Summary

• Cases of reactivation of tuberculosis (TB) or new TB infections have been observed in patients receiving REMICADE, including patients who have previously received treatment for latent or active TB. Cases of active TB have also occurred in patients being treated with REMICADE during treatment for latent TB. Patients should be evaluated for TB risk factors and tested for latent infection prior to initiating REMICADE and periodically during therapy.¹
• Anti-TB therapy should also be considered prior to initiation of REMICADE in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision whether initiating anti-TB therapy is appropriate for an individual patient.¹
• TB should be strongly considered in patients who develop a new infection during REMICADE treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of TB, or who have had close contact with a person with active TB.¹

PRODUCT LABELING

Please refer to the following sections of the enclosed REMICADE full Prescribing Information that are relevant to your inquiry: BOXED WARNINGS, SERIOUS INFECTIONS; DOSAGE AND ADMINISTRATION, Monitoring to Assess Safety; WARNINGS AND PRECAUTIONS, Serious Infections; ADVERSE REACTIONS.¹

CLINICAL DATA

Controlled Studies

The START (A Randomized, Double-blind Trial of the Safety of Anti-TNF Chimeric Monoclonal Antibody [Infliximab] in Combination with Methotrexate Compared to Methotrexate Alone in Subjects with Rheumatoid Arthritis on Standard Disease-modifying Antirheumatic Drug Background Therapy) trial evaluated the safety and efficacy of REMICADE in 1082 active RA patients.^2,3

Study Design/Methods

• Patients were randomized through week 54 as follows:
  • Group 1: 361 subjects received placebo plus weekly methotrexate (MTX) doses at weeks 0, 2, 6, and 14. At week 22, all patients crossed over to receive REMICADE 3 mg/kg plus MTX at weeks 22, 26, 30, and every 8 weeks thereafter.
  • Group 2: 360 patients received REMICADE 3 mg/kg plus MTX at weeks 0, 2, 6, and then every 8 weeks thereafter. At week 22, patients had their dose titrated in increments of 1.5 mg/kg if they were classified as “nonresponders” (<20% reduction from the combined number of tender and swollen joints seen at baseline) or patients experiencing disease flare (50% worsening of an initial improvement from baseline to week 22). The maximum dose given to any patient in this group was 9 mg/kg.
  • Group 3: 361 patients received REMICADE 10 mg/kg plus MTX at weeks 0, 2, 6, and then every 8 weeks thereafter.
• All patients received concomitant MTX (≤25 mg/week).
• Patients in Groups II and III received a placebo infusion at week 26 to maintain blinding.
• The primary endpoint of the study was the proportion of patients who developed serious infections through week 22.
• Serious infection was defined as a serious adverse event that the investigator reported as an infection.
• Secondary endpoint included proportion of patients achieving American College of Rheumatology 20% improvement response (ACR 20) at week 22.
• Patients with a history of active TB were to have taken a full course of anti-tubercular antibiotic therapy at least 2 years before the baseline visit.

Results

• A total of 80 subjects required treatment for latent TB: 78 before the first infusion and 2 after initiation of study infusions (newly detected latent TB).
• None of these patients developed active TB.
• Fifteen subjects had a previous history of appropriately treated active TB; none of those subjects developed active TB.
• Active TB was reported in 7 subjects (one in Group I after crossover, 2 in Group II, 4 in Group III).
• All 7 subjects with active TB had negative purified protein derivative (PPD) test results at baseline screening.
• Six of the 7 cases of active TB and the 2 cases of newly detected latent TB occurred in Europe, while 1 case of active TB occurred in the South America.
• Five of the 7 subjects with active TB had evidence of extrapulmonary TB.

The results of a review of United States (US) TB cases after October 2001 in patients who have received REMICADE were generally consistent with previous findings related to the issue.⁴

• One important finding in the analysis revealed that in approximately 44% of evaluable cases, TB was diagnosed after 1 year of initiating therapy with REMICADE (in previous analyses, most patients who developed active TB were within 1 year of initiation of REMICADE, suggesting reactivation of preexisting or latent TB). Further investigation of these new data suggest that patients are also at risk for contracting TB after new exposure to individuals with active TB.
• Examination of case histories revealed that approximately 53% of the cases had at least 1 known risk factor for TB other than concomitant immunosuppressants, such as a history of having been born, lived in, or traveled to a country with a higher TB rate than the US (some classified by the World Health Organization [WHO] as “high TB burden” countries).
• Considering the potential for false negative tuberculin skin tests, a thorough patient history prior to initiating REMICADE is essential, especially for patients who were born, lived in, or traveled to countries that may have a high background prevalence of TB. Furthermore, patients on REMICADE should be advised of the risk of traveling to an area where TB is prevalent.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 10 October 2022.

Summarized in the response are data on the occurrence of TB from the START clinical trial and a review of cases of instance of TB in US patients who received REMICADE .