Infliximab and the Risk of Administration Reactions in Patients With Rheumatoid Arthritis - Clinical Trial Information
Three Phase III studies have been conducted evaluating the safety and efficacy of infliximab in patients with rheumatoid arthritis—these 3 trials known as ASPIRE, ATTRACT and START are described below relative to infusion reactions.
REMICADE in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.3204
ASPIRE Trial (Study of Infliximab in Early-Onset Rheumatoid Arthritis (<3 years))
The ASPIRE trial (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset), conducted
by St. Clair, et al. (2004), was a randomized, controlled, double-blind
trial to study the efficacy and safety of infliximab plus methotrexate
(MTX) compared to MTX plus placebo in 1049 patients who had been classified
with persistent rheumatoid arthritis (1987 American College of Rheumatology
Criteria) for more than 3 months and less than 3 years and who had
no history of treatment with MTX.3218 Patients
were randomized to receive MTX plus placebo infusions
Seventy-nine patients (22%) from the
At some time during the study, serum antibodies
to infliximab were detected in 46 of 317 patients (14.5%) in the
ATTRACT Trial (Study of Infliximab in Rheumatoid Arthritis with Methotrexate Treatment)
The ATTRACT trial (Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy ), conducted
by Maini, et al. (1999), was a Phase III, randomized, double-blind,
placebo-controlled study that evaluated the safety and efficacy of
infliximab in 428 patients with active rheumatoid arthritis despite
treatment with methotrexate (MTX).1944, 6467 All
patients received treatment with MTX (median dose
During the first 30 weeks of the study, patients experiencing infusion reactions across the 4 infliximab-treated groups ranged from 16-20% of patients in each treatment group compared with 10% of patients treated with placebo. In this study, the frequency of infusion reactions was highest after the first infusion. Most of the infusion reactions were considered mild and transient, with headache and nausea as the most common symptoms. The study design allowed symptoms of infusion reactions to be controlled by slowing the rate of the infusion, and prophylactic use of antihistamines and/or corticosteroids. Two patients treated with infliximab discontinued treatment because of an infusion reaction (one urticaria, one dyspnea). No reactions were classified as serious infusion reactions by the investigators. Adverse events suggestive of an immediate hypersensitivity reaction were infrequent and mild, including hypotension in 8 infliximab-treated patients and urticaria in 4 infliximab patients. No delayed hypersensitivity reactions were reported 1 hour after the completion of the infusion or at the next observed time-point 4 weeks later.
During the entire 102-week study period, infusion reactions led to the discontinuation of infliximab plus MTX therapy in 8 of the 183 infliximab infusions with an associated infusion reaction. One patient treated with infliximab at 3 mg/kg plus MTX every 4 weeks had a serious infusion reaction during the Week 86 infusion. This patient reported dizziness and shortness of breath during the infusion, which was stopped, and later experienced a seizure that resolved the same day. Infliximab treatment was discontinued. Another patient on the same dosing regimen experienced a serum sickness-like reaction at Week 86 but proceeded to complete the study with no further adverse events. During the entire 102-week study period, 8% of patients receiving infliximab developed antibodies to infliximab.1944, 6467
START Trial (Study of Safety Profile and Dose Escalation of Infliximab in Rheumatoid Arthritis)
The START trial (A Randomized, Double-blind Trial of the Safety of Anti-TNF Chimeric Monoclonal Antibody [iniximab] in Combination with Methotrexate Compared to Methotrexate Alone in Subjects with Rheumatoid Arthritis on Standard Disease-Modifying Antirheumatic Drug Background Therapy), conducted by Westhovens, et al. (2006), evaluated the safety and efficacy of infliximab in 1082 active rheumatoid arthritis (RA) patients.3227 Patients were randomized through Week 54 as follows:
-
Group 1: 361 patients received placebo plus weekly methotrexate (MTX)
(≤25 mg/week) doses at Weeks 0, 2, 6, and 14. At Week 22, all patients crossed over to receive infliximab3 mg/kg plus MTX at Weeks 22, 26, 30, and every 8 weeks thereafter. -
Group 2: 360 patients received infliximab 3 mg/kg plus MTX
(≤25 mg/week) 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 are (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 infliximab 10 mg/kg plus MTX
(≤25 mg/week) at Weeks 0, 2, 6, and then every 8 weeks thereafter.
Seventeen of 361 patients (4.7%) receiving Group
1 placebo, 36 of 338 patients (10.7%) receiving Group 1 infliximab
Content on this page was last reviewed on January 30, 2009.
Content on this page was last changed on March 19, 2009.
References:| 1943. | Centocor. Data on file. 2003. |
| 1944. | Maini R, St Clair EW, Breedveld F, et al; ATTRACT Study Group. Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet. 1999;354(9194):1932-1939. |
| 3204. | Remicade [prescribing information]. Malvern, PA: Centocor Ortho Biotech Inc.; November 2009. |
| 3218. | St Clair EW, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432-3443. |
| 3227. | Westhovens R, Yocum D, Han J, et al.; START Study Group. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075-1086. |
| 6027. | Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastrolenterol Hepatol. 2004;2(7):542-553. |
| 6467. | Maini RN, Breedveld FC, Kalden JR, et al.; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum . 2004;50(4):1051-1065. |
| 8136. | Centocor. Data on file. 2004. |
| 8155. | Centocor. Data on file. 2004. |
Prescribing Information and Medication Guide
REMICADE® (infliximab) Indications and Important Safety Information
INDICATIONS AND USAGE
Crohn’s Disease
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy.
REMICADE is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease.
Ulcerative Colitis
REMICADE is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
Rheumatoid Arthritis
REMICADE, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.
Ankylosing Spondylitis
REMICADE is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
Psoriatic Arthritis
REMICADE is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.
Plaque Psoriasis
REMICADE is indicated for the treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. REMICADE should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.
IMPORTANT SAFETY INFORMATION
RISK OF INFECTIONS
Patients treated with REMICADE® (infliximab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious infection or sepsis.
Reported infections include:
- Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE®. 1,2 Treatment for latent infection should be initiated prior to treatment with REMICADE®.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral, and other infections due to opportunistic pathogens.
The risks and benefits of treatment with REMICADE® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
In clinical trials, other serious infections observed in patients treated with REMICADE® included pneumonia, cellulitis, abscess, and skin ulceration.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including REMICADE®. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.
Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including REMICADE®. These cases have had a very aggressive disease course and have been fatal. All reported REMICADE® cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of treatment with REMICADE®, especially in these patient types.
In clinical trials of all TNF inhibitors, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF inhibitors, including REMICADE®, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with REMICADE® was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF inhibitors in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).
CONTRAINDICATIONS
REMICADE® is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. REMICADE® should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue REMICADE® if new or worsening CHF symptoms appear. REMICADE® should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.
HEPATITIS B REACTIVATION
TNF inhibitors, including REMICADE®, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating REMICADE®. Exercise caution when prescribing REMICADE® for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE® and monitor patients closely.
HEPATOTOXICITY
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving REMICADE® postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥ 5 times the upper limit of normal) develop, REMICADE® should be discontinued, and a thorough investigation of the abnormality should be undertaken.
HEMATOLOGIC EVENTS
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE® in patients who develop significant hematologic abnormalities.
HYPERSENSITIVITY
REMICADE® has been associated with hypersensitivity reactions that differ in their time of onset. Acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Serious infusion reactions including anaphylaxis were infrequent. Medications for the treatment of hypersensitivity reactions should be available.
NEUROLOGIC EVENTS
TNF inhibitors, including REMICADE®, have been associated with rare cases of new or exacerbated symptoms of demyelinating disorders including multiple sclerosis, optic neuritis, and Guillain-Barré syndrome, seizure, and CNS manifestations of systemic vasculitis. Exercise caution when considering REMICADE® in all patients with these disorders. Consider discontinuation for significant CNS adverse reactions.
AUTOIMMUNITY
Treatment with REMICADE® may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.
ADVERSE REACTIONS
In clinical trials, the most common REMICADE® adverse reactions occurring in >10% of patients included infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.
USE WITH OTHER DRUGS
The concomitant use of a TNF blocker and anakinra was associated with a higher risk of serious infections, therefore the use of REMICADE® in combination with anakinra is not recommended. Live vaccines should not be given with REMICADE®. Bring pediatric Crohn's patients up to date with all vaccinations prior to initiating REMICADE®.
Please see full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion.
References: 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221–S247. 2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.