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 regarding dosing interval reduction with REMICADE in patients with Crohn’s disease (CD).
• A decrease in the dosing interval with REMICADE in patients with CD has been evaluated in several retrospective studies.^1-9

CLINICAL DATA

Retrospective Studies

Tun et al (2019)¹ reported the effect of dose escalation on clinical response, drug level, and antidrug antibodies in patients with antibodies to infliximab (ATI) with CD or ulcerative colitis (UC).

• This was a retrospective analysis of available data from patients who had infliximab trough and antibody levels measured at each infusion at a single center.
• Dose escalation was defined as a reduction in the dosing interval between maintenance infusions <8 weeks ± a dose increase of REMICADE to 10 mg/kg.
• Clinical remission for CD was defined as Harvey Bradshaw Index (HBI) ≤4 and a C-reactive protein (CRP) ≤5 mg/L.
• Positive ATI >10 mg/L were defined as transient if resolved within two consecutive infusions.
• Dose escalation occurred in 78 patients (CD, n=40) due to loss of response (n=48) and to optimize therapeutic drug monitoring levels (n=30).
  • There were 73 patients who received dose escalations for a median of 36 weeks (range 4-140 weeks) and 5 patients who stopped REMICADE after 1 additional dose due to loss of response (n=2) and for acute infusion reactions (n=3 in patients with ATI >10mg/L).
• At the time of dose escalation, 31/78 (40%) patients were positive for ATI.
• For the median infliximab levels following dose escalation, see Table: Mean Infliximab Levels Following Dose Escalation.

• After dose escalation, 13/33 patients with positive ATI had a fall in ATI to ≤10 mg/L.
• At 24 weeks following dose escalation, 16/31 patients who were positive for ATI were in clinical remission (10 recaptured after loss of response, 6 maintained clinical remission) vs 30/47 patients with negative ATI (22 recaptured after loss of response, 8 maintained clinical remission).
• The duration in clinical remission was shorter in patients with positive ATI (median 24 weeks, range 0-88) vs patients with negative ATI (median 36 weeks, range 0-126), P=not significant (NS).

Kopylov et al (2011)² retrospectively evaluated the efficacy of REMICADE given at a once every six week dosing interval for the treatment of Crohn's disease in patients with a lost response to REMICADE maintenance dosing of 5mg/kg every 8 weeks.

• The clinical outcome of patients who had received REMICADE dosing of either 10mg/kg every 8 weeks or 5mg/kg every 4 weeks (Group II) was compared to the clinical outcome of patients who were treated with REMICADE 5mg/kg every 6 weeks (Group I).
• Patients in the study had a lost response to REMICADE 5mg/kg administered every 8 weeks as determined by the judgement of their treating physician.
• The study included a total of 94 patients.
  • 59% (n=55) of patients were in Group I
  • 41% (n=39) of patients were in Group II
• Both groups had similar demographics and disease characteristics.
• Short term response to the intensified therapeutic regimens of both groups was achieved by 64 of 94 (68%) patients. 38 of 55 (69%) of patients in Group I experienced immediate short-term clinical response to the every 6 week dosing interval as compared to 26 of 39 (67%) of patients in Group II.
• 76 patients completed a follow up period of at least one year. After dose intensification with REMICADE, 36% (27 of 76) of these patients experienced a sustained clinical response at 12 months.
  • 40% (18 of 45) of patients with complete follow up in Group I achieved a sustained response at year 1 as compared to 29% (9 of 31) of patients with complete follow up in Group II.
• Sustained clinical response after the first escalation of REMICADE dosage was not obtained by 49 patients from the entire cohort. 57% (28 of 49) of these patients received further dose escalation.
• 39% (11 of 28) of the patients who received a second dose escalation responded to the further escalation of the REMICADE dosing.

Chaparro (2009)³ conducted a retrospective multicenter survey of 34 CD patients (64% with ileocolic disease, 47% with fistulizing phenotype and 60% with perianal disease) who received REMICADE 5 mg/kg at 0, 2 and 6 weeks and later needed their maintenance therapy (given every 8 weeks) to be intensified due to loss of response.

• Treatment intensification consisted of escalating the REMICADE dose to 10 mg/kg given every 8 weeks or reducing the REMICADE 5 mg/kg maintenance therapy dosing interval to every 4 weeks.
• Patients received standard maintenance therapy of REMICADE 5 mg/kg given every 8 weeks a mean of 15 months (range: 3–43 months) before intensification.
• Patients in whom REMICADE therapy was adjusted for dose or interval were followed for a mean of 56 weeks (range: 4–169 weeks).
• Response to REMICADE therapy was measured using the Harvey-Bradshaw Index for luminal CD.
• A complete response in fistulizing CD was defined as complete closure of fistulas and a partial response was defined as a 50% or more reduction in the number of fistulas.
• Short-term results indicated that after the first intensification dose, 78% of patients exhibited a response (32% complete response and 46% partial response).
• Long-term results indicated that after the last intensification dose, 61% of patients were still responding (22% complete response and 39% partial response).
• Seventy-two percent of patients were treated with concomitant immunomodulator therapy.
• An infusion reaction that subsided by slowing the infusion rate occurred in 1 patient after 36 doses of intensified treatment.
• An episode of herpes zoster which did not alter treatment with REMICADE was reported in 1 patient.

Schnitzler et al (2008,2009)^4,5 retrospectively evaluated the loss of response and assessed how many interventions were necessary to maintain clinical response in 614 CD patients receiving long-term treatment with REMICADE at a single-center (between 1994 to 2007).

• An intervention was defined as a shortening of the interval between infusions, an increase of the dose of REMICADE or a change from episodic to scheduled treatment given every 8 weeks.
• A total of 7,433 REMICADE infusions were administered to 614 patients with CD over a median follow-up of 55 months.
• Short term response was observed in 89.1% (547/614) of patients, whereas therapy was stopped in 10.9% (67/614) of patients due to no initial response to REMICADE after a median of two infusions.
• Of the initial responders, 50% (273/547) of patients did not need any intervention, 26% (143/547) of patients needed 1 intervention, 10% (56/547) of patients needed 2 interventions and 14% (73/547) of patients needed 3 or more interventions.
• In 163 patients (29.8%), the median time to switch to every 8-week therapy in the episodic treatment group was 26 months and/or 6 infusions.
• The specific dose of REMICADE evaluated in this study was not provided.
• There were 194 (35.5%) patients who received scheduled therapy with REMICADE from the start of the study.
• Episodic treatment was started in 190 (34.7%) patients and episodic with switch to maintenance treatment occurred in 163 (29.8%) patients.
• Fifty-nine percent of patients were on concomitant immunomodulators and 32% of patients were on corticosteroids at the time of the first REMICADE infusion.
• An interval reduction between REMICADE infusions was implemented in 108 (19.7%) patients, an increase in REMICADE dose was implemented in 144 (26.3%) patients and an increase in REMICADE dose plus a reduction of the interval was implemented in 21 (3.8%) patients.
• Overall, 200/547 patients (36.6%) stopped therapy with REMICADE, due to loss of response (n=118, 21.6%), side effects (n=70, 12.8%) or for other reasons (n=12, 2.2%).

Regueiro et al (2007)⁶ retrospectively reviewed all CD patients receiving REMICADE at the University of Pittsburgh Medical Center outpatient infusion center to determine the proportion of patients who require dose intensification and factors associated with dose intensification.

• Dose intensification was defined as either an increase in REMICADE dose (e.g. from 5 mg/kg to 10 mg/kg) or a decrease in infusion interval (e.g. from every 8–week infusions to every 4–7 weeks, or both a dose increase and interval decrease).
• All patients in this analysis received at least 8 doses of REMICADE (n=108).
• At 30 months from the initial infusion, 69.1% of all patients were event-free from an interval decrease, 48.5% were event-free from a dose increase, and 45.7% were event-free from dose intensification.
• The 30–month event-free rates for 38 REMICADE-naive patients who started at an initial dose of 5 mg/kg were 68.1% for an interval decrease, 57.4% for a dose increase, and 52.8% for dose intensification.
• The 30–month event-free rates for 62 patients with a known history of REMICADE therapy were 68.7% for an interval decrease, 43.0% for a dose increase, and 41.0% for dose intensification.
• A dose increase was the primary reason for dose intensification in both groups.
• Of the patients who required dose intensification, 75.9% (41/54) were receiving REMICADE at study conclusion.
• The 30–month event-free rates did not differ by whether a lapse in therapy occurred (P=0.75), being REMICADE-naive at study entry (P=0.49), or being on concomitant immunosuppressive therapy (P=0.82).
• Twenty-nine patients (26.9%) received 0, 2, and 6–week induction doses followed by every-8–week maintenance doses without a lapse in therapy and also received concomitant immunomodulators.
• At 30 months, 55.2% of these patients had a change in their dose and/or interval.
• The 30–month event-free rate for patients without immunomodulator use or with a lapse in REMICADE infusions of at least 6 months was 46.1% (P=0.94).
• In Cox regression analysis, no variables were independently associated with the risk of dose intensification.
• Age at diagnosis <25 years and current smoking were nonsignificantly associated with a lower risk of dose intensification.
• Colonic only disease and prior REMICADE use were nonsignificantly associated with an increased risk of dose intensification.

Corman et al (2006)⁷ conducted a retrospective observational study of 125 CD patients treated with REMICADE maintenance therapy for >1 year between 1999 and 2005.

• The objective of the study was to determine the rate of REMICADE dose escalation and the clinical parameters associated with an escalation in dose.
• Dose escalation was defined as either a shortening of the infusion interval to <7 weeks or a dosage increase to >5 mg/kg.
• Clinical parameters assessed included CD duration, disability status, smoking status, prior use of immunomodulators (azathioprine, 6MP, methotrexate), intolerance to purine analogs, and patient demographics.
• In this study, 38% of patients required an escalation in dose, compared to 62% of patients who received the standard maintenance regimen.
• Of note, the majority of patients who received an escalation in dose required a reduction in the dosage interval.
  • Specifically, almost 96% of patients necessitating a dose escalation required a shortened infusion interval, compared to 52.1% requiring a dosage increase to 10 mg/kg.
• The 2 clinical parameters shown to be statistically significant different between patients receiving the standard regimen and patients receiving the escalated regimen were the use of concomitant immunomodulators and the rate of permanent disability (P<0.025 and P<0.05, respectively).
• Patients in the standard regimen had higher rates of concomitant immunomodulator use and lower rates of permanent disability than patients in the escalated regimen.

Thameem et al (2005)⁸ conducted a retrospective observational study in 71 CD patients receiving  maintenance therapy with REMICADE over a 5-year period.

• Patients eligible for this analysis must have received >4 REMICADE infusions.
• Acceleration was defined as a decrease in dosing interval or an increase in drug dosage of REMICADE (>5 mg/kg).
• A scheduled dosing regimen included loading with 0, 2, 6 and then every 8 weeks, while, all other infusion regimens were labeled as episodic treatment.
• In this study, 33.8% of CD patients receiving maintenance therapy with REMICADE required acceleration.
  • Specifically, a shortened infusion interval was required in all of these patients and 20% (14/71) required a dose increase to 10 mg/kg.
• When comparing episodic and scheduled infusions, an increase in dose was noted in patients with a history of prior episodic infusions, 11/30 versus 3/41, respectively (P<0.02).

Shih et al (2004)⁹ conducted a retrospective analysis in 56 CD patients who received REMICADE over a 5-year period.

• A total of 37 infusions (total 731) infusions were administered and concomitant azathioprine or methotrexate use was reported in 82% of patients.
• Complete response was defined as a sustained absence of symptoms.
• While partial response was a decrease in abdominal pain, decrease in the number of bowel movements, reduction in fistulae drainage, weight gain, and/or an increase in sense of wellbeing.
• A total of 27 (48%) patients required an increase in dosage and/or a decrease in the interval between infusions to maintain response.
  • Specifically, a dose increase to 10 mg/kg was required to maintain response in 18 (32%) patients.
• Additionally, due to loss of response, the interval of infusion administration was shortened in 15 patients (27%): every 6 weeks (n=10), every 5 weeks (n=2) and every 4 weeks (n=3).
• At the time of evaluation, all 20 luminal disease patients were in complete or partial response.
• Of those patients with perineal fistulae, 11 (31%) responded completely, 13 (36%) responded partially, and 12 (33%) had continued fistula drainage but partial improvement in their disease.
• Reduction or discontinuation of steroids was noted in all 34 steroid dependent or steroid refractory patients.
• A total of 6 patients experienced adverse events, however, no patient discontinued therapy.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 29 August 2023.