Summary

• REMICADE has been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions (including anaphylaxis, urticaria, dyspnea, and/or hypotension), have occurred during or within 2 hours of REMICADE infusion.¹
• An infusion reaction was defined in clinical trials as any adverse event (AE) occurring during an infusion or within 1 hour after an infusion. In all the clinical studies, approximately 20% of REMICADE-treated patients experienced an infusion reaction compared with 10% of placebo-treated patients.¹
• Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of REMICADE infusion. Cases of transient visual loss have been reported during or within 2 hours of infusion of REMICADE. Monitor patients during infusion and if serious reaction occurs, discontinue infusion. Further management of reactions should be dictated by signs and symptoms.¹
• Prior to treatment, ensure appropriate personnel and medication are available to treat reactions (eg, hypersensitivity, other reactions) that occur during infusion and shortly after infusion. Prior to infusion with REMICADE, patients may be premedicated with histamine-1 receptor antagonists, histamine-2 receptor antagonists, acetaminophen, and/or corticosteroids.¹
• For mild to moderate reactions during the infusion, consider slowing or stopping the infusion. Upon resolution of these reactions, may reinitiate at a lower infusion rate and/or with histamine-1 receptor antagonists, histamine-2 receptor antagonists, acetaminophen, and/or corticosteroids. Discontinue the infusion if the mild to moderate reactions reoccur.¹
• Discontinue the infusion if severe hypersensitivity reactions occur during the infusion.¹
• Use of concomitant immunosuppressant agents appeared to reduce the frequency of both antibodies to infliximab and infusion reactions.¹
• Several retrospective studies and open-label studies are available in the published literature that discuss the management of infusion-related reactions in patients treated with REMICADE.^2-14

CLINICAL DATA

Retrospective Studies

Yilmaz Topal et al (2021)² conducted a single-center, retrospective review of medical records of pediatric patients evaluating the incidence, features, and management of infusion reactions to various biological drugs, including REMICADE, used for the treatment of inflammatory, neoplastic, and rheumatologic diseases.

Study Design/Methods

• The medical records were reviewed between October 2011 and August 2019, and patients’ characteristics, features and management of the adverse reaction, and changes in the biological drug therapy regimen after the adverse reaction were recorded.

Results

• The study included 211 patients, of whom 23 received REMICADE. Of these 23 patients, 3 (13%) reported hypersensitivity reactions. The patient characteristics, characterization and classification of the reactions, and their management are described in Table: Characteristics of Patients Who Had Hypersensitivity to REMICADE.

Szymanska et al (2021)³ evaluated the effect of corticosteroid therapy as premedication on the incidence of infusion reactions in pediatric patients who received infliximab (REMICADE or biosimilars) for the treatment of inflammatory bowel disease (IBD).

Study Design/Methods

• Data from medical charts were reviewed between 2013 and May 2020.
• Patients were divided into 4 groups based on the use of premedication and the version of infliximab received (REMICADE or biosimilars).
• Infusion reactions were classified as mild (skin changes) or severe (anaphylactic shock).

Results

• Overall, 105 patients were included in the study who received 1276 infusions. Of these, 19 received REMICADE, 70 received REMSIMA, and 16 received FLIXABI.
• All patients in the REMICADE group received premedication.
  • Infusion reactions were reported in 8 patients, including anaphylactic shock (n=3), urticaria (n=2), and erythema (n=3).

Checkley et al (2019)⁴ evaluated the incidence and management of infusion reactions to REMICADE administered in the home or ambulatory infusion suite in patients with Crohn’s disease (CD) or ulcerative colitis (UC).

Study Design/Methods

• A retrospective chart review was conducted of all IBD patients receiving REMICADE in the home setting or ambulatory infusion suite through 1 home infusion company from January 1, 2014 to November 23, 2016.
• All infusions were administered and monitored by a trained nurse.
• Use of premedication (eg, antihistamines, acetaminophen, and/or intravenous steroids) was determined by the referring physician.
• Acute reactions were defined as anything occurring during the infusion or within 24 hours of the infusion.
• Delayed reactions were defined as any reaction occurring greater than 24 hours after the infusion but within 14 days of the infusion.
• Though delayed and acute infusion reactions can be classified according to severity, in this study, the analysis of severity was limited to acute reactions due to the voluntary nature of patient reporting and the difficulty of distinguishing delayed reactions from symptoms of diagnoses.
• The Chi-square test was used to compare rates of infusion reactions between maintenance and induction infusions, gender, and administration site.

Results

• During the study period, 796 patients (69% with CD and 31% with UC) received a total of 5581 REMICADE infusions.
• A total of 105 new patients (13.2%) received an induction infusion during the study period, accounting for 251 infusions (4.5% of all infusions administered).
• A total of 3052 (54.7%) infusions were administered in the patient’s home and 2529 (45.3%) were administered in an ambulatory infusion suite.
• The mean patient age was 36 (range, 6-88) years at the start of the data collection period.
• Patients received a mean of 7 infusions during the study period and a mean REMICADE dose of 531 mg (median, 500 mg).
• The mean REMICADE maintenance interval was 7.1 weeks.
• A total of 109 infusion reactions (2% of all infusions) were noted in 62 patients (7.8% of all patients) Table: Acute and Delayed Infusion Reactions and Proportion for Each Age Range classifies the infusion reactions by age.
  • Of these reactions, 87 (79.8%) infusions were assessed as acute (the majority of which were classified as mild [57.5%] or moderate [31.0%] in severity).
  • A total of 22 (20.2%) infusions were delayed.
  • Ten of the acute reactions were associated with a severe reaction (11.5%, 0.2% of all infusions), and of these, 8 (9.2%, 0.1% of all infusions) resulted in an emergency room visit.

• Table: Type and Frequency of Acute and Delayed Infusion Reactions to REMICADE lists the type and frequency of all acute reactions that occurred in ≥2% of reactions and a comprehensive list of type and frequency of delayed reactions.

• The overall per-infusion incidence of infusion reactions was 2% in CD and 1.9% in UC (Table: Infusion Reactions According to Diagnosis).

• Post-infusion reaction management approaches carried out by the infusion nurse are listed in Table: Management Approaches to Acute Infusion Reactions.

• The infusion reactions that did not receive an intervention were assessed as mild in severity and consisted of either headache, pruritus around the infusion site, and/or flushing; these reactions resolved following the completion of the infusion.
• Resolution of acute infusion reactions was sufficient to allow continuation of the infusion in most cases.
• There were 14 reactions (16.1% of 87 acute infusion reactions; 0.3% of all infusions) in 14 patients in which the infusion was stopped and not continued; 5 of the 14 patients were able to maintain their scheduled treatment plan and completed their next scheduled infusion, while 9 patients did not return for any additional infusions in the home or ambulatory infusion suite.
• Overall, 69.4% (43/62) patients who experienced an infusion reaction returned for their next scheduled infusion in the home or ambulatory infusion suite; of these 43 patients, 30 (69.8%) did not experience any subsequent reactions, 10 patients experienced between 1 and 5 additional reactions. Two patients experienced 10 infusion reactions, and 1 patient experienced 16 infusion reactions.

van Wassenaer et al (2019)⁵ conducted a retrospective chart review to investigate the influence of steroids as premedication on the incidence of acute infusion reactions in pediatric patients with IBD receiving REMICADE.

Study Design/Methods

• A case-control study of patients diagnosed with IBD (CD, UC, or indeterminate IBD) under 18 years and treated with REMICADE between 1998 and 2018 was conducted in 2 tertiary care centers in Amsterdam, The Netherlands.
• Premedication with steroids was part of standard care in one tertiary care center but not the other.
• All patients received REMICADE 5 mg/kg on weeks 0, 2, and 6, and every 8 weeks thereafter, with an infusion time of 2 hours.
• Adjustments on interval and dosage of REMICADE were made by the clinician based on clinical disease activity, REMICADE levels, and presence of antibodies.
• In the premedication group, patients routinely received hydrocortisone (100 mg intravenously [IV] for patients aged ≥5 years, 50 mg IV for patients aged <5 years), 30 minutes before the administration of REMICADE, with a 10-minute infusion time.
• Patients who were treated with steroids as remission-induction therapy for IBD or for concomitant autoimmune hepatitis while on REMICADE therapy did not receive additional hydrocortisone.
• Acute infusion reactions were divided into mild or severe reactions and in grade 1/2/3/4 for detailed exploration:
  • Mild: self-limiting or disappears when infusion is slowed down or paused
  • Severe: discontinuation of the infusion is required
  • Grade 1: no interventions necessary, only observation
  • Grade 2: interruption of infusion and/or oral medication required
  • Grade 3: IV medication is necessary
  • Grade 4: infusion is required to stop
• Comedication was defined as using an immunomodulator (any thiopurine or methotrexate [MTX]) started within 1 month after the start of REMICADE therapy and continued for at least 6 months.

Results

• A total of 226 patients (91 of whom were premedicated and 135 of whom were not premedicated) received a total of 3433 infusions (mean number of infusions per patient was 15 [standard deviation (SD) 12.3, range 1-75]).
• In the premedication group, a total of 15 infusion reactions (1.4% of all infusions) occurred in 13 (14.3%) patients, compared with a total of 34 infusion reactions (1.4% of all infusions) in 23 (17.0%) patients in the non-premedication group.
  • Three severe infusion reactions were reported (all in the premedication group), and four grade 4 infusion reactions were reported, of which 3 were in the premedication group.
  • Severe reactions included dyspnea and angioedema.
  • Other reported infusion reactions were headache (n=7); nausea and/or vomiting (n=6); rash (n=6); chest pain (n=4); dizziness (n=2); and chills, pruritus, edema, and temperature rise (n=1).
  • The first (n=36), second (n=11), and third (n=2) infusion reactions occurred on average at the 6th (SD 5.72, range 1-24), 7th (SD 5.52, range 2-18), and 6th (SD 3.54, range 3-8) infusions, respectively.
• In the non-premedication group, 9 (6.7%) patients eventually did receive premedication because of previous infusion reactions.
  • Four of these did not experience a subsequent infusion reaction and 3 did.
  • In 2 patients, documentation was too limited to tell.
• The number of patients developing any infusion reaction was not statistically different between the premedication and non-premedication groups (13/91 vs 23/135, P=0.58).
• When correcting for comedication usage, the odds ratio of developing an infusion reaction when using premedication was 1.06 (95% confidence interval [CI], 0.49-2.27, P=0.89), and the odds ratio of developing a grade 3 or 4 infusion reaction when using premedication was 0.90 (95% CI, 0.24-3.39, P=0.88).

Gold et al (2017)⁶ conducted a single center retrospective chart review to evaluate the efficacy of premedications in reducing REMICADE related infusion reactions in patients with IBD.

Study Design/Methods

• For each REMICADE infusion, the type, dose, and route of administration of premedication were recorded along with all reactions experienced.

Results

• A total of 473 patients with a total of 5620 REMICADE infusions were reviewed.
• Among the patients, 57.7% had CD and 41.4% had UC.
• All premedications were administered immediately prior to the infusions and accounted for 78.0% of all infusions. The premedications included IV fluids (250 cc normal saline), IV/oral (PO) diphenhydramine, or IV hydrocortisone.
• A total of 94 infusion reactions were recorded, with an infusion reaction rate of 1.67%.
• See Table: Infusion Reaction Rates by Premedication Protocol.
• Premedication use was not associated with fewer infusion reactions (P=0.356). None of the premedications used demonstrated a significant reduction in the number of reactions compared to no premedication use.
• There was no difference in the rate of reactions between those who received PO diphenhydramine as compared to IV diphenhydramine (P=0.380).
• The dose of oral or IV diphenhydramine nor the dose of hydrocortisone was associated with a decrease in reactions (P=0.453, P=0.104, P=0.543, respectively).

Keshavarzian et al (2007)⁷ conducted a multicenter, retrospective chart review study of patients with CD to determine infusion reaction management practices, identify common reactions, and determine REMICADE treatment persistence in the presence of infusion reactions.

Study Design/Methods

• A total of 447 patient charts of patients <90 years of age (mean age 40.9 years) were reviewed from 9 gastroenterology centers.
• Infusion reactions, defined as infusion-related AEs occurring during or within 1 hour post infusion, were reported as 1 or more of the following symptoms: infusion syndrome, flushing, headache, urticaria, nausea/vomiting, pruritis, chest pain, dypsnea, hypertension, hypotension, chills, allergic reaction, anaphylaxis, rash, tachycardia, angioedema, abdominal pain, back pain, bronchospasm, face edema, fever, or throat tightness.

Results

• A total of 6469 infusions of REMICADE were administered in up to 5 years of follow-up.
• Of the 6468 evaluable infusions, 3.5% resulted in infusion reactions (n=226) and less than 0.1% (n=2) of the infusions resulted in a serious infusion reaction (Table: Infusion Reaction Rates by Pretreatment Protocol).
• When assessed on a per-patient basis, infusion reactions occurred in 19.7% (n=88) of patients and 0.4% (n=2) were classified as serious infusion reactions.
• The most commonly used pretreatment regimen was acetaminophen (3298/3625 infusions).

• Seventy-two percent of patients received concomitant immunosuppressive therapy.
• On a per-infusion basis, the number of infusion reactions reported in patients who received concomitant immunosuppressive therapy was significantly lower than the number of infusion reactions that occurred in patients not receiving concomitant immunosuppressive therapy (2.3% of infusions [91/4036] vs 5.6% of infusions [135/2432], P<0.001).
• A total of 142 patients (31.8%) discontinued therapy with REMICADE. AEs were responsible for 8.5% (n=38) of the discontinuations of therapy.
• A smaller proportion of patients discontinued due to lack of efficacy (6.5% [n=29]) or because of an infusion reaction (4.3% [n=19]). Sixty-three patients (14.1%) were lost to follow-up or moved and their continued REMICADE treatment status was unknown.

Augustsson et al (2007)⁸ investigated the role of glucocorticoid use on infusion-related reactions in patients treated with REMICADE for rheumatoid arthritis (RA).

Study Design/Methods

• Forty-three patients experiencing immediate-type infusion reactions, identified from the STURE registry, were compared with the entire cohort (n=673) and to a nested matched control group (n=43).
• An immediate-type infusion reaction was defined as an anaphylactic/anaphylactoid reaction and/or urticaria and itching that resulted in discontinuation of REMICADE treatment.
• The percentage of REMICADE infusions associated with infusion reactions significantly decreased from the year 2000 (9/152, 5.92%) to the year 2003 (5/438, 1.14%; P=0.0024).
• The most common symptoms were shortness of breath and flushing/urticaria. All patients who experienced an infusion reaction were administered prophylactic treatment prior to their next REMICADE infusion.

Results

• In the cohort study, 50% (323/643) of patients received daily low-dose glucocorticoids at baseline.
• Of these patients, 15 patients experienced an infusion reaction compared to 28 patients not receiving glucocorticoids (P=0.057).
• A 46.4% risk reduction (95% CI, 3.1%-74.4%) was observed with oral prednisolone treatment.
• In the matched study comparison, 35% (15/43) of patients experiencing infusion reactions had received glucocorticoids, compared with 64% (28/43) of controls (P=0.017).

Jacobstein et al (2005)⁹ evaluated the potential effects of premedication on infusion reactions in pediatric patients receiving REMICADE. Investigators established a registry to collect and retrospectively review demographic, clinical, and epidemiologic data from pediatric patients with IBD.

Study Design/Methods

• Subjects <18 years of age that were diagnosed with any form of IBD (ie, UC, CD, and indeterminate colitis) were eligible for enrollment into the registry.
• During the enrollment period from January 2000 through May 2003, a total of 243 patients were enrolled and were administered 1652 REMICADE infusions.
• The mean number of REMICADE infusions administered per patient was 6.8 (range, 1-34 infusions).

Results

• Thirty-three of the 243 patients that received REMICADE were premedicated with antipyretics, antihistamines, or corticosteroids prior to the first infusion reaction, whereas 210 patients did not receive premedication until the occurrence of the first infusion reaction.
• Twelve of the 33 (86.4%) patients who received premedication before the first infusion reaction had an infusion reaction vs 28 of the 210 (13%) patients who were not premedicated before the first infusion (P<0.01).
• Of the 210 patients who did not receive premedication before the first infusion reaction, 182 (87%) did not experience an infusion reaction.
• Of the 28 patients who did have an infusion reaction, 12 continued therapy without premedication, 10 received premedication prior to each subsequent infusion, and 6 did not continue infusion therapy.
• The most common infusion reaction symptoms included chest tightness, shortness of breath, and cough.

Cheifetz et al (2003)¹⁰ evaluated the incidence and management of acute infusion reactions to REMICADE in a retrospective study of 165 patients with CD who had received a total of 479 REMICADE infusions.

• Most acute infusion reactions were mild to moderate in severity, with only 1% of infusions being associated with an acute severe reaction. The authors concluded that the overall incidence of infusion reactions to REMICADE was low, occurring in 10% of patients, or 6% of infusions.
• As part of their study, the investigators developed treatment protocols for the management of mild, moderate, and severe reactions, as well as prophylaxis protocols for subsequent REMICADE infusions.
• The use of these treatment protocols resulted in rapid symptom resolution in all patients, and patients who had experienced an initial mild or moderate acute infusion reaction were able to receive additional REMICADE infusions.
• Of the 4 patients with reactions that were classified as severe, 3 patients were retreated with REMICADE.
• Two patients had no further problems; 1 patient had a second severe acute reaction, and no further infusions were attempted.

Open-Label Studies

Choquette et al (2015)¹¹ evaluated the incidence and management of infusion reactions to REMICADE in a multicenter, prospective, Canadian observational registry (RemiTRAC Infusion).

Study Design/Methods

• A total of 1632 patients were enrolled from August 2005 to October 2012. There were 24,852 infusions recorded.
• Patients were treated for RA (40.1%), CD (18.8%), ankylosing spondylitis (17.5%), plaque psoriasis (9.4%), UC (6.7%), or psoriatic arthritis (5.5%).
• The mean number of REMICADE infusions administered per patient was 15.3.
• A total of 52.3% of patients did not receive premedication while 33.9% received acetaminophen, 22.8% received antihistamines, and 22.5% received steroids.

Results

• A total of 201 (12.3%) patients reported ≥1 infusion reaction.
• Three hundred twenty-two infusions were associated with an infusion reaction (1.3%), and most were mild to moderate (95%).
• Infusion reactions included: pruritus (19.9%), flushing (9.9%), dyspnea (6.2%), nausea (4.7%), urticaria (4.7%), headache (4.0%), hypertension (3.7%), rash (3.4%), chest discomfort (3.1%), chest pain (2.8%), dizziness (2.8%), back pain (2.5%), muscle spasms (2.5%), blood pressure increased (2.2%), generalized pruritus (2.2%), and other, with an incidence of <2% (25.5%).
• Medication management of infusion reactions included: antihistamines (54.97%), steroids (22.05%), oxygen (4.97%), and epinephrine (0.62%).
• Other management of infusion reactions included: saline infusion (70.81%), stopping infusion (66.77%), increased monitoring (55.28%), restarting infusion (50.62%), slowing infusion (36.65%), reincreasing infusion rate (31.06%), emergency medical services activation (0.93%), and other (0.31%).

Lequerré et al (2006)¹² evaluated the prevalence of acute infusion reactions in a total of 203 patients with RA or spondyloarthritis (SpA) treated with REMICADE.

Study Design/Methods

• Recommendations for management of the infusion reactions were devised according to the type and the severity of the reaction. Infusion reactions were classified into 2 groups:
  • Group A (hypertension, pruritus, erythema and/or sudden flush, nausea and/or vomiting, lumbar pain and/or myalgia, shivers, and/or fever)
  • Group B (state of shock, larynx irritation and/or labial edema, Quincke's edema, urticaria, dyspnea, hypotension, and distress)
• Patients received REMICADE 3 mg/kg (RA) or 5 mg/kg (SpA) administered over a 2-hour period and at 0, 2, 6, 14, and every 2 months thereafter.
• The initial infusion rate was 120 mL/hour.
• Precise recommendations were formulated to manage symptoms of the infusion reaction.
  • The infusion rate was reduced to 60-80 mL/hour if a patient experienced sudden flush, fever, pruritus, nausea, or increased blood pressure.
  • The infusion was interrupted and another venous access was established if the patient experienced Quincke's edema, facial edema, urticaria, throat irritation, thoracic pain, dypsnea, state of shock, or hypotension.
  • Symptomatic treatment (antihistamine or acetaminophen or calcium inhibitor) was prescribed for patients with group A symptoms that did not improve with a reduction in infusion rate.
  • Patients with group B symptoms (excluding Quincke’s edema, hypotension, and shock) were treated with methylprednisolone (1 mg/kg) and/or dexchlorpheniramine and premedicated with an antihistamine (cetirizine) 2 days prior to and 3 days following a REMICADE infusion.
  • The infusion was stopped and appropriate treatment with methylprednisolone, oxygen, or cardiopulmonary resuscitation was initiated in the event of Quincke's edema.
  • Infusions were continued at a lower infusion rate with symptomatic improvement but were halted if no improvement or aggravation of symptoms occurred.

Results

• Infusion reactions were reported in 13.8% (28/203) of patients, including 14.2% of patients with RA and 15.9% of patients with SpA.
• There were 23 acute reactions and 5 delayed reactions.
• Eight patients discontinued REMICADE therapy due to occurrence of acute infusion reaction prior to application of the symptomatic management recommendations.
• Group A symptoms occurred in 8 patients.
  • In this group, a reduction in infusion rate to 60-80 mL/hour resulted in symptomatic improvement and continuation of REMICADE therapy.
• In patients experiencing group B symptoms (n=7), REMICADE infusion was immediately discontinued, and appropriate symptomatic therapy was administered.
  • The infusion was resumed at a lower rate (60 mL/hour) when the symptoms disappeared.
  • Patients were premedicated with an antihistamine for subsequent infusions.

Sany et al (2005)¹³ evaluated the incidence of infusion reactions in patients with RA receiving REMICADE with or without betamethasone premedication.

Study Design/Methods

• A total of 355 patients were randomly assigned to receive either REMICADE + betamethasone 0.15 mg/kg 30 minutes prior to each infusion (n=179) or REMICADE + placebo infusion (n=176).
• All patients received a 2-hour infusion of REMICADE 3 mg/kg at weeks 0, 2, 6, 14, and 22.

Results

• The overall incidence of infusion reactions for both groups was 3.8%.
• Forty-two of the 840 infusions (5%) in the REMICADE + betamethasone group resulted in infusion reactions compared with 21 of 827 infusions (2.5%) in the REMICADE + placebo group (P=0.05).
• Thirty patients (16.8%) in the REMICADE + betamethasone group experienced an infusion reaction compared with 18 patients (10.2%) in the REMICADE + placebo group (P=0.08).

Wasserman et al (2004)¹⁴ evaluated the relationship between infusion-related reactions and REMICADE dose, week of infusion, and the influence of pretreatment with diphenhydramine in an observational study of 113 patients with RA.

Study Design/Methods

• Patients received REMICADE 3 mg/kg infusions over a 2-hour period at an average rate of 125 mL/hour, administered at weeks 0, 2, 6, and every 8 weeks thereafter.
• At week 14, patients were able to have their dose increased to 5 mg/kg.

Results

• Of the 1183 infusions administered, 104 infusion reactions (8.8%) were observed and 53% of patients (n=60) experienced at least 1 reaction.
• Allergic reactions (ie, pruritis, urticaria and/or facial or generalized swelling) and cardiopulmonary reactions (ie, hypotension, hypertension, tachycardia and/or shortness of breath) were the most frequent types of reactions (3.8% and 3.0%, respectively).
• Most reactions were mild in severity and 2.7% of patients (n=3) discontinued therapy as a result.
• Infusion reactions were most common during infusion 3 at week 6 (23%, n=24) and during infusion 4 at week 14 (19%, n=20).
• No significant increase in infusion-related reactions was observed between the 3 mg/kg dose (n=63, 8.0% of infusions) and the 5 mg/kg dose (n=41, 10.3% of infusions).
• Of the 104 infusions resulting in reactions, 13.2% occurred in patients pretreated with diphenhydramine vs 7.5% occurred in patients who were not pretreated (P<0.05).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 05 July 2022.