observed with etanercept alone.1,167,194,195 Similar toxicities would be expected with concomitant use of anakinra and other agents that block TNF, including infliximab products.1,167,194,195 Concomitant use of infliximab products and anakinra is not recommended.1,167,194,195

Tocilizumab

Avoid concomitant use of tocilizumab and biologic DMARDs such as TNF blocking agents, including infliximab products, because of the possibility of increased immunosuppression and increased risk of infection.1,167,194,195

Methotrexate

Although specific pharmacokinetic interaction studies have not been performed, data from one double-blind, placebo-controlled study in adults with rheumatoid arthritis suggest that concomitant use of methotrexate may affect the pharmacokinetics of infliximab.18,39 In this study, patients who received infliximab in a dosage of 1 mg/kg (given by IV infusion over 2 hours at weeks 0, 2, 6, 10, and 14) concomitantly with oral placebo (once weekly) had mean serum infliximab concentrations that decreased to 0.1 mcg/mL (the limits of detection) by the fourth week after the second infusion and by the second week after each subsequent infusion; however, patients who received the same dosage of infliximab concomitantly with oral methotrexate (7.5 mg once weekly) had mean serum infliximab concentrations that were maintained at approximately 2-20 mcg/mL during each interval.18 Although patients receiving infliximab in a dosage of 3 or 10 mg/kg had serum infliximab concentrations that were similar regardless of whether they were receiving the drug alone or in conjunction with methotrexate (7.5 mg once weekly), serum infliximab concentrations after the final infusion were consistently higher and decreased at a slower rate in those receiving methotrexate than in those receiving placebo.18

The mechanisms and clinical importance of this possible pharmacokinetic interaction have not been determined.18,39 There is some evidence that development of antibodies to infliximab occurs less frequently in patients receiving infliximab in conjunction with methotrexate than in those receiving infliximab alone.1,167,194,195 It has been suggested that methotrexate, by decreasing the immunogenic potential of infliximab, may result in a slower rate of clearance of infliximab.39

Vaccines and Therapeutic Infectious Agents

Do not administer live vaccines and other live therapeutic infectious agents (e.g., BCG for intravesical instillation) to patients receiving infliximab products.1,167,194,195,225 Use of live vaccines or live therapeutic infectious agents could result in infections, including disseminated infections.1,167,194,195 Limited data are available regarding whether infliximab products would affect the rate of secondary transmission of infection following administration of a live vaccine or regarding the response to live vaccines in patients receiving the drug.1,167,194,195 Fatal disseminated BCG infection has been reported in an infant who received BCG vaccine after having been exposed to infliximab in utero.1,167,194,195,225 Do not administer live vaccines to infants exposed to infliximab products in utero for at least 6 months following birth.1,167,194,195,225

Other Information ⬆ ⬇

Description

Infliximab and its biosimilars are chimeric human-murine immunoglobulin G1 kappa (IgG1 kappa) monoclonal antibodies that have a high affinity for tumor necrosis factor (TNF-α).1,7,20,24,167,194,195 Infliximab products consist of the constant region of human IgG₁ kappa coupled to the variable region of a high-affinity neutralizing murine anti-human TNF antibody.1,7,20,24,167,194,195 Because of the presence of human constant region sequences, the chimeric antibody is less immunogenic, has a longer half-life, and is more potent in binding and neutralizing human TNF compared with the murine antibody.7 194,195

Infliximab is produced by continuous fermentation of a mouse myeloma cell line that has been transfected with cloned DNA coding for the chimeric antibody.1,7,20 The drug is purified from the culture supernatant using column chromatography and undergoes measures to inactivate and remove viruses.1,20

Infliximab products have a high affinity for and bind specifically to soluble and transmembrane forms of TNF thereby inhibiting binding of TNF to cell surface tumor necrosis factor receptors (TNFRs).1,5,7,8,9,25,33,37,39,42,43,50,57,59,167,194,195 By binding to TNF, infliximab and infliximab products neutralize the cytokine.1,167,194,195 Although the exact mechanism(s) of the anti-inflammatory effects of infliximab products in the management of Crohn disease or rheumatoid arthritis remains to be more fully determined, binding and neutralization of TNF appears to be the principal mechanism.1,3,5,7,8,9,25,33,37,38,39,42,43,50,57,59,167 There also is some evidence that infliximab may inhibit expression of TNF by binding soluble TNF attached to TNF receptors present on activated macrophages and T cells.8,25,33,39,42,50,55,59,68

While it is clear that chronic inflammatory processes are not due solely to overexpression of TNF, the regulatory cytokine plays a critical role in the control of the production of other cytokines involved in the pathogenesis of inflammation of Crohn disease and rheumatoid arthritis.25,33,39,42,43,50,52,57,59,60,68,69,97 A variety of physiologic and pathologic functions have been ascribed to TNF-TNF receptor interactions and the effects of TNF include induction of proinflammatory cytokines such as interleukin 1(IL-1), IL-6 and IL-8, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase proteins (C-reactive protein, serum amyloid A [SAA] haptoglobin, fibrinogen) and tissue degrading enzymes produced by synoviocytes and/or chondrocytes.1,33,39,42,43,49,52,55,56,57,58,59,60,68,167 TNF blocks the action of lipoprotein lipase, causing severe cachexia in experimental models of chronic infection.39,42,43,49,52,55,56,57,58,59,60,68 In addition, TNF induces programmed cell death (apoptosis), stimulates the release matrix metalloproteinases from fibroblasts, chondrocytes, and neutrophils, and up-regulates the expression of endothelial adhesion molecules, leading to the migration of leukocytes into extravascular tissues.1,39,42,43,50,56,57,60,68 TNF also mediates pain, fever, shock, and anemia.59,68,69

The complex interactions of paracrine or autocrine pathways mediated by networks of pro- and anti-inflammatory cytokines are implicated in many chronic inflammatory disorders and TNF plays a prominent role in the pathogenesis of Crohn disease, rheumatoid arthritis, multiple sclerosis, systemic vasculitis, allograft rejection, and graft-versus-host disease.8,9,33,39,42,43,50,51,52,55,57,59,96,97 Mucosal biopsies from patients with Crohn disease demonstrate increased TNF concentrations and intestinal mononuclear cell infiltrates in the lamina propria.42,50,69,96,97 Increased concentrations of TNF have been measured in fecal samples from Crohn disease patients and in the joints of patients with rheumatoid arthritis and levels correlated with disease manifestations in these patients.1,5,37,42,43,49,50,51,52,57,59,71,97,167 Increased concentrations of TNF also have been reported in involved tissues and fluids of patients with ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.1,167

The ability of infliximab and its biosimilars to inhibit the functional activity of TNF has been demonstrated in a variety of in vitro bioassays utilizing human fibroblasts, endothelial and epithelial cells, neutrophils, and B and T cells.1,9,25,33,43,167 The relationship of these biological response markers to the mechanism(s) of infliximab products' clinical effects is not known.1,167 In addition, cell lysis by complement or effector cells has been observed in vitro in cells that express transmembrane TNF and are bound by infliximab.8,12,33 In vivo studies have shown that anti-TNF antibodies reduce GI manifestations in a nonhuman primate model of colitis (cotton-top tamarin) and reduce synovitis and joint erosions in a murine model of collagen-induced arthritis.1,25,33,43,53,59,167,194,195

In patients with Crohn disease, infliximab products have been shown to reduce inflammatory cell migration, reduce TNF production in areas of intestinal inflammation, and reduce the proportion of lamina propria mononuclear cells able to express TNF and interferon.1,4,50,51,69,167,194,195

In patients with rheumatoid arthritis, infliximab products reduce infiltration of inflammatory cells into inflamed areas of the joint and downregulate expression of molecules that mediate cellular adhesion (E-selectin, intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]), chemoattraction (IL-8 and monocyte chemotactic protein [MCP-1]), and tissue degradation (MMP 1 and 3).1,25,33,37,39,42,43,49,50,52,53,54,56,57,60,61,167,194,195 Infliximab also has been shown to inhibit pannus neoangiogenesis and proliferation through down-regulation of vascular endothelial growth factor (VEGF).19,53,54,57,68 Results of studies in transgenic mice that develop polyarthritis as the result of constitutive expression of TNF indicate that infliximab products can prevent such disease in these mice and, if administered after disease onset, allow eroded joints to heal.1,9,25,33,37,43,50,167,194,195 There is evidence that infliximab can prevent or inhibit progression of structural damage in patients with rheumatoid arthritis.1,14,15

In patients with Crohn disease or rheumatoid arthritis, therapy with infliximab products may result in decreases in proinflammatory cytokines (IL-1, IL-6) and decreases in systemic measures of inflammation, including C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR).1,4,5,6,37,38,51,58,60,69,167 Peripheral blood lymphocytes from patients treated with infliximab products exhibit a normal proliferative response to in vitro mitogenic stimulation and lymphocyte counts are not decreased in patients who receive the drugs.1,167,194,195

In patients with psoriatic arthritis, therapy with infliximab products results in a reduction in the number of T-cells and blood vessels in the synovium and psoriatic skin lesions and a reduction of macrophages in the synovium.1,167,194,195 In patients with plaque psoriasis, therapy with infliximab products may reduce the epidermal thickness and infiltration of inflammatory cells.1,167,194,195

Pharmacokinetic similarity between infliximab and its biosimilars has been demonstrated, and FDA considers that the pharmacokinetic data provide support for a totality-of-evidence determination of biosimilarity for infliximab-abda, infliximab-axxq, and infliximab-dyyb.168,174,176,177,188,193,223,224

Data from adults who received single IV infusions of 1-20 mg/kg of infliximab indicate a predictable and linear relationship between the dose administered and the maximum serum concentration and AUC.1,18,39,41,42 In one study in adults with rheumatoid arthritis who received single 5-, 10-, or 20-mg/kg doses of infliximab given by IV infusion over 2 hours, peak serum concentrations were achieved 1-4 hours after the start of the infusion; serum concentrations of the drug then decreased exponentially from day 3 through week 12 and were still detectable in most patients at week 10.41 Systemic accumulation of infliximab does not appear to occur in adults receiving multiple doses of the drug given by IV infusion once every 4 or 8 weeks following an initial 3-dose induction regimen (doses at 0, 2, and 6 weeks).1,38,39,41 Distribution of infliximab into body tissues and fluids, including joints, has not been characterized.39 The volume of distribution of infliximab at steady state is independent of dose, indicating that the drug is distributed principally within the vascular compartment.1,39 The terminal elimination half-life of infliximab in adults with Crohn disease, rheumatoid arthritis, or plaque psoriasis has been reported to be about 8-12 days.1,14,41 After a single subcutaneous dose of infliximab-dyyb 120 mg in healthy subjects, the median time to maxium serum concentration was 7 days; the mean half-life was 332 hours.225

The metabolic fate of infliximab has not been determined to date, but the drug may be eliminated by the reticuloendothelial system.47 Infliximab is not metabolized by hepatic cytochrome P-450 (CYP) enzymes.39 While differences in clearance of infliximab have not been observed in patient subgroups defined by age, weight, or gender, clearance of infliximab is increased in patients who have developed antibodies to the drug.1 Whether renal or hepatic impairment affects infliximab clearance has not been determined.1

Advice to Patients

Advise patients or their caregivers about the potential benefits and risks of receiving infliximab products.1,167,194,195,225 Provide a copy of the manufacturer's patient information (Medication Guide) for infliximab products to all patients or their caregivers prior to each infusion session.1,167,194,195
Risk of increased susceptibility to infection.1,167,194,195,225 Inform patients or their caregivers to seek immediate medical attention if signs and symptoms suggestive of infection (e.g., fever; fatigue; cough; warm, red, or painful skin; sores on the body) develop.1,167,194,195,225
Risk of malignancies, including lymphoma, with use of TNF blocking agents in children, adolescents, and young adults.1,167,194,195 225 Advise patients to promptly inform clinicians if signs and symptoms of malignancies occur (e.g., unexplained weight loss; fatigue; abdominal pain; persistent fever; night sweats; easy bruising or bleeding; swollen lymph nodes in the neck, underarm, or groin; hepatomegaly or splenomegaly).154,160
Inform patients or their caregivers to immediately notify their clinician if manifestations of liver dysfunction (e.g., jaundice, dark brown urine, right-sided abdominal pain, fever, fatigue) occur.1,167,194,195,225
Advise patients or their caregivers to seek immediate medical attention if any new or worsening symptoms of heart failure occur.1,167,194,195,225
Advise patients or their caregivers to inform their clinician if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever).1,167,194,195,225
Advise the patient or their caregivers to seek immediate medical care if they develop symptoms of serious hypersensitivity reactions,1,167,194,195,225
Advise the patient or their caregivers to seek immediate medical care if they develop symptoms of cardiovascular and cerebrovascular reactions during and within 24 hours of the infliximab infusion.1,167,194,195
Advise the patient or their caregivers to seek medical care if they develop signs or symptoms of neurologic reactions.1,167,194,195,225
Advise patients or their caregivers of the importance to avoid receiving live vaccines or therapeutic infectious agents.1,167,194,195,225 For postpartum women who received infliximab products during pregnancy, inform the infant's clinician of this use since alteration of the infant's vaccination schedule may be indicated.1,167,194,195
Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1,167,194,195,225
Advise patients or their caregivers to inform their healthcare provider about all concomitant medications, including prescription medicine, over the counter drugs, vitamins, and herbal products.1,167,194,195,225
Inform patients or their caregivers of other important precautionary information.1,167,194,195,225

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

inFLIXimab

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	100 mg	Remicade ®	Janssen

inFLIXimab-abda (biosimilar)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	100 mg	Renflexis ®	Organon

inFLIXimab-axxq (biosimilar)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	100 mg	Avsola ®	Amgen

inFLIXimab-dyyb (biosimilar)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	100 mg	Inflectra ®	Pfizer
	For subcutaneous injection	120 mg/mL	Zymfentra ® (available as single-dose prefilled syringe, single-dose prefilled syringe with needle shield, and single-dose prefilled pen)

AHFS^® Drug Information. © Copyright, 1959-2024, Selected Revisions May 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

1. Janssen Biotech, Inc. REMICADE (infliximab) for IV injection prescribing information. Horsham, PA; 2021 Oct.

3. Van Hogezand RA, Verspaget HW. The future role of anti-tumour necrosis factor-α products in the treatment of Crohn's disease. Drugs . 1998; 56:299-305. [PubMed 9777308]

4. D'Haens G, van Deventer S, van Hogezand R et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European Multicenter Trial. Gastroenterology . 1999; 116:1029-34. [PubMed 10220494]

5. Targan SR, Hanauer SB, Van Deventer SJH. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease. N Engl J Med . 1997; 337:1029-35. [PubMed 9321530]

6. van Dullemen HM, van Deventer SJH, Hommes DW et al. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology . 1995;109:129-35. [PubMed 7797011]

7. Knight DM, Trinh H, Le Junming L et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol . 1993; 30:1443-53. [PubMed 8232330]

8. Scallon BJ, Moore MA, Trinh H et al. Chimeric anti-TNF-α monoclonal antibody cA2 binds recombinant transmembrane TNF-α and activates immune effector functions. Cytokine .1995;7:251-9.

9. Siegel SA, Shealy DJ, Nakada MT et al. The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine . 1995;7:15-25. [PubMed 7538333]

10. Mouser JF, Hyams JS. Infliximab: a novel chimeric monoclonal antibody for the treatment of Crohn's disease. Clin Ther . 1999;21:932-42. [PubMed 10440618]

12. Hochberg MC, Chang RW, Dwosh I et al. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum . 1992; 35:498-502. [PubMed 1575785]

13. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum . 1995; 38:727-35. [PubMed 7779114]

14. Maini R, St Clair EW, Breedveld F et al. Infliximab (chimeric anti-tumor necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. Lancet . 1999; 354:1932-9. [PubMed 10622295]

15. Lipsky PE, van der Heijde DM, St Clair EW et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med . 2000; 343:1594-1602. [PubMed 11096166]

17. Antoni C; Kalden JR. Combination therapy of the chimeric monoclonal anti-tumor necrosis factor α antibody (infliximab) with methotrexate in patients with rheumatoid arthritis. Clin Exp Rheumatol . 1999. 17(Suppl 18):S73-7.

18. Maini RN, Breedveld FC, Kalden JR et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum . 1998;41:1552-63. (IDIS 411263). [PubMed 9751087]

19. Jones RE, Moreland LW. Tumor necrosis factor inhibitors for rheumatoid arthritis. Bull Rheum Dis . 1999; 48:1-4. [PubMed 10408141]

20. Elliot MJ, Maini RN, Feldmann M et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor α. Arthritis Rheum . 1993; 36:1681-90. [PubMed 8250987]

21. Elliott MJ, Maini RN, Feldmann M et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis. Lancet . 1994;344:1105-10. [PubMed 7934491]

23. Elliott MJ, Maini RN, Feldmann M et al. Repeated therapy with monoclonal antibody to tumour necrosis factor α (cA2) in patients with rheumatoid arthritis. Lancet . 1994;344:1125-7. [PubMed 7934495]

24. Breedveld FC. Therapeutic monoclonal antibodies. Lancet . 2000; 355:735-40. [PubMed 10703815]

25. Feldman M, Charles P, Taylor P et al. Biological insights from clinical trials with anti-TNF therapy. Sem Immunopathol . 1998; 20:211-28.

28. Hanauer SB. Review article: safety of infliximab in clinical trials. Aliment Pharmacol Ther . 1999;13(Suppl 4):16-22. [PubMed 10597335]

30. Bickston SJ, Lichtenstein GR, Arseneau KO et al. The relationship between infliximab treatment and lymphoma in Crohn's disease. Gastroenterology . 1999;117:1433-7. [PubMed 10579985]

33. Kavanaugh AF. Anti-tumor necrosis factor-α monoclonal antibody therapy for rheumatoid arthritis. Rheum Dis Clin N Am . 1998;24:593-614.

34. Furst DE, Breedveld FC, Kalden JR et al. Building towards a consensus for the use of tumour necrosis factor blocking agents. Ann Rheum Dis . 1999; 58:725-6. [PubMed 10577955]

35. Furst DE, Breedveld FC, Burmester GR et al. Access to disease modifying treatments for rheumatoid arthritis patients. Ann Rheum Dis . 1999; 58(Suppl 1):1129-30.

36. Soykan I, Ertan C, Ozden A. Severe anaphylactic reaction to infliximab: report of a case. Am J Gastroenterol . 2000; 95:2395-6. [PubMed 11007258]

37. Camussi G, Lupia E. The future role of anti-tumour necrosis factor (TNF) products in the treatment of rheumatoid arthritis. Drugs . 1998;55:613-20. [PubMed 9585859]

38. Rutgeerts P, D'Haens G, Targan S et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology . 1999;117:761-9. [PubMed 10500056]

39. Markham A, Lamb HM. Infliximab: a review of its use in the management of rheumatoid arthritis. Drugs . 2000;59:1341-59. [PubMed 10882166]

40. McCloskey RV. Dear doctor letter regarding new prescribing information for infliximab. Malvern, PA: Centocor Inc; 1998 Nov 10.

41. Kavanaugh A, St. Clair EW, McCune WJ et al. Chimeric anti-tumor necrosis factor-α monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy. J Rheumatol . 2000; 27:841-50. [PubMed 10782805]

42. Feldman M, Elliott MJ, Woody JN. Anti-tumor necrosis factor-α therapy of rheumatoid arthritis. Advan Immunol . 1997; 64:283-350.

43. Miani RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Ann Rev Med . 2000;51:207-29. [PubMed 10774461]

44. Furst DE, Keystone E, Maini RN et al. Recapitulation of the round-table discussion—assessing the role of anti-tumour necrosis factor therapy in the treatment of rheumatoid arthritis. Rheumatology (Oxford) . 1999; 38(Suppl 2):50-3. [PubMed 10646494]

47. Reviewers' comments (personal observations).

49. Chu CQ, Field M, Feldmann M et al Localization of tumor necrosis factor α in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum . 1991; 34:1125-32.

50. Van Deveneter SJH. Review article: targeting TNFα as a key cytokine in the inflammatory processes of Crohn's disease—the mechanisms of action of infliximab. Aliment Pharmacol Ther . 1999; 13(Suppl 4):3-8.

51. Rutgeerts PJ. Review article: efficacy of infliximab in Crohn's disease—induction and maintenance of remission. Aliment Pharmacol Ther . 1999;13(Suppl 4):9-15. [PubMed 10597334]

52. Tak PP, Taylor PC, Breedveld FC et al. Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor α monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum . 1996; 39:1077-81. [PubMed 8670314]

53. Paleolog EM, Hunt M, Elliott MJ et al. Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor α antibody in rheumatoid arthritis. Arthritis Rheum . 1996; 39:1082-91. [PubMed 8670315]

54. Paleolog EM, Young S, Stark AC et al. Modulation of anagiogenic vascular endothelial growth factor by tumor necrosis factor α and interleukin-1 in rheumatoid arthritis. Arthritis Rheum . 1998; 41:1258-65. [PubMed 9663484]

55. Charles P, Elliott MJ, Davis D et al. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-α therapy in rheumatoid arthritis. J Immunol . 1999;163:1521-8. [PubMed 10415055]

56. Nakada MT, Tam SH, Woulfe DS et al. Neutralization of TNF by the antibody cA2 reveals differential regulation of adhesion molecule expression on TNF-activated endothelial cells. Cell Adhes Comm . 1998; 5:491-503.

57. Maini RN, Taylor PC, Paleolog E et al. Anti-tumour necrosis factor specific antibody (infliximab) treatment provides insights into the pathophysiology of rheumatoid arthritis. Ann Rheum Dis . 1999;58(Suppl 1):56-60.

58. Gabay C, Kushner I. Acute-phase proteins and other systemic responses in inflammation. N Engl J Med . 1999; 340:448-54. [PubMed 9971870]

59. Fox DA. Cytokine blockade as a new strategy to treat rheumatoid arthritis. Arch Intern Med . 2000; 160: 437-44. [PubMed 10695684]

60. Lorenz HM; Grunke M; Hieronymus T et al. In vivo blockade of tumor necrosis factor-α in patients with rheumatoid arthritis: longterm effects after repeated infusion of chimeric monoclonal antibody cA2. J Rheumatol . 2000; 27:304-10. [PubMed 10685789]

61. Taylor PC, Peters AM, Paleolog E et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor α blockade in patients with rheumatoid arthritis. Arth Rheum . 2000;43:38-47.

64. Present DH, Rutgeerts P, Targan S et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med . 1999; 340:1398-405. [PubMed 10228190]

68. Beutler BA. The role of tumor necrosis factor in health and disease. J Rheumatol . 1999; 26(Suppl 57):16-21.

69. Baert FJ, D'Haens GR, Peeters M et al. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis. Gastroenterology . 1999; 116:22-8. [PubMed 9869598]

71. Braegger CP, Nicholls S, Murch SH et al. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet . 1992;339:89-91. [PubMed 1345871]

72. Centocor Inc, Malvern, PA: Personal communication.

84. Rezaian MM. Do infliximab and methotrexate act synergistically in the treatment of rheumatoid arthritis? Arthritis Rheum . 1999; 42:1779. Letter.

85. Maini RN, Feldmann M, Schaible T. Do infliximab and methotrexate act synergistically in the treatment of rheumatoid arthritis? Arthritis Rheum . 1999; 42:1779-81. Reply.

86. Hyams JS, Markowitz J, Wyllie R. Use of infliximab in the treatment of Crohn's disease in children and adolescents. J Pediatr . 2000; 137:192-6. [PubMed 10931411]

87. Kugathasan S, Werlin SL, Martinez A et al. Prolonged duration of response to infliximab in early but not late pediatric Crohn's disease. Am J Gastroenterol . 2000; 95:3189-94. [PubMed 11095340]

89. Nikolaus S, Raedler A, Kuhbacher T et al. Mechanisms in failure of infliximab for Crohn's disease. Lancet . 2000; 356:1475-9. [PubMed 11081530]

90. Charles PJ, Smeenk RJT, De Jong J et al. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor α. Arthritis Rheumatism . 2000; 43:2383-90. [PubMed 11083258]

92. Puchner TC, Kugathasan S, Kelly KJ et al. Successful desensitization and therapeutic use of infliximab in adult and pediatric Crohn's disease patients with prior anaphylactic reaction. Inflamm Bowel Dis . 2001; 7:34-7. [PubMed 11233658]

93. Hassard PV, Binder SW, Nelson V et al. Anti-tumor necrosis factor monoclonal antibody therapy for gastrointestinal Behcet's disease: a case report. Gastroenterology . 2001; 120:995-9. [PubMed 11231954]

96. Breese EJ, Michie CA, Nicholls SW et al. Tumor necrosis factor α-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology . 1994; 106:1455-66. [PubMed 8194690]

97. MacDonald TT, Hutchings P, Choy MY et al. Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin Exp Immunol . 1990; 81:301-5. [PubMed 2117510]

102. Robertson LP, Hickling P. Treatment of recalcitrant orogenital ulceration of Behcet's syndrome with infliximab. Rheumatology . 2001; 40:473-4. [PubMed 11312390]

103. Elliott MJ, Woo P, Charles P et al. Suppression of fever and the acute-phase response in a patient with juvenile chronic arthritis treated with monoclonal antibody to tumour necrosis factor-α (cA2). Br J Rheumatol . 1997; 36:589-93. [PubMed 9189062]

104. Gerloni V, Pontikaki I, Desiati F et al. Infliximab in the treatment of persistently active refractory juvenile idiopathic (chronic) arthritis: a short-term pilot study. American College of Rheumatology 64th Annual Scientific Meeting, Philadelphia, PA, Oct 30 to Nov 2 2000. Abstract No. 1139.

115. Robertson LP, Hickling P. Treatment of recalcitrant orogenital ulceration of Behcet's syndrome with infliximab. Rheumatology . 2001; 40:473-4. [PubMed 11312390]

116. Sfikakis PP, Theodossiadis PG, Katsiari CG et al. Effect of infliximab on sight-threatening panuveitis in Behcet's disease. Lancet . 2001; 358:295-6. [PubMed 11498218]

118. Keane J, Gershon S, Wise RP et al. Tuberculosis associated with infliximab a tumor necrosis factor α neutralizing agent. N Engl J Med . 2001; 345:1098-104. [PubMed 11596589]

123. Keane J, Gershon SK, Braun MM. Tuberculosis and treatment with infliximab. N Engl J Med . 2002; 346:625-6.

128. Lankarani KB. Mortality associated with infliximab. J Clin Gastroenterol . 2001; 33:255-6. [PubMed 11500623]

135. de' Clari F, Salani, I, Safwan E, et al. Sudden death in a patient without heart failure after a single infusion of 200 mg infliximab: does TNF-α have protective effects on the failing heart, or does infliximab have direct harmful cardiovascular effects? Circulation . 2002; 105:183e. From AHA web site. [Web]

136. Hanauer SB, Feagan BG, Lichtenstein GR et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet . 2002; 359:1541-49. [PubMed 12047962]

137. Braun J, Brandt J, Listing J et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet . 2002; 359:1187-93. [PubMed 11955536]

139. Chung ES, Packer M, Lo KH et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-(alpha), in patients with moderate-to-sever heart failure: results of the anti-TNF therapy against congestive heart failure (ATTCH) trial. Circulation . 2003. From AHA web site [Web]

140. Sands BE, Anderson FH, Bernstein CN et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med . 2004; 350:876-85. [PubMed 14985485]

141. Fiocchi C. Closing fistulas in Crohn's disease — Should the accent be on maintenance or safety? N Engl J Med . 2004; 350:934-6. Editorial.

142. Panaccione R, Fedorak RN, Aumais G et al. Canadian Association of Gastroenterology clinical practice guidelines: the use of infliximab in Crohn's disease. Can J Gastroenterol . 2004; 18:503-8. [PubMed 15372114]

145. St Clair EW, van der Heijde DM, Smolen JS et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum . 2004; 50:3432-43. [PubMed 15529377]

146. Wallis RS, Broder MS, Wong JY et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis . 2004; 38:1261-5. [PubMed 15127338]

147. Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med . 2005; 353:2462-76. [PubMed 16339095]

153. Ruperto N, Lovell DJ, Cuttica R et al. A randomized, placebo-controlled trial of infliximab plus methotrexate for treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum . 2007; 56:3096-106. [PubMed 17763439]

154. Food and Drug Administration, Center for Drug Evaluation and Research. Information for healthcare professionals: Tumor necrosis factor (TNF) blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi). FDA alert. Rockville MD; 2009 Aug 4. Available from FDA website. Accessed 2021 Sep 20. [Web]

155. Food and Drug Administration, Center for Drug Evaluation and Research. FDA alert: Information for healthcare professionals Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab). Rockville MD: Food and Drug Administration; 2008 Sep 4. Available from FDA website. Accessed 2021 Sep 20. [Web]

157. Rennard SI, Fogarty C, Kelsen S et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med . 2007; 175:926-34. [PubMed 17290043]

159. Food and Drug Administration. FDA drug safety communication: Drug labels for the tumor necrosis factor-alpha (TNFα) blockers now include warnings about infection with Legionella and Listeria bacteria. Rockville, MD; 2011 Sep 7. From FDA website. Accessed 2021 Sep 20. [Web]

160. Food and Drug Administration. FDA drug safety communication: Safety review update on reports of hepatosplenic T-cell lymphoma in adolescents and young adults receiving tumor necrosis factor (TNF) blockers, azathioprine and/or mercaptopurine. Rockville, MD; 2011 Apr 14. From FDA website. Accessed 2021 Sep 20. [Web]

167. Pfizer, Inc. Inflectra^® (infliximab-dyyb) for IV injection prescribing information. New York, NY; 2021 Jun.

168. Food and Drug Administration, Center for Drug Evaluation and Research. Application number 125544Orig1s000: Summary review. From FDA website. [Web]

169. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Considerations in demonstrating interchangeability with a reference product guidance for industry. Guidance for industry. From FDA website. Accessed 2021 Nov. [Web]

170. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. Guidance for industry. From FDA website. Accessed 2021 Nov. [Web]

171. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. From FDA website. Accessed 2021 Nov. [Web]

172. Food and Drug Administration. FDA Purple Book Database of Licensed Biological Products. Rockville, MD. From FDA website. Accessed 2021 Nov 8. [Web]

173. Yoo DH, Prodanovic N, Jaworski J et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis . 2017; 76:355-363. [PubMed 27130908]

174. Yoo DH, Racewicz A, Brzezicki J et al. A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results from the PLANETRA study. Arthritis Res Ther . 2016; 18:82. [PubMed 27038608]

175. Park W, Hrycaj P, Jeka S et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis . 2013; 72:1605-12. [PubMed 23687259]

176. Yoo DH, Hrycaj P, Miranda P et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis . 2013; 72:1613-20. [PubMed 23687260]

177. Park W, Yoo DH, Jaworski J et al. Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study. Arthritis Res Ther . 2016; 18:25. [PubMed 26795209]

188. Park W, Lee SJ, Yun J et al. Comparison of the pharmacokinetics and safety of three formulations of infliximab (CT-P13, EU-approved reference infliximab and the US-licensed reference infliximab) in healthy subjects: a randomized, double-blind, three-arm, parallel-group, single-dose, Phase I study. Expert Rev Clin Immunol . 2015; 11 Suppl 1:S25-31. [PubMed 26395834]

190. Food and Drug Administration, Center for Drug Evaluation and Research. Application number 125544Orig1s000: Chemistry review(s). From FDA website. [Web]

191. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2021 Nov 26. [Web]

192. Park W, Yoo DH, Miranda P et al. Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis . 2017; 76:346-354. [PubMed 27117698]

193. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125544Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]

194. Organon LLC. Renflexis^® (infliximab-abda) for IV injection prescribing information. Jersey City, NJ; 2022 Jan

195. Amgen, Inc. Avsola^® (infliximab-axxq) for IV injection prescribing information. Thousand Oaks, CA; 2021 Sep.

196. Genovese MC, Sanchez-Burson J, Oh M, et al. Comparative clinical efficacy and safety of the proposed biosimilar ABP 710 with infliximab reference product in patients with rheumatoid arthritis. Arthritis Res Ther. 2020;22(1):60.

197. Ye BD, Pesegova M, Alexeeva O, et al. Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study. Lancet. 2019;393(10182):1699-1707.

198. Choe JY, Prodanovic N, Niebrzydowski J, et al. A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2017;76(1):58-64.

199. Smolen JS, Choe JY, Prodanovic N, et al. Comparing biosimilar SB2 with reference infliximab after 54 weeks of a double-blind trial: clinical, structural and safety results. Rheumatology (Oxford). 2017;56(10):1771-1779.

200. Smolen JS, Choe JY, Prodanovic N, et al. Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: results of a randomised, double-blind, phase III transition study. Ann Rheum Dis. 2018;77(2):234-240.

201. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology. 2007;132(3):863-1166.

202. Hyams J, Walters TD, Crandall W, et al. Safety and efficacy of maintenance infliximab therapy for moderate-to-severe Crohn's disease in children: REACH open-label extension. Curr Med Res Opin. 2011;27(3):651-662.

203. Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 2012;10(4):391-9.e1.

204. van der Heijde D, Dijkmans B, Geusens P, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum. 2005;52(2):582-591.

205. Braun J, Deodhar A, Dijkmans B, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis over a two-year period. Arthritis Rheum. 2008;59(9):1270-1278.

206. Braun J, Baraliakos X, Listing J, et al. Persistent clinical efficacy and safety of anti-tumour necrosis factor alpha therapy with infliximab in patients with ankylosing spondylitis over 5 years: evidence for different types of response. Ann Rheum Dis. 2008;67(3):340-345.

207. Giardina AR, Ferrante A, Ciccia F, et al. A 2-year comparative open label randomized study of efficacy and safety of etanercept and infliximab in patients with ankylosing spondylitis. Rheumatol Int. 2010;30(11):1437-1440.

208. Antoni C, Krueger GG, de Vlam K, et al. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis. 2005;64(8):1150-1157.

209. Kavanaugh A, Krueger GG, Beutler A, et al. Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial. Ann Rheum Dis. 2007;66(4):498-505.

210. van der Heijde D, Kavanaugh A, Gladman DD, et al. Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis through one year of treatment: Results from the induction and maintenance psoriatic arthritis clinical trial 2. Arthritis Rheum. 2007;56(8):2698-2707.

211. Kavanaugh A, Antoni C, Krueger GG, et al. Infliximab improves health related quality of life and physical function in patients with psoriatic arthritis. Ann Rheum Dis. 2006;65(4):471-477.

212. Antoni CE, Kavanaugh A, Kirkham B, et al. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum. 2005;52(4):1227-1236.

213. Antoni CE, Kavanaugh A, van der Heijde D, et al. Two-year efficacy and safety of infliximab treatment in patients with active psoriatic arthritis: findings of the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT). J Rheumatol. 2008;35(5):869-876.

214. Kavanaugh A, Antoni CE, Gladman D, et al. The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): results of radiographic analyses after 1 year. Ann Rheum Dis. 2006;65(8):1038-1043.

215. Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet. 2005;366(9494):1367-1374.

216. Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2007;56(1):31.e1-31.e315.

217. Gottlieb AB, Evans R, Li S, et al. Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2004;51(4):534-542.

218. Reich K, Nestle FO, Papp K, et al. Improvement in quality of life with infliximab induction and maintenance therapy in patients with moderate-to-severe psoriasis: a randomized controlled trial. Br J Dermatol. 2006;154(6):1161-1168.

219. Feldman SR, Gordon KB, Bala M, et al. Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: a double-blind placebo-controlled trial. Br J Dermatol. 2005;152(5):954-960.

220. de Vries AC, Thio HB, de Kort WJ, et al. A prospective randomized controlled trial comparing infliximab and etanercept in patients with moderate-to-severe chronic plaque-type psoriasis: the Psoriasis Infliximab vs. Etanercept Comparison Evaluation (PIECE) study. Br J Dermatol. 2017;176(3):624-633.

221. Brooklyn TN, Dunnill MG, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut. 2006;55(4):505-509.

222. Institute for Safe Medication Practices. List of confused drug names. 2019 Feb 28. Accessed 2021 Dec 1.

223. Food and Drug Administration, Center for Drug Evaluation and Research. Application number 761054Orig1s000: Summary review. From FDA website.

224. Food and Drug Administration, Center for Drug Evaluation and Research. Application number 761086Orig1s000: Multi-discipline review. From FDA website.

225. Celltrion, Inc. Zymfentra^® (infliximab-dyyb) injection, for subcutaneous use prescribing information. Jersey City, NJ; 2023 Oct.

2000. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical guideline: management of Crohn disease in adults. Am J Gastroenterol. 2018;113(4):481-517.

2001. Feuerstein JD, Ho EY, Shmidt E, et al. AGA clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn disease. Gastroenterology. 2021;160(7):2496-2508.

2002. Nguyen GC, Loftus EV Jr, Hirano I, et al. American Gastroenterological Association Institute guideline on the management of Crohn disease after surgical resection. Gastroenterology. 2017;152(1):271-275.

2003. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021;73(7):924-939.

2004. Ward MM, Deodhar A, Gensler LS, et al. 2019 update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2019;71(10):1599-1613.

2005. Singh JA, Guyatt G, Ogdie A, et al. Special article: 2018 American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic arthritis. Arthritis Rheumatol. 2019;71(1):5-32.

2006. Schoels MM, Aletaha D, Alasti F, Smolen JS. Disease activity in psoriatic arthritis (PsA): defining remission and treatment success using the DAPSA score. Ann Rheum Dis. 2016;75(5):811-818.

2007. Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol. 2019;80(4):1029-1072.

2008. Elmets CA, Korman NJ, Prater EF, et al. Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures. J Am Acad Dermatol. 2021;84(2):432-470.

2009. Menter A, Gelfand JM, Connor C, et al. Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020;82(6):1445-1486.

2010. Menter A, Cordoro KM, Davis DMR, et al. Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis in pediatric patients. J Am Acad Dermatol. 2020;82(1):161-201.

2011. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019;80(4):1073-1113.

2012. Armstrong AW, Read C. Pathophysiology, clinical presentation, and treatment of psoriasis: a review. JAMA. 2020;323(19):1945-1960.

2015. Fuller MK. Pediatric inflammatory bowel disease: special considerations. Surg Clin North Am. 2019;99(6):1177-1183.

2016. Grover Z, Alex G. Management of inflammatory bowel disease in children: it is time for an individualised approach. J Paediatr Child Health. 2020;56(11):1677-1684.

2017. Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology. 2021;160(5):1570-1583.

2018. Ko CW, Singh S, Feuerstein JD, et al. AGA clinical practice guidelines on the management of mild-to-moderate ulcerative colitis. Gastroenterology. 2019;156(3):748-764.

2019. Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020;158(5):1450-1461.

2020. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114(3):384-413.

section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Uses ⬆ ⬇

Table 1: Infliximab Biosimilar Products and FDA-licensed Indications167,194,195

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

inFLIXimab

inFLIXimab-abda (biosimilar)

inFLIXimab-axxq (biosimilar)

inFLIXimab-dyyb (biosimilar)

Copyright ⬆ ⬇

References ⬆