Summary

• The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
• Please refer to the local labeling for relevant information on retreatment with REMICADE after a drug-free interval.
• In rheumatoid arthritis, Crohn’s disease (CD) and psoriasis clinical trials, re-administration of REMICADE after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment. In general, the benefit risk of re-administration of REMICADE after a period of no-treatment, especially as a reinduction regimen given at weeks 0, 2 and 6, should be carefully considered. In the case where REMICADE maintenance therapy for psoriasis is interrupted, REMICADE should be reinitiated as a single dose followed by maintenance therapy.¹
• Data related to this topic from the study extension for the UC phase 3 trials, Active Ulcerative Colitis Trial 1 (ACT 1) and ACT 2, is also reported here.^2,3
• Clinical data from prospective studies pertaining to the initiation of REMICADE therapy after a drug-free period in patients with CD or ulcerative colitis (UC) are available through several prospective studies.^4–8

CLINICAL DATA

Ulcerative Colitis Clinical Trials - ACT 1 and ACT 2

Two placebo-controlled, phase 3 trials (ACT 1 and ACT 2) were conducted to evaluate the safety and efficacy of REMICADE in patients with active UC.^2,3

• Study participants were randomized to receive REMICADE 5 mg/kg, REMICADE 10 mg/kg, or placebo.
• Induction of clinical response, the primary endpoint, was evaluated 8 weeks following the initial infusion. Major secondary endpoints were evaluated at Week 30. The study was continued through week 54. A study extension allowed patients to continue receiving REMICADE following the last study treatment at week 46.
• At the time the study extension was initiated, some patients may have completed their participation in the main study with more than 8 weeks elapsing between infusions.
• All patients returned for infusions every 8 weeks, except for patients with a gap of >8 weeks between the week-46 infusion and the study extension week-0 infusions. These patients had an extra study visit 2 weeks following their first infusion in the extension because it is possible that those with a gap >8 weeks between infusions may have lost the response achieved by week 54 in the main study and may require an additional infusion at week 2 of the study extension. The decision on whether to administer an additional infusion was based on physician assessment. Pretreatment with acetaminophen (paracetamol) and diphenhydramine for these patients was at the discretion of the investigator.
• Although the absolute risk is unknown, previous data suggests that intervals between REMICADE infusions of >16 weeks, particularly intervals of 6 months to 1 year or more, may be associated with an increased incidence of delayed hypersensitivity reactions and/or infusion reactions. For this reason, any patient who had >16 weeks elapse since his/her last study infusion received preinfusion prophylaxis with acetaminophen and diphenhydramine, unless contraindicated. Some patients may have a gap between infusions of >8 but ≤16 weeks. Pretreatment with acetaminophen and diphenhydramine for these patients was at the discretion of the investigator.
• To obtain additional information on the potential benefit of corticosteroid prophylaxis, the patients with a gap of >16 weeks were randomized to receive corticosteroid pretreatment with a single intravenous (IV) dose of 200 mg hydrocortisone (or equivalent) prior to their first infusion in the extension or to receive no IV corticosteroid pretreatment. The corticosteroid pretreatment was administered open-label and any patient with a contraindication to corticosteroids was re-allocated to the other treatment group. Preinfusion prophylaxis with acetaminophen and diphenhydramine was administered to all patients with a gap of >16 weeks unless contraindicated.
• Patients with a gap >16 weeks who were randomized to receive IV corticosteroid prophylaxis received 200 mg hydrocortisone IV administered according to manufacturer’s instructions. This infusion began at least 30 minutes prior to the beginning of the REMICADE infusion. Patients receiving other comparable IV corticosteroid preparations received a dose comparable to 200 mg hydrocortisone, which was administered according to the product label for that study agent.

Prospective Studies – Inflammatory Bowel Disease

Steenholdt et al (2011)⁴ conducted a prospective, single-center study to evaluate the immunogenicity of REMICADE in patients with inflammatory bowel disease (IBD) who were treated either continuously (receiving REMICADE every 4-12 weeks) or episodically (reinitiated after more than 12 weeks without REMICADE).

• Antibodies to REMICADE and cross-reactivity with adalimumab were measured prior to the initiation of a new treatment series and/or after an acute severe infusion reaction.
• Acute severe infusion reactions were retrospectively identified using patient files.
• All patients received premedication with 100 mg intravenous (IV) hydrocortisone, 10 mg cetirizine, and 1 g acetaminophen prior to REMICADE infusion.
• Of 315 IBD patients were included in the study, 25 (8%) experienced an acute severe infusion reaction.
• Reactions occurred more frequently in episodically-treated patients compared to those treated continuously (72% vs 28%, P<0.001).
• Based on univariate analysis, younger age at diagnosis of IBD (P=0.013), younger age at time of first REMICADE infusion (P=0.012), and episodic treatment (P<0.001) were risk factors for developing an acute severe infusion reaction.
• When a multivariate model was utilized, the only variable associated with development of severe infusion reactions was episodic REMICADE therapy (Odds Ratio [OR] 4.9 [1.9-12.5]; P<0.001).
• A significantly higher proportion of infusions during the second treatment series resulted in an infusion reaction. Of the 18 reactions that occurred during episodic treatment, 14 (88%) occurred during the 2nd infusion in the second treatment series (P=0.006).
• In 19 of 20 patients, antibodies to REMICADE (IgG) were highly positive after the reaction.
• In 7/11 patients with reactions during episodic therapy, antibodies to infliximab (IgG) antibodies were negative prior to the initiation of the new treatment series.
• All 19 patients who were tested for cross-reactivity of antibodies to infliximab (IgG) with adalimumab were negative.
• Antibodies to infliximab (IgE) were negative in all patients with reactions.

Prospective Studies – Crohn’s Disease

Boschetti et al (2022)⁵ conducted a prospective, multicenter cohort study to evaluate the efficacy and safety of REMICADE retreatment (REGAIN) using data from the Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID).

• Patients who were retreated with REMICADE after ≥6 months of discontinuation due to loss of response (LOR) or intolerance were included.
• REMICADE was reintroduced at 5 mg/kg and infused over 2-hours at weeks 0, 4, 8 and then every 8 weeks.
• Premedication with an infusion of dexchlorpheniramine and hydrocortisone were administered prior to each REMICADE infusion.
• The primary outcome was clinical remission (CDAI<150) at week 26 in the absence of REMICADE discontinuation or use of steroids, surgery, or other biologics.
• Sixty-nine patients were included in this analysis. The median duration of disease was 10.1 (7.6-16.1) years. Median duration between initial REMICADE discontinuation and inclusion was 43.4 (21.0-76.2) months.
  • Reasons for initial discontinuation of REMICADE included secondary LOR in 48 (70%) patients and intolerance in 21 (30%) patients.
• At week 26, 24 (35%) patients achieved clinical remission (95% confidence interval [CI]: 24%-48%).
  • There was no significant difference between rates of clinical remission in patients with initial secondary LOR and those with intolerance.
  • A shorter median duration between initial discontinuation and retreatment with REMICADE was significantly associated with the success of retreatment (31.6 vs 56.1 months; P=0.024).
  • The detection of positive anti-drug antibodies at week 4 was predictive of REMICADE treatment failure at week 26 or infusion reaction.
• Among the 91 patients evaluated during the study period, 314 adverse events (AEs) were reported and 56 of these were serious in 40 (38%) patients.
  • Infections were the most common AE and occurred in 40 (32.3%) patients.
• Among the 69 patients included in the final analysis, 32 infusion reactions were reported in 27 patients which led to the withdrawal of REMICADE in 20 of these patients.

Domenech et al (2010)⁶ compared the occurrence of immune-related AEs in patients with inflammatory bowel disease treated with a 3-dose REMICADE induction regimen and subsequently retreated after ≥4 months due to disease relapse (reintroduction group; n=29) with those who received ≥4 consecutive REMICADE doses (3-dose induction regimen followed by ≥1 maintenance infusion [continuous group; n=47]).

• Patients received REMICADE 5 mg/kg infusions at week 0, 2, and 6 (induction regimen) and were premedicated with IV hydrocortisone 200 mg before each infusion. Concomitant immunomodulators were maintained when possible.
• Immune-related AEs evaluated in the study included acute infusion reactions (any AE during or within 24 hours following the REMICADE infusion), delayed hypersensitivity reactions (arthralgia, myalgia, skin rash, fever, and/or fatigue occurring 24 hours to 14 days following the REMICADE infusion), and secondary LOR (relapse before the following scheduled REMICADE infusion in a patient in whom remission was induced and maintained).
• The continuous group had received a median of 6 consecutive REMICADE infusions (range: 4 to 48) and the reintroduction group had received a median of 8 REMICADE infusions (range: 4 to 18).
• The median drug-free interval in the reintroduction group was 13 months (range: 4 to 47 months) following the 3 consecutive induction infusions.
• No significant differences were noted between the continuous and the reintroduction groups with respect to baseline demographics. A majority of the patients were diagnosed with CD (82% in the continuous group and 90% in the reintroduction group) with the remaining being diagnosed with UC.
• Concomitant immunomodulators (thiopurines or methotrexate) were received by 79% and 83% of patients in the continuous and reintroduction group, respectively.
• Additionally, premedication with 200 mg of IV hydrocortisone prior to every REMICADE infusion was received by 81% and 63% of patients, respectively.
• Any immune-related AE was reported by 30% of patients.
• The occurrence of acute infusion reactions was similar between the continuous group (17% [8/47]) and the reintroduction group (17% [5/29]).
• Delayed hypersensitivity reaction was reported in 1 patient (continuous group).
• Among the 40 patients with active luminal disease, secondary LOR was reported in 26% (7/27) of patients in the continuous group and 15% (2/13) of patients in the reintroduction group.
• Of note, a significant association was observed between acute infusion reactions and the lack of concomitant immunomodulators and/or pretreatment with IV hydrocortisone (P=0.002).

Magro et al (2008)⁷ described the occurrence of infusion reactions in 11 patients with steroid-refractory, active CD following a variable drug-free interval and retreatment with REMICADE on a maintenance schedule. All patients had previously been treated with REMICADE induction and episodic therapy.

• Of the 11 patients, 4 developed an acute infusion reaction and 7 developed a delayed reaction. All patients received premedication with prednisolone 75 mg and clemastine prior to the REMICADE infusion.
• Acute infusion reactions developed 15-30 minutes after the start of the infusion and clinical manifestations included dyspnea, facial rubor, chest pain, nausea, paresthesias, diaphoresis, tachycardia, chills, and fever. The median drug-free interval between episodic and maintenance REMICADE treatment in these patients was 35 months (range: 5-66 months). All patients were receiving azathioprine concomitantly.
• In contrast, delayed reactions developed between the second and the eighth day following the last REMICADE infusion and manifested as arthralgias, myalgias, fever, malaise, skin eruptions, and asthenia. The median drug-free interval between episodic and maintenance REMICADE treatment in these patients was lower (14.5 months [range: 5-28 months]).
• Acute infusion reactions developed during reinduction or during the first infusion of the maintenance period in 50% of patients. Over the same reinfusion period, delayed reactions developed in 71% of patients. Of note, titers of autoantibodies (anti-histones, anti-double stranded DNA, and antinuclear antibodies) were negative in all patients.

Duburque et al (2006)⁸ evaluated the safety and efficacy of an induction of tolerance protocol to REMICADE that permitted re-administration of REMICADE treatment in CD patients that previously experienced infusion reactions requiring discontinuation of therapy.

• Fourteen patients (mean age 30 years) with a history of CD (mean duration of 9.9 years) were included in the protocol. All patients previously developed an infusion reaction to REMICADE treatment after a mean of 5.6 infusions (range 3 - 9 infusions) despite prophylactic treatment with hydrocortisone. Thirteen patients had experienced an immediate infusion reaction (severe reaction; n=11) occurring during or within 24 hours of infusion and one patient had a delayed serum-sickness like reaction 8 days after an infusion.
• At the time of re-treatment with REMICADE, patients had a median drug–free interval of 4.5 months (range 1 - 67 months) between the last REMICADE infusion and the induction of tolerance protocol.
• Patients received REMICADE 5 mg/kg infusions at 0, 2, and 6 weeks and then maintenance therapy every 8 weeks.
• The induction of tolerance protocol involved dividing the REMICADE infusion into 11 escalating increments administered every 15 minutes. Four of the increments included a dilution of REMICADE of 2 x 10^–3 mg/mL/kg with an increasing infusion rate, then seven increments with a dilution of 0.2 mg/mL/kg with an increasing infusion rate. The complete dose escalation infusion occurred over 2 hour and 45 minutes. The infusion protocol was repeated for each new infusion.
• Nine of the 14 patients experienced a significant response to therapy with REMICADE with 7 patients achieving a complete remission of symptoms after a mean of 2.5 infusions.
• Four of the patients did not have a response to REMICADE and subsequently discontinued therapy.
• All patients with fistulizing CD (n=4) had a significant clinical response with one patient achieving complete remission.
• Eight patients tolerated all further infusions using the tolerance method with a mean number of 4.5 infusions administered. Three patients experienced mild immediate hypersensitivity reactions that were controlled after discontinuation of REMICADE and initiation of therapy with antihistamines and steroids. Two patients had severe immediate hypersensitivity reactions that led to interruption of therapy.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 18 September 2023.