Summary

• REMICADE is not approved to be administered in doses greater than 10 mg/kg.¹
• The use of REMICADE at doses greater than 10 mg/kg has been reported in the published literature for different disease states, including rheumatoid arthritis,² Crohn's disease,^3-5 and ulcerative colitis.⁶

PRODUCT LABELING

Refer to Section 2 of the full Prescribing Information for the recommended dosage of REMICADE for FDA-approved indications.¹

Refer to Section 12.3 of the full Prescribing Information for the pharmacokinetics of single, intravenous REMICADE infusions of 3 mg/kg to 20 mg/kg in adult patients.¹

CLINICAL DATA

In an effort to streamline this response, only data on the use of REMICADE at doses greater than 10 mg/kg in FDA-approved indications is provided.

Rheumatoid Arthritis

Kavanaugh et al (2000)² conducted a dose-ranging study of REMICADE in 28 patients who were receiving stable doses of methotrexate. Patients were randomized to receive a single infusion of placebo or REMICADE 5, 10, or 20 mg/kg.

• Twenty-three patients completed the blinded portion of the study and entered an open-label, repeated treatment extension phase in which they received up to 3 additional 10 mg/kg infusions at 8 week intervals.
• In the blinded portion of the study, 81% (17/21) of patients who received REMICADE compared to 14.3% (1/7) of patients who received placebo achieved an American College of Rheumatology (ACR) 20 response at some point during the 12-week follow-up period (P=0.003). ACR 20 response rates were similar among the 3 REMICADE dose groups.
• Among the 7 patients who received REMICADE 20 mg/kg in the blinded portion of the trial, 86% (6/7) achieved an ACR 20 response and 71% (5/7) achieved an ACR 50 response at any evaluation point during the study.
• There were no withdrawals during the blinded portion of the study and adverse event rates were similar between the REMICADE treatment groups and the placebo group.
• There were 3 patients in the placebo group and 5 patients in the REMICADE treatment groups that developed 1 or more infections and required antibiotic therapy during the blinded portion of the study (2 received 20 mg/kg; ulcerative stomatitis and mastitis).
• The mean terminal half-life of REMICADE (5-20 mg/kg) ranged from 9-12 days and was detectable in sera 8-12 weeks after dosing in most patients.

Crohn's Disease

Targan et al (1997)³ described a multicenter, double-blind, placebo-controlled study of REMICADE in 108 patients with moderately to severely active Crohn's disease unresponsive to conventional therapy.

• The study was divided into 3 phases. In the first phase, patients (mean age, 36-39.3 years) were randomized to receive a single dose of placebo or REMICADE 5, 10, or 20 mg/kg.
• The primary endpoint was the proportion of patients who experienced a clinical response, defined as a decrease in Crohn’s Disease Activity Index (CDAI) ≥70 points from baseline at the 4-week evaluation without an increase in Crohn's disease medications or surgery for Crohn's disease.
• Secondary endpoints included the proportion of patients who were in clinical remission at week 4 (CDAI <150), and clinical response over time.
• At week 4, 81% of patients who received REMICADE 5 mg/kg, 50% of patients who received 10 mg/kg, and 64% of patients who received 20 mg/kg achieved a clinical response compared with 17% of patients who received placebo (P<0.001, combined REMICADE groups compared to placebo).
• One of 25 (4%) placebo patients and 13 of 27 (48%) patients receiving REMICADE 5 mg/kg were in clinical remission at week 4.
• The maximum response to any dose of REMICADE was observed within 2-4 weeks.
• The proportion of patients responding gradually diminished over the 12-week evaluation period.
• No dose response was observed among the 3 REMICADE treatment groups; doses higher than 5 mg/kg did not result in a significantly greater proportion of responders.
• At week 12, significantly more REMICADE-treated patients continued to have a response compared to placebo patients.
• However, the proportion of patients in remission was not statistically different between treatment groups.
• By week 4, patients treated with REMICADE compared with placebo demonstrated significant improvement in health-related quality of life, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) (P=0.001).
• Overall, REMICADE was well-tolerated.
  • There were no significant differences between the REMICADE and placebo treatment groups in the percentage of patients experiencing adverse events.
  • The most common adverse events in both groups included headache, nausea, upper respiratory tract infection, and fatigue.
• In the second phase of the trial, 29 patients who did not respond to the single dose of 5, 10, or 20 mg/kg of REMICADE entered the open-label phase and received a single 10 mg/kg dose of REMICADE 4 weeks after the initial dose. Ten of 29 (34%) patients experienced a response 4 weeks after receiving the second dose.

Rutgeerts et al (2004)⁴ reported on the difference in efficacy between episodic and scheduled treatment strategies with REMICADE in a multi-center, randomized international trial (ACCENT - A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen) of 573 patients with moderately to severely active Crohn's disease.

• The objectives of the trial included evaluation of the efficacy of a 3-dose induction regimen compared to a single dose; the effects on response, remission, and quality of life of an every 8 week maintenance regimen compared to a single dose; the steroid-sparing effects of REMICADE; the mucosal healing effects of REMICADE; and the safety of long-term maintenance therapy.⁴
• All patients received an initial infusion of REMICADE 5 mg/kg at week 0. At week 2, patients were randomized based on clinical response, defined as a reduction in CDAI ≥25% and ≥70 points, to one of the following maintenance treatment groups:⁴
  • Group I: placebo at weeks 2 and 6, then placebo every 8 weeks (n=188)
  • Group II: REMICADE 5 mg/kg at weeks 2 and 6, then 5 mg/kg every 8 weeks (n=192)
  • Group III: REMICADE 5 mg/kg at weeks 2 and 6, then 10 mg/kg every 8 weeks (n=193)
• Patients who initially responded to treatment but then lost their clinical benefit at week 14 or later were eligible to cross over to active episodic retreatment with REMICADE 5 mg/kg, 10 mg/kg, or 15 mg/kg for patients that were originally assigned to placebo,5 mg/kg scheduled treatment, or 10 mg/kg scheduled treatment, respectively.
• Fifty-one of the 193 (26%) patients in the REMICADE 10 mg/kg scheduled treatment strategy group crossed over to episodic treatment and received 15 mg/kg at week 14.
• The efficacy of scheduled REMICADE therapy was better than episodic treatment. Median CDAI scores were significantly lower in the 10 mg/kg scheduled treatment group compared to the episodic treatment group from week 10 through week 54.
• Similar results were observed in the 5 mg/kg scheduled treatment group from week 10 through week 30.
• A greater percent of patients in the combined scheduled group achieved clinical remission compared to the episodic strategy group at week 30 (40% vs 32% [P=0.07], respectively).
• Approximately 80% of patients who lost response in the 10 mg/kg group achieved response after receiving 15 mg/kg.

Hendler et al (2015)⁵ retrospectively evaluated the efficacy and safety of high-dose REMICADE therapy (REMICADE ≥10 mg/kg every 7 weeks as maintenance therapy) in a group of 86 patients with Crohn's disease.

• Patients included in this study received REMICADE 10 mg/kg every 4, 5, 6, or 7 weeks; 15 mg/kg every 4, 6, 7, or 8 weeks; 20 mg/kg every 4, 6, or 8 weeks; or 22.5 mg/kg every 4 weeks.
• A total of 49% of patients had ≥1 previous exposure to REMICADE with at least a 24-week hiatus, whereas the remaining 51% had been receiving their first standard-dose REMICADE infusion or maintenance regimen continuously when the decision was made to escalate to high-dose REMICADE therapy.
• At the time of escalation to a high-dose REMICADE regimen, 13 patients (15%) were receiving 1 of the first 3 induction doses to a standard-dose REMICADE regimen, 57 patients (66%) were receiving standard-dose REMICADE maintenance treatment, 6 patients (7%) were receiving non-infliximab biologic therapy (adalimumab, certolizumab pegol, or clinical trial), and 7 (8%) were receiving non-biologic treatment (steroids or immunomodulators only). The context of high-dose escalation was unknown in 3 patients.
• Of the 86 patients, 57 (66%) were maintained on the initial high-dose REMICADE regimen throughout the time of data collection, 22 patients (25%) underwent 1 subsequent escalation, 14 patients (16%) underwent 2 subsequent escalations, and 1 patient (1%) underwent 3 subsequent escalations.
• In early high-dose REMICADE therapy (week 1-16), 25.8%, 59.1%, and 15.2% of 66 patients with available data experienced full, partial, and no response, respectively.
• In later high-dose REMICADE therapy (week 38-100), 27.9%, 34.4%, and 37.7% of 61 patients with available data experienced full, partial, and no response, respectively.
• Median serum REMICADE levels increased from 1.7 at baseline to 7.3 µg/mL after a median of 20.7 weeks in 10 available patients with available data (P=0.017), and median C-reactive protein (CRP) values decreased from 20.5 mg/L at baseline to 4.7 mg/L after a median of 16.4 weeks in 54 patients with available data (P<0.001).
• High-dose REMICADE therapy was discontinued in 25.6% and 7.3% of patients for inadequate response and adverse events/infusion reactions, respectively.
• Adverse events included infections (59 events, the most common being respiratory infection [21 events] and skin infection [10 events]), autoimmune conditions (8 events), and neoplasia (3 events).
• A total of 10 (11.6%) patients experienced acute infusion reactions, 9 of whom subsequently tolerated infusions after premedication with acetaminophen, steroids, and/or antihistamines.
• A total of 5 (5.8%) patients experienced delayed infusion reactions, and pre-medications for subsequent infusions successfully prevented symptoms in 4 of these patients.

Ulcerative Colitis

Sands et al (2001)⁶ conducted a phase 2 trial to evaluate the efficacy, safety, and tolerability of REMICADE in patients with severe ulcerative colitis.

• This trial was a randomized, multi-center, placebo-controlled, double-blind study in 11 patients with active ulcerative colitis refractory to intravenous corticosteroid therapy.
• Patients were randomized to receive a single, intravenous infusion of REMICADE at doses of 5 (n=3), 10 (n=3), or 20 mg/kg (n=2) or placebo (n=3).
• The primary endpoint for this trial was treatment failure at the 2-week evaluation. Treatment failure was defined as 1 or more of the following criteria: failure to achieve a clinical response (defined as a modified Truelove and Witts Severity Assessment of <10 and a 5-point reduction from baseline), colectomy, addition of immunosuppressants or an increase in corticosteroids to a dosage above 60 mg/day, and death.
• At week 2, none (0%) of the placebo-treated patients and 4 (50%) of the 8 REMICADE-treated patients were considered treatment responders. Each of the placebo-treated patients underwent colectomy by the week 2 evaluation.
• Of the 4 REMICADE-treatment failures, 2 did not meet the modified Truelove and Witts criteria for a clinical response (1 each in the 10 and 20 mg/kg group), 1 required an increase in corticosteroids above 60 mg/day with a subsequent initiation of cyclosporine (5 mg/kg group), and 1 underwent elective colectomy (10 mg/kg group).
• During the follow-up period, 2 patients who received 5 mg/kg (1 treatment responder and 1 treatment failure) and 1 patient who received 10 mg/kg (classified as a treatment failure) underwent colectomies.
• Neither of the 2 patients who received 20 mg/kg underwent either elective or nonelective colectomy.
• In general, treatment with REMICADE was well-tolerated. All 11 patients in this trial experienced at least 1 adverse event, most of which were mild or moderate in intensity.
• The most frequently reported adverse events in REMICADE-treated patients were pruritus, headache, and urinary tract infection, each reported by 2 patients.
• Of the 5 adverse events reported as serious, 2 were reported in REMICADE-treated patients (cellulitis and renal calculus) and were not considered by the investigator to be study-related.
• Additionally, 1 patient in the 5 mg/kg REMICADE group reported dyspepsia of short duration, which occurred 3 hours after onset of infusion.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent^® (and/or other resources, including internal/external databases) was conducted on 27 February 2023.