Other
SERIOUS INFECTIONS
Patients treated with infliximab products are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
RENFLEXIS should be discontinued if a patient develops a serious infection or sepsis.
Reported infections include:
- Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before RENFLEXIS use and during therapy.1,2 Treatment for latent infection should be initiated prior to RENFLEXIS use.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. 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, including Legionella and Listeria.
The risks and benefits of treatment with RENFLEXIS should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with RENFLEXIS, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.
MALIGNANCY
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including infliximab products [see Warnings and Precautions (5.2)].
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including infliximab products. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and most were in adolescent and young adult males.
Tuberculosis
Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving infliximab products, including patients who have previously received treatment for latent or active tuberculosis. Cases of active tuberculosis have also occurred in patients being treated with infliximab products during treatment for latent tuberculosis.
Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating RENFLEXIS and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating RENFLEXIS, even for patients previously vaccinated with Bacille Calmette-Guérin (BCG).
Anti-tuberculosis therapy should also be considered prior to initiation of RENFLEXIS in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Tuberculosis should be strongly considered in patients who develop a new infection during RENFLEXIS treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
Monitoring
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with RENFLEXIS, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with RENFLEXIS.
RENFLEXIS should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with RENFLEXIS should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.
Invasive Fungal Infections
For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.
Lymphomas
In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. In the controlled and open-label portions of infliximab clinical trials, 5 patients developed lymphomas among 5707 patients treated with infliximab (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately three-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were observed for a rate of 0.10 cases per 100 patient-years of follow-up, which is approximately four-fold higher than expected in the general population. Patients with Crohn's disease, rheumatoid arthritis or plaque psoriasis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.
Hepatosplenic T-cell lymphoma (HSTCL)
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including infliximab products. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and most were in adolescent and young adult males. It is uncertain whether the occurrence of HSTCL is related to TNF-blockers or TNF-blockers in combination with these other immunosuppressants. When treating patients, consideration of whether to use RENFLEXIS alone or in combination with other immunosuppressants such as azathioprine or 6-mercaptopurine should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with infliximab product monotherapy from the clinical trial data from studies with infliximab [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].
Skin Cancer
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab products [see Adverse Reactions (6.2)]. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Cervical Cancer
A population-based retrospective cohort study using data from Swedish national health registries found a 2 to 3 fold increase in the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between infliximab products and cervical cancer cannot be excluded. Periodic screening should continue in women treated with RENFLEXIS [see Adverse Reactions (6.2)].
Other Malignancies
In the controlled portions of clinical trials of some TNF-blocking agents including infliximab products, more malignancies (excluding lymphoma and nonmelanoma skin cancer [NMSC]) have been observed in patients receiving those TNF-blockers compared with control patients. During the controlled portions of infliximab trials in patients with moderately to severely active rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) among 4019 infliximab-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among infliximab-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for infliximab-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast, colorectal, and melanoma. The rate of malignancies among infliximab-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected.
In a clinical trial exploring the use of infliximab in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, the majority of lung or head and neck origin, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking [see Adverse Reactions (6.1)]. Prescribers should exercise caution when considering the use of RENFLEXIS in patients with moderate to severe COPD.
Psoriasis patients should be monitored for nonmelanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for infliximab, NMSCs were more common in patients with previous phototherapy [see Adverse Reactions (6.1)].
The potential role of TNF-blocking therapy in the development of malignancies is not known [see Adverse Reactions (6.1)]. Rates in clinical trials for infliximab cannot be compared to rates in clinical trials of other TNF-blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering RENFLEXIS treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving RENFLEXIS.
Adverse Reactions in Adults
The data described herein reflect exposure to infliximab in 4779 adult patients (1304 patients with rheumatoid arthritis, 1106 patients with Crohn's disease, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 484 with ulcerative colitis, 1373 with plaque psoriasis, and 17 patients with other conditions), including 2625 patients exposed beyond 30 weeks and 374 exposed beyond 1 year. [For information on adverse reactions in pediatric patients see Adverse Reactions (6.1).] One of the most-common reasons for discontinuation of treatment was infusion-related reactions (e.g., dyspnea, flushing, headache and rash).
Infusion-related Reactions
An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In Phase 3 clinical studies, 18% of infliximab-treated patients experienced an infusion reaction compared to 5% of placebo-treated patients. Of infliximab-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.
Among all infliximab infusions, 3% were accompanied by nonspecific symptoms such as fever or chills, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or dyspnea), and <1% were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in <1% of patients and included anaphylaxis, convulsions, erythematous rash and hypotension. Approximately 3% of patients discontinued infliximab because of infusion reactions, and all patients recovered with treatment and/or discontinuation of the infusion. Infliximab infusions beyond the initial infusion were not associated with a higher incidence of reactions. The infusion reaction rates remained stable in psoriasis through 1 year in psoriasis Study I. In psoriasis Study II, the rates were variable over time and somewhat higher following the final infusion than after the initial infusion. Across the 3 psoriasis studies, the percent of total infusions resulting in infusion reactions (i.e., an adverse event occurring within 1 hour) was 7% in the 3 mg/kg group, 4% in the 5 mg/kg group, and 1% in the placebo group.
Patients who became positive for antibodies to infliximab were more likely (approximately two-to three-fold) to have an infusion reaction than were those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of both antibodies to infliximab and infusion reactions [see Adverse Reactions (6.1) and Drug Interactions (7.4)].
Infusion Reactions following Re-administration
In a clinical trial of patients with moderate to severe psoriasis designed to assess the efficacy of long-term maintenance therapy versus re-treatment with an induction regimen of infliximab following disease flare, 4% (8/219) of patients in the re-treatment therapy arm experienced serious infusion reactions versus < 1% (1/222) in the maintenance therapy arm. Patients enrolled in this trial did not receive any concomitant immunosuppressant therapy. In this study, the majority of serious infusion reactions occurred during the second infusion at Week 2. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, infliximab treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
Delayed Reactions/Reactions Following Re-administration
In psoriasis studies, approximately 1% of infliximab-treated patients experienced a possible delayed hypersensitivity reaction, generally reported as serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash. These reactions generally occurred within 2 weeks after repeat infusion.
Infections
In infliximab clinical studies, treated infections were reported in 36% of infliximab-treated patients (average of 51 weeks of follow-up) and in 25% of placebo-treated patients (average of 37 weeks of follow-up). The infections most frequently reported were respiratory tract infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. Among infliximab-treated patients, serious infections included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection. In clinical trials, 7 opportunistic infections were reported; 2 cases each of coccidioidomycosis (1 case was fatal) and histoplasmosis (1 case was fatal), and 1 case each of pneumocystosis, nocardiosis and cytomegalovirus. Tuberculosis was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported post-marketing. Most of these cases of tuberculosis occurred within the first 2 months after initiation of therapy with infliximab and may reflect recrudescence of latent disease [see Warnings and Precautions (5.1)]. In the 1year placebo-controlled studies RA I and RA II, 5.3% of patients receiving infliximab every 8 weeks with MTX developed serious infections as compared to 3.4% of placebo patients receiving MTX. Of 924 patients receiving infliximab, 1.7% developed pneumonia and 0.4% developed TB, when compared to 0.3% and 0.0% in the placebo arm respectively. In a shorter (22-week) placebo-controlled study of 1082 RA patients randomized to receive placebo, 3 mg/kg or 10 mg/kg infliximab infusions at 0, 2, and 6 weeks, followed by every 8 weeks with MTX, serious infections were more frequent in the 10 mg/kg infliximab group (5.3%) than the 3 mg/kg or placebo groups (1.7% in both). During the 54-week Crohn's II Study, 15% of patients with fistulizing Crohn's disease developed a new fistula-related abscess.
In infliximab clinical studies in patients with ulcerative colitis, infections treated with antimicrobials were reported in 27% of infliximab-treated patients (average of 41 weeks of follow-up) and in 18% of placebo-treated patients (average 32 weeks of follow-up). The types of infections, including serious infections, reported in patients with ulcerative colitis were similar to those reported in other clinical studies.
The onset of serious infections may be preceded by constitutional symptoms such as fever, chills, weight loss, and fatigue. The majority of serious infections, however, may also be preceded by signs or symptoms localized to the site of the infection.
Autoantibodies/Lupus-like Syndrome
Approximately half of infliximab-treated patients in clinical trials who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately one-fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately one-fifth of infliximab-treated patients compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.
Malignancies
In controlled trials, more infliximab-treated patients developed malignancies than placebo-treated patients [see Warnings and Precautions (5.2)].
In a randomized controlled clinical trial exploring the use of infliximab in patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 patients were treated with infliximab at doses similar to those used in rheumatoid arthritis and Crohn's disease. Of these infliximab-treated patients, 9 developed a malignancy, including 1 lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 3.51 -14.56). There was 1 reported malignancy among 77 control patients for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 0.04 -9.10). The majority of the malignancies developed in the lung or head and neck.
Patients with Heart Failure
In a randomized study evaluating infliximab in moderate to severe heart failure (NYHA Class III/IV; left ventricular ejection fraction ≤ 35%), 150 patients were randomized to receive treatment with 3 infusions of infliximab 10 mg/kg, 5 mg/kg, or placebo, at 0, 2, and 6 weeks. Higher incidences of mortality and hospitalization due to worsening heart failure were observed in patients receiving the 10 mg/kg infliximab dose. At 1 year, 8 patients in the 10 mg/kg infliximab group had died compared with 4 deaths each in the 5 mg/kg infliximab and the placebo groups. There were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg infliximab treatment groups, versus placebo. Infliximab has not been studied in patients with mild heart failure (NYHA Class I/II) [see Contraindications (4) and Warnings and Precautions (5.5)].
Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other infliximab products may be misleading.
Treatment with infliximab products can be associated with the development of antibodies to infliximab products. An enzyme immunoassay (EIA) method was originally used to measure anti-infliximab antibodies in clinical studies of infliximab. The EIA method is subject to interference by serum infliximab, possibly resulting in an underestimation of the rate of patient antibody formation. A separate, drug-tolerant electrochemiluminescence immunoassay (ECLIA) method for detecting antibodies to infliximab was subsequently developed and validated. This method is 60-fold more sensitive than the original EIA. With the ECLIA method, all clinical samples can be classified as either positive or negative for antibodies to infliximab without the need for the inconclusive category.
The incidence of antibodies to infliximab was based on the original EIA method in all clinical studies of infliximab except for the Phase 3 study in pediatric patients with ulcerative colitis where the incidence of antibodies to infliximab was detected using both the EIA and ECLIA methods [see Adverse Reactions, Pediatric Ulcerative Colitis (6.1)].
The incidence of antibodies to infliximab in patients given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of treatment with infliximab. A higher incidence of antibodies to infliximab was observed in Crohn's disease patients receiving infliximab after drug-free intervals >16 weeks. In a study of psoriatic arthritis in which 191 patients received 5 mg/kg with or without MTX, antibodies to infliximab occurred in 15% of patients. The majority of antibody-positive patients had low titers. Patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and to experience an infusion reaction [see Adverse Reactions (6.1)] than were patients who were antibody negative. Antibody development was lower among rheumatoid arthritis and Crohn's disease patients receiving immunosuppressant therapies such as 6-MP/AZA or MTX.
In the psoriasis Study II, which included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year, and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the psoriasis Study III, which also included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (weeks 0, 2 and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in Studies I and II in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year and in Study III in patients treated with 5 mg/kg induction (14.1%-23.0%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in psoriasis patients as compared to patients with other diseases treated with infliximab products over the long term is not known.
Hepatotoxicity
Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported in patients receiving infliximab products [see Warnings and Precautions (5.4)]. Reactivation of hepatitis B virus has occurred in patients receiving TNF-blocking agents, including infliximab products, who are chronic carriers of this virus [see Warnings and Precautions (5.3)].
In clinical trials in rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis, elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving infliximab than in controls (Table 1), both when infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of infliximab, or modification of concomitant medications.
| Proportion of patients with elevated ALT | ||||||
|---|---|---|---|---|---|---|
| > 1 to < 3 × ULN | ≥ 3 × ULN | ≥ 5 × ULN | ||||
| Placebo | Infliximab | Placebo | Infliximab | Placebo | Infliximab | |
| Rheumatoid arthritis Placebo patients received methotrexate while infliximab patients received both infliximab and methotrexate. Median follow-up was 58 weeks. | 24% | 34% | 3% | 4% | < 1% | < 1% |
| Crohn's disease Placebo patients in the 2 Phase 3 trials in Crohn's disease received an initial dose of 5 mg/kg infliximab at study start and were on placebo in the maintenance phase. Patients who were randomized to the placebo maintenance group and then later crossed over to infliximab are included in the infliximab group in ALT analysis. Median follow-up was 54 weeks. | 34% | 39% | 4% | 5% | 0% | 2% |
| Ulcerative colitis Median follow-up was 30 weeks. Specifically, the median duration of follow-up was 30 weeks for placebo and 31 weeks for infliximab. | 12% | 17% | 1% | 2% | < 1% | < 1% |
| Ankylosing spondylitis Median follow-up was 24 weeks for the placebo group and 102 weeks for the infliximab group. | 15% | 51% | 0% | 10% | 0% | 4% |
| Psoriatic arthritis Median follow-up was 39 weeks for the infliximab group and 18 weeks for the placebo group. | 16% | 50% | 0% | 7% | 0% | 2% |
| Plaque psoriasis ALT values are obtained in 2 Phase 3 psoriasis studies with median follow-up of 50 weeks for infliximab and 16 weeks for placebo. | 24% | 49% | <1% | 8% | 0% | 3% |
Adverse Reactions in Psoriasis Studies
During the placebo-controlled portion across the 3 clinical trials up to Week 16, the proportion of patients who experienced at least 1 serious adverse reaction (SAE; defined as resulting in death, life threatening, requires hospitalization, or persistent or significant disability/incapacity) was 0.5% in the 3 mg/kg infliximab group, 1.9% in the placebo group, and 1.6% in the 5 mg/kg infliximab group.
Among patients in the 2 Phase 3 studies, 12.4% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 SAE in Study I. In Study II, 4.1% and 4.7% of patients receiving infliximab 3 mg/kg and 5 mg/kg every 8 weeks, respectively, through 1 year of maintenance treatment experienced at least 1 SAE. One death due to bacterial sepsis occurred 25 days after the second infusion of 5 mg/kg infliximab. Serious infections included sepsis, and abscesses. In Study I, 2.7% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 serious infection. In Study II, 1.0% and 1.3% of patients receiving infliximab 3 mg/kg and 5 mg/kg, respectively, through 1 year of treatment experienced at least 1 serious infection. The most common serious infection (requiring hospitalization) was abscess (skin, throat, and peri-rectal) reported by 5 (0.7%) patients in the 5 mg/kg infliximab group. Two active cases of tuberculosis were reported: 6 weeks and 34 weeks after starting infliximab.
In the placebo-controlled portion of the psoriasis studies, 7 of 1123 patients who received infliximab at any dose were diagnosed with at least one NMSC compared to 0 of 334 patients who received placebo.
In the psoriasis studies, 1% (15/1373) of patients experienced serum sickness or a combination of arthralgia and/or myalgia with fever, and/or rash, usually early in the treatment course. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility.
Other Adverse Reactions
Safety data are available from 4779 adult patients treated with infliximab, including 1304 with rheumatoid arthritis, 1106 with Crohn's disease, 484 with ulcerative colitis, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis and 17 with other conditions. [For information on other adverse reactions in pediatric patients, see Adverse Reactions (6.1)]. Adverse reactions reported in ≥ 5% of all patients with rheumatoid arthritis receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis and Crohn's disease patients treated with infliximab except for abdominal pain, which occurred in 26% of patients with Crohn's disease. In the Crohn's disease studies, there were insufficient numbers and duration of follow-up for patients who never received infliximab to provide meaningful comparisons.
| Placebo | Infliximab | |
|---|---|---|
| (n = 350) | (n = 1129) | |
| Average weeks of follow-up | 59 | 66 |
| Gastrointestinal | ||
| Nausea | 20% | 21% |
| Abdominal pain | 8% | 12% |
| Diarrhea | 12% | 12% |
| Dyspepsia | 7% | 10% |
| Respiratory | ||
| Upper respiratory tract infection | 25% | 32% |
| Sinusitis | 8% | 14% |
| Pharyngitis | 8% | 12% |
| Coughing | 8% | 12% |
| Bronchitis | 9% | 10% |
| Skin and appendages disorders | ||
| Rash | 5% | 10% |
| Pruritus | 2% | 7% |
| Body as a whole-general disorders | ||
| Fatigue | 7% | 9% |
| Pain | 7% | 8% |
| Resistance mechanism disorders | ||
| Fever | 4% | 7% |
| Moniliasis | 3% | 5% |
| Central and peripheral nervous system disorders | ||
| Headache | 14% | 18% |
| Musculoskeletal system disorders | ||
| Arthralgia | 7% | 8% |
| Urinary system disorders | ||
| Urinary tract infection | 6% | 8% |
| Cardiovascular disorders, general | ||
| Hypertension | 5% | 7% |
The most common serious adverse reactions observed in clinical trials of infliximab were infections [see Adverse Reactions (6.1)]. Other serious, medically relevant adverse reactions ≥ 0.2% or clinically significant adverse reactions by body system were as follows:
Body as a whole: allergic reaction, edema
Blood: pancytopenia
Cardiovascular: hypotension
Gastrointestinal: constipation, intestinal obstruction
Central and Peripheral Nervous: dizziness
Heart Rate and Rhythm: bradycardia
Liver and Biliary: hepatitis
Metabolic and Nutritional: dehydration
Platelet, Bleeding and Clotting: thrombocytopenia
Neoplasms: lymphoma
Red Blood Cell: anemia, hemolytic anemia
Resistance Mechanism: cellulitis, sepsis, serum sickness, sarcoidosis
Respiratory: lower respiratory tract infection (including pneumonia), pleurisy, pulmonary edema
Skin and Appendages: increased sweating
Vascular (Extracardiac): thrombophlebitis
White Cell and Reticuloendothelial: leukopenia, lymphadenopathy
Adverse Reactions in Pediatric Patients
Pediatric Crohn's Disease
There were some differences in the adverse reactions observed in the pediatric patients receiving infliximab compared to those observed in adults with Crohn's disease. These differences are discussed in the following paragraphs.
The following adverse reactions were reported more commonly in 103 randomized pediatric Crohn's disease patients administered 5 mg/kg infliximab through 54 weeks than in 385 adult Crohn's disease patients receiving a similar treatment regimen: anemia (11%), leukopenia (9%), flushing (9%), viral infection (8%), neutropenia (7%), bone fracture (7%), bacterial infection (6%), and respiratory tract allergic reaction (6%).
Infections were reported in 56% of randomized pediatric patients in Study Peds Crohn's and in 50% of adult patients in Study Crohn's I. In Study Peds Crohn's, infections were reported more frequently for patients who received every 8-week as opposed to every 12-week infusions (74% and 38%, respectively), while serious infections were reported for 3 patients in the every 8-week and 4 patients in the every 12-week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Pneumonia was reported for 3 patients, (2 in the every 8week and 1 in the every 12-week maintenance treatment groups). Herpes zoster was reported for 2 patients in the every 8-week maintenance treatment group.
In Study Peds Crohn's, 18% of randomized patients experienced 1 or more infusion reactions, with no notable difference between treatment groups. Of the 112 patients in Study Peds Crohn's, there were no serious infusion reactions, and 2 patients had non-serious anaphylactoid reactions.
In Study Peds Crohn's, in which all patients received stable doses of 6-MP, AZA, or MTX, excluding inconclusive samples, 3 of 24 patients had antibodies to infliximab. Although 105 patients were tested for antibodies to infliximab, 81 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample.
Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in Crohn's disease clinical trials; 4% had ALT elevations ≥ 3 × ULN, and 1% had elevations ≥ 5 × ULN. (Median follow-up was 53 weeks.)
Pediatric Ulcerative Colitis
Overall, the adverse reactions reported in the pediatric ulcerative colitis trial and adult ulcerative colitis (Study UC I and Study UC II) studies were generally consistent. In a pediatric UC trial, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache.
Infections were reported in 31 (52%) of 60 treated patients in the pediatric UC trial and 22 (37%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in the pediatric UC trial was similar to that in the pediatric Crohn's disease study (Study Peds Crohn's) but higher than the proportion in the adults' ulcerative colitis studies (Study UC I and Study UC II). The overall incidence of infections in the pediatric UC trial was 13/22 (59%) in the every 8 week maintenance treatment group. Upper respiratory tract infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequently reported respiratory system infections. Serious infections were reported in 12% (7/60) of all treated patients.
In the pediatric UC trial, 58 patients were evaluated for antibodies to infliximab using the EIA as well as the drug-tolerant ECLIA. With the EIA, 4 of 58 (7%) patients had antibodies to infliximab. With the ECLIA, 30 of 58 (52%) patients had antibodies to infliximab [see Adverse Reactions, Immunogenicity (6.1)]. The higher incidence of antibodies to infliximab by the ECLIA method was due to the 60-fold higher sensitivity compared to the EIA method. While EIA-positive patients generally had undetectable trough infliximab concentrations, ECLIA-positive patients could have detectable trough concentrations of infliximab because the ECLIA assay is more sensitive and drug-tolerant.
Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 17% (10/60) of pediatric patients in the pediatric UC trial; 7% (4/60) had ALT elevations ≥ 3 × ULN, and 2% (1/60) had elevations ≥ 5 × ULN (median follow-up was 49 weeks).
Overall, 8 of 60 (13%) treated patients experienced one or more infusion reactions, including 4 of 22 (18%) patients in the every 8-week treatment maintenance group. No serious infusion reactions were reported.
In the pediatric UC trial, 45 patients were in the 12 to 17 year age group and 15 in the 6 to 11 year age group. The numbers of patients in each subgroup are too small to make any definitive conclusions about the effect of age on safety events. There were higher proportions of patients with serious adverse events (40% vs. 18%) and discontinuation due to adverse events (40% vs. 16%) in the younger age group than in the older age group. While the proportion of patients with infections was also higher in the younger age group (60% vs. 49%), for serious infections, the proportions were similar in the two age groups (13% in the 6 to 11 year age group vs. 11% in the 12 to 17 year age group). Overall proportions of adverse reactions, including infusion reactions, were similar between the 6 to 11 and 12 to 17 year age groups (13%).
Infusion-related Reactions
In post-marketing experience, cases of anaphylactic reactions, including anaphylactic shock, laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with administration of infliximab products.
Cases of transient visual loss have been reported in association with infliximab products during or within 2 hours of infusion. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported [see Warnings and Precautions (5.8)].
Adverse Reactions in Pediatric Patients
The following serious adverse reactions have been reported in the post-marketing experience in children: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, and hypersensitivity reactions.
Serious adverse reactions in the post-marketing experience with infliximab products in the pediatric population have also included malignancies, including hepatosplenic T-cell lymphomas [see Boxed WARNINGS and Warnings and Precautions (5.2)], transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.
Risk Summary
Available data from published literature on the use of infliximab products during pregnancy have not reported a clear association with infliximab products and adverse pregnancy outcomes. Infliximab products cross the placenta and infants exposed in utero should not be administered live vaccines for at least 6 months after birth [see Clinical Considerations]. In a development study conducted in mice using an analogous antibody, no evidence of maternal toxicity, embryotoxicity or teratogenicity was observed [see Data].
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Fetal/Neonatal adverse reactions
Infliximab products cross the placenta, and have been detected in the serum of infants up to 6 months following birth. Consequently, these infants may be at increased risk of infection, including disseminated infection which can become fatal. At least a six month waiting period following birth is recommended before the administration of live vaccines (e.g., BCG vaccine or other live vaccines, such as the rotavirus vaccine) to these infants [see Warnings and Precautions (5.15)]. Cases of agranulocytosis in infants exposed in utero have also been reported [see Adverse Reactions (6.2)].
Data
Animal Data
Because infliximab products do not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab products. An embryofetal development study was conducted in pregnant mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα. This antibody, administered during the period of organogenesis on gestation day 6 and 12 at IV doses up to 40 mg/kg produced no evidence of maternal toxicity, embryotoxicity, or teratogenicity. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness.
Risk Summary
Available information is insufficient to inform the amount of infliximab products present in human milk, and the effects on the breastfed infant. There are no data on the effects of infliximab products on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for an infliximab product and any potential adverse effects on the breastfed infant from infliximab products or from the underlying maternal condition.
Pediatric Crohn's Disease
RENFLEXIS is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy [see Boxed Warnings, Warnings and Precautions (5), Indications and Usage (1.2), Dosage and Administration (2.2), Clinical Studies (14.2) and Adverse Reactions (6.1)].
Infliximab has been studied only in combination with conventional immunosuppressive therapy in pediatric Crohn's disease. The longer term (greater than 1 year) safety and effectiveness of infliximab products in pediatric Crohn's disease patients have not been established in clinical trials.
Pediatric Ulcerative Colitis
The safety and effectiveness of infliximab products for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy are supported by evidence from adequate and well-controlled studies of infliximab in adults. Additional safety and pharmacokinetic data were collected in 60 pediatric patients aged 6 years and older [see Clinical Pharmacology (12.3), Dosage and Administration (2.4), Adverse Reactions (6.1), and Clinical Studies (14.4)]. The effectiveness of infliximabin inducing and maintaining mucosal healing could not be established. Although 41 patients had a Mayo endoscopy subscore of 0 or 1 at the Week 8 endoscopy, the induction phase was open-label and lacked a control group. Only 9 patients had an optional endoscopy at Week 54.
In the pediatric UC trial, approximately half of the patients were on concomitant immunomodulators (AZA, 6-MP, MTX) at study start. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when RENFLEXIS is used in combination with other immunosuppressants.
The longer term (greater than 1 year) safety and effectiveness of infliximab products in pediatric ulcerative colitis patients have not been established in clinical trials.
Juvenile Rheumatoid Arthritis (JRA)
The safety and efficacy of infliximab in patients with juvenile rheumatoid arthritis (JRA) were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension, for a maximum of 44 weeks. Patients with active JRA between the ages of 4 and 17 years who had been treated with MTX for at least 3 months were enrolled. Concurrent use of folic acid, oral corticosteroids (≤0.2 mg/kg/day of prednisone or equivalent), NSAIDs, and/or disease modifying antirheumatic drugs (DMARDs) was permitted.
Doses of 3 mg/kg infliximab or placebo were administered intravenously at Weeks 0, 2 and 6. Patients randomized to placebo crossed-over to receive 6 mg/kg infliximab at Weeks 14, 16, and 20, and then every 8 weeks through Week 44. Patients who completed the study continued to receive open-label treatment with infliximab for up to 2 years in a companion extension study.
The study failed to establish the efficacy of infliximab in the treatment of JRA. Key observations in the study included a high placebo response rate and a higher rate of immunogenicity than what has been observed in adults. Additionally, a higher rate of clearance of infliximab was observed than had been observed in adults [see Clinical Pharmacology (12.3)].
A total of 60 patients with JRA were treated with doses of 3 mg/kg and 57 patients were treated with doses of 6 mg/kg. The proportion of patients with infusion reactions who received 3 mg/kg infliximab was 35% (21/60) over 52 weeks compared with 18% (10/57) in patients who received 6 mg/kg over 38 weeks. The most common infusion reactions reported were vomiting, fever, headache, and hypotension. In the 3 mg/kg infliximab group, 4 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg infliximab group, 2 patients had a serious infusion reaction, 1 of whom had a possible anaphylactic reaction. Two of the 6 patients who experienced serious infusion reactions received infliximab by rapid infusion (duration of less than 2 hours). Antibodies to infliximab developed in 38% (20/53) of patients who received 3 mg/kg infliximab compared with 12% (6/49) of patients who received 6 mg/kg.
A total of 68% (41/60) of patients who received 3 mg/kg infliximab in combination with MTX experienced an infection over 52 weeks compared with 65% (37/57) of patients who received 6 mg/kg infliximab in combination with MTX over 38 weeks. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was pneumonia. Other notable infections included primary varicella infection in 1 patient and herpes zoster in 1 patient.
Active Crohn's Disease
The safety and efficacy of single and multiple doses of infliximab were assessed in 2 randomized, double-blind, placebo-controlled clinical studies in 653 patients with moderate to severely active Crohn's disease [Crohn's Disease Activity Index (CDAI) ≥ 220 and ≤ 400] with an inadequate response to prior conventional therapies. Concomitant stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents were permitted and 92% of patients continued to receive at least one of these medications.
In the single-dose trial of 108 patients, 16% (4/25) of placebo patients achieved a clinical response (decrease in CDAI ≥ 70 points) at Week 4 vs. 81% (22/27) of patients receiving 5 mg/kg infliximab (p < 0.001, two-sided, Fisher's Exact test). Additionally, 4% (1/25) of placebo patients and 48% (13/27) of patients receiving 5 mg/kg infliximab achieved clinical remission (CDAI < 150) at Week 4.
In a multidose trial (ACCENT I [Study Crohn's I]), 545 patients received 5 mg/kg at Week 0 and were then randomized to one of three treatment groups; the placebo maintenance group received placebo at Weeks 2 and 6, and then every 8 weeks; the 5 mg/kg maintenance group received 5 mg/kg at Weeks 2 and 6, and then every 8 weeks; and the 10 mg/kg maintenance group received 5 mg/kg at Weeks 2 and 6, and then 10 mg/kg every 8 weeks. Patients in response at Week 2 were randomized and analyzed separately from those not in response at Week 2. Corticosteroid taper was permitted after Week 6.
At Week 2, 57% (311/545) of patients were in clinical response. At Week 30, a significantly greater proportion of these patients in the 5 mg/kg and 10 mg/kg maintenance groups achieved clinical remission compared to patients in the placebo maintenance group (Table 3). Additionally, a significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg infliximab maintenance groups were in clinical remission and were able to discontinue corticosteroid use compared to patients in the placebo maintenance group at Week 54 (Table 3).
| Single 5-mg/kg Dose Infliximab at Week 0 | Three-Dose Induction Infliximab 5 mg/kg administered at Weeks 0, 2 and 6 | ||
|---|---|---|---|
| Placebo Maintenance | Infliximab Maintenance q 8 wks | ||
| 5 mg/kg | 10 mg/kg | ||
| Week 30 | 25/102 | 41/104 | 48/105 |
| Clinical remission | 25% | 39% | 46% |
| P-value P-values represent pairwise comparisons to placebo | 0.022 | 0.001 | |
| Week 54 | 6/54 | 14/56 | 18/53 |
| Patients in remission able to discontinue corticosteroid use Of those receiving corticosteroids at baseline | 11% | 25% | 34% |
| P-value | 0.059 | 0.005 | |
Patients in the infliximab maintenance groups (5 mg/kg and 10 mg/kg) had a longer time to loss of response than patients in the placebo maintenance group (Figure 1). At Weeks 30 and 54, significant improvement from baseline was seen among the 5 mg/kg and 10 mg/kg infliximab-treated groups compared to the placebo group in the disease-specific inflammatory bowel disease questionnaire (IBDQ), particularly the bowel and systemic components, and in the physical component summary score of the general health-related quality of life questionnaire SF-36.
Figure 1 (Renflexis 01)
Figure 1 Kaplan-Meier estimate of the proportion of patients who had not lost response through Week 54
In a subset of 78 patients who had mucosal ulceration at baseline and who participated in an endoscopic substudy, 13 of 43 patients in the infliximab maintenance group had endoscopic evidence of mucosal healing compared to 1 of 28 patients in the placebo group at Week 10. Of the infliximab-treated patients showing mucosal healing at Week 10, 9 of 12 patients also showed mucosal healing at Week 54.
Patients who achieved a response and subsequently lost response were eligible to receive infliximab on an episodic basis at a dose that was 5 mg/kg higher than the dose to which they were randomized. The majority of such patients responded to the higher dose. Among patients who were not in response at Week 2, 59% (92/157) of infliximab maintenance patients responded by Week 14 compared to 51% (39/77) of placebo maintenance patients. Among patients who did not respond by Week 14, additional therapy did not result in significantly more responses [see Dosage and Administration (2)].
Fistulizing Crohn's Disease
The safety and efficacy of infliximab were assessed in 2 randomized, double-blind, placebo-controlled studies in patients with fistulizing Crohn's disease with fistula(s) that were of at least 3 months duration. Concurrent use of stable doses of corticosteroids, 5-aminosalicylates, antibiotics, MTX, 6-mercaptopurine (6-MP) and/or azathioprine (AZA) was permitted.
In the first trial, 94 patients received 3 doses of either placebo or infliximab at Weeks 0, 2 and 6. Fistula response (≥ 50% reduction in number of enterocutaneous fistulas draining upon gentle compression on at least 2 consecutive visits without an increase in medication or surgery for Crohn's disease) was seen in 68% (21/31) of patients in the 5 mg/kg infliximab group (P = 0.002) and 56% (18/32) of patients in the 10 mg/kg infliximab group (P = 0.021) vs. 26% (8/31) of patients in the placebo arm. The median time to onset of response and median duration of response in infliximab-treated patients was 2 and 12 weeks, respectively. Closure of all fistulas was achieved in 52% of infliximab-treated patients compared with 13% of placebo-treated patients (P < 0.001).
In the second trial (ACCENT II [Study Crohn's II]), patients who were enrolled had to have at least 1 draining enterocutaneous (perianal, abdominal) fistula. All patients received 5 mg/kg infliximab at Weeks 0, 2 and 6. Patients were randomized to placebo or 5 mg/kg infliximab maintenance at Week 14. Patients received maintenance doses at Week 14 and then every 8 weeks through Week 46. Patients who were in fistula response (fistula response was defined the same as in the first trial) at both Weeks 10 and 14 were randomized separately from those not in response. The primary endpoint was time from randomization to loss of response among those patients who were in fistula response.
Among the randomized patients (273 of the 296 initially enrolled), 87% had perianal fistulas and 14% had abdominal fistulas. Eight percent also had rectovaginal fistulas. Greater than 90% of the patients had received previous immunosuppressive and antibiotic therapy.
At Week 14, 65% (177/273) of patients were in fistula response. Patients randomized to infliximab maintenance had a longer time to loss of fistula response compared to the placebo maintenance group (Figure 2). At Week 54, 38% (33/87) of infliximab-treated patients had no draining fistulas compared with 22% (20/90) of placebo-treated patients (P=0.02). Compared to placebo maintenance, patients on infliximab maintenance had a trend toward fewer hospitalizations.
Figure 2 (Renflexis 02)
Figure 2 Life table estimates of the proportion of patients who had not lost fistula response through Week 54
Patients who achieved a fistula response and subsequently lost response were eligible to receive infliximab maintenance therapy at a dose that was 5 mg/kg higher than the dose to which they were randomized. Of the placebo maintenance patients, 66% (25/38) responded to 5 mg/kg infliximab, and 57% (12/21) of infliximab maintenance patients responded to 10 mg/kg.
Patients who had not achieved a response by Week 14 were unlikely to respond to additional doses of infliximab.
Similar proportions of patients in either group developed new fistulas (17% overall) and similar numbers developed abscesses (15% overall).
Clinical Response, Clinical Remission, and Mucosal Healing
In both Study UC I and Study UC II, greater percentages of patients in both infliximab groups achieved clinical response, clinical remission and mucosal healing than in the placebo group. Each of these effects was maintained through the end of each trial (Week 54 in Study UC I, and Week 30 in Study UC II). In addition, a greater proportion of patients in infliximab groups demonstrated sustained response and sustained remission than in the placebo groups (Table 5).
Of patients on corticosteroids at baseline, greater proportions of patients in the infliximab treatment groups were in clinical remission and able to discontinue corticosteroids at Week 30 compared with the patients in the placebo treatment groups (22% in infliximab treatment groups vs. 10% in placebo group in Study UC I; 23% in infliximab treatment groups vs. 3% in placebo group in Study UC II). In Study UC I, this effect was maintained through Week 54 (21% in infliximab treatment groups vs. 9% in placebo group). The infliximab-associated response was generally similar in the 5 mg/kg and 10 mg/kg dose groups.
| Study UC I | Study UC II | |||||
|---|---|---|---|---|---|---|
| Placebo | 5 mg/kg infliximab | 10 mg/kg infliximab | Placebo | 5 mg/kg infliximab | 10 mg/kg infliximab | |
| Patients randomized | 121 | 121 | 122 | 123 | 121 | 120 |
| Clinical Response Defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1. (The Mayo score consists of the sum of four subscores: stool frequency, rectal bleeding, physician's global assessment and endoscopy findings.) ,Patients who had a prohibited change in medication, had an ostomy or colectomy, or discontinued study infusions due to lack of efficacy are considered to not be in clinical response, clinical remission or mucosal healing from the time of the event onward. | ||||||
| Week 8 | 37% | 69% P < 0.001, | 62% | 29% | 65% | 69% |
| Week 30 | 30% | 52% | 51% P < 0.01 | 26% | 47% | 60% |
| Week 54 | 20% | 45% | 44% | NA | NA | NA |
| Sustained Response | ||||||
| (Clinical response at both Week 8 and 30) | 23% | 49% | 46% | 15% | 41% | 53% |
| (Clinical response at Week 8, 30 and 54) | 14% | 39% | 37% | NA | NA | NA |
| Clinical Remission Defined as a Mayo score ≤2 points, no individual subscore >1. , | ||||||
| Week 8 | 15% | 39% | 32% | 6% | 34% | 28% |
| Week 30 | 16% | 34% | 37% | 11% | 26% | 36% |
| Week 54 | 17% | 35% | 34% | NA | NA | NA |
| Sustained Remission | ||||||
| (Clinical response at both Week 8 and 30) | 8% | 23% | 26% | 2% | 15% | 23% |
| (Clinical response at Week 8, 30 and 54) | 7% | 20% | 20% | NA | NA | NA |
| Mucosal Healing Defined as a 0 or 1 on the endoscopy subscore of the Mayo score. , | ||||||
| Week 8 | 34% | 62% | 59% | 31% | 60% | 62% |
| Week 30 | 25% | 50% | 49% | 30% | 46% | 57% |
| Week 54 | 18% | 45% | 47% | NA | NA | NA |
The improvement with infliximab was consistent across all Mayo subscores through Week 54 (Study UC I shown in Table 6; Study UC II through Week 30 was similar).
| Study UC I | |||
|---|---|---|---|
| Infliximab | |||
| Placebo | 5 mg/kg | 10 mg/kg | |
| (n = 121) | (n = 121) | (n = 122) | |
| Stool frequency | |||
| Baseline | 17% | 17% | 10% |
| Week 8 | 35% | 60% | 58% |
| Week 30 | 35% | 51% | 53% |
| Week 54 | 31% | 52% | 51% |
| Rectal bleeding | |||
| Baseline | 54% | 40% | 48% |
| Week 8 | 74% | 86% | 80% |
| Week 30 | 65% | 74% | 71% |
| Week 54 | 62% | 69% | 67% |
| Physician's Global Assessment | |||
| Baseline | 4% | 6% | 3% |
| Week 8 | 44% | 74% | 64% |
| Week 30 | 36% | 57% | 55% |
| Week 54 | 26% | 53% | 53% |
| Endoscopy findings | |||
| Baseline | 0% | 0% | 0% |
| Week 8 | 34% | 62% | 59% |
| Week 30 | 26% | 51% | 52% |
| Week 54 | 21% | 50% | 51% |
Clinical Response
In Study RA I, all doses/schedules of infliximab + MTX resulted in improvement in signs and symptoms as measured by the American College of Rheumatology response criteria (ACR 20) with a higher percentage of patients achieving an ACR 20, 50 and 70 compared to placebo + MTX (Table 7). This improvement was observed at Week 2 and maintained through Week 102. Greater effects on each component of the ACR 20 were observed in all patients treated with infliximab + MTX compared to placebo + MTX (Table 8). More patients treated with infliximab reached a major clinical response than placebo-treated patients (Table 7).
In Study RA II, after 54 weeks of treatment, both doses of infliximab + MTX resulted in statistically significantly greater response in signs and symptoms compared to MTX alone as measured by the proportion of patients achieving ACR 20, 50 and 70 responses (Table 7). More patients treated with infliximab reached a major clinical response than placebo-treated patients (Table 7).
| Study RA I | Study RA II | |||||||
|---|---|---|---|---|---|---|---|---|
| Infliximab + MTX | Infliximab + MTX | |||||||
| 3 mg/kg | 10 mg/kg | 3 mg/kg | 6 mg/kg | |||||
| Response | Placebo + MTX | q8 wks | q4 wks | q8 wks | q4 wks | Placebo + MTX | q8 wks | q8 wks |
| (n = 88) | (n = 86) | (n = 86) | (n = 87) | (n = 81) | (n = 274) | (n = 351) | (n = 355) | |
| ACR20 | ||||||||
| Week 30 | 20% | 50% P ≤ 0.001 | 50% | 52% | 58% | N/A | N/A | N/A |
| Week 54 | 17% | 42% | 48% | 59% | 59% | 54% | 62% P < 0.05 | 66% |
| ACR50 | ||||||||
| Week 30 | 5% | 27% | 29% | 31% | 26% | N/A | N/A | N/A |
| Week 54 | 9% | 21% | 34% | 40% | 38% | 32% | 46% | 50% |
| ACR70 | ||||||||
| Week 30 | 0% | 8% P < 0.01 | 11% | 18% | 11% | N/A | N/A | N/A |
| Week 54 | 2% | 11% | 18% | 26% | 19% | 21% | 33% | 37% |
| Major clinical response A major clinical response was defined as a 70% ACR response for 6 consecutive months (consecutive visits spanning at least 26 weeks) through week 102 for Study RA I and week 54 for Study RA II. | 0% | 7% | 8% | 15% | 6% | 8% | 12% | 17% |
| Placebo + MTX | Infliximab + MTX All doses/schedules of infliximab + MTX | |||
|---|---|---|---|---|
| (n = 88) | (n = 340) | |||
| Parameter (medians) | Baseline | Week54 | Baseline | Week54 |
| No. of Tender Joints | 24 | 16 | 32 | 8 |
| No. of Swollen Joints | 19 | 13 | 20 | 7 |
| Pain Visual Analog Scale (0=best, 10=worst) | 6.7 | 6.1 | 6.8 | 3.3 |
| Physician's Global Assessment | 6.5 | 5.2 | 6.2 | 2.1 |
| Patient's Global Assessment | 6.2 | 6.2 | 6.3 | 3.2 |
| Disability Index (HAQ-DI) Health Assessment Questionnaire, measurement of 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities (0=best, 3=worst) | 1.8 | 1.5 | 1.8 | 1.3 |
| CRP (mg/dL) | 3.0 | 2.3 | 2.4 | 0.6 |
Radiographic Response
Structural damage in both hands and feet was assessed radiographically at Week 54 by the change from baseline in the van der Heijde-modified Sharp (vdH-S) score, a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing in hands/wrists and feet.3
In Study RA I, approximately 80% of patients had paired X-ray data at 54 weeks and approximately 70% at 102 weeks. The inhibition of progression of structural damage was observed at 54 weeks (Table 9) and maintained through 102 weeks.
In Study RA II, >90% of patients had at least 2 evaluable X-rays. Inhibition of progression of structural damage was observed at Weeks 30 and 54 (Table 9) in the infliximab + MTX groups compared to MTX alone. Patients treated with infliximab + MTX demonstrated less progression of structural damage compared to MTX alone, whether baseline acute-phase reactants (ESR and CRP) were normal or elevated: patients with elevated baseline acute-phase reactants treated with MTX alone demonstrated a mean progression in vdH-S score of 4.2 units compared to patients treated with infliximab + MTX who demonstrated 0.5 units of progression; patients with normal baseline acute phase reactants treated with MTX alone demonstrated a mean progression in vdH-S score of 1.8 units compared to infliximab + MTX who demonstrated 0.2 units of progression. Of patients receiving infliximab + MTX, 59% had no progression (vdH-S score ≤ 0 unit) of structural damage compared to 45% of patients receiving MTX alone. In a subset of patients who began the study without erosions, infliximab + MTX maintained an erosion-free state at 1 year in a greater proportion of patients than MTX alone, 79% (77/98) vs. 58% (23/40), respectively (P<0.01). Fewer patients in the infliximab + MTX groups (47%) developed erosions in uninvolved joints compared to MTX alone (59%).
| Study RA I | Study RA II | |||||
|---|---|---|---|---|---|---|
| Infliximab + MTX | Infliximab + MTX | |||||
| Placebo + MTX (n = 64) | 3 mg/kg q8 wks (n = 71) | 10 mg/kg q8 wks (n = 77) | Placebo + MTX (n = 282) | 3 mg/kg q8 wks (n = 359) | 6 mg/kg q8 wks (n = 363) | |
| Total score | ||||||
| Baseline | ||||||
| Mean | 79 | 78 | 65 | 11.3 | 11.6 | 11.2 |
| Median | 55 | 57 | 56 | 5.1 | 5.2 | 5.3 |
| Change from baseline | ||||||
| Mean | 6.9 | 1.3 P < 0.001 for each outcome against placebo. | 0.2 | 3.7 | 0.4 | 0.5 |
| Median | 4.0 | 0.5 | 0.5 | 0.4 | 0.0 | 0.0 |
| Erosion Score | ||||||
| Baseline | ||||||
| Mean | 44 | 44 | 33 | 8.3 | 8.8 | 8.3 |
| Median | 25 | 29 | 22 | 3.0 | 3.8 | 3.8 |
| Change from baseline | ||||||
| Mean | 4.1 | 0.2 | 0.2 | 3.0 | 0.3 | 0.1 |
| Median | 2.0 | 0.0 | 0.5 | 0.3 | 0.0 | 0.0 |
| JSN Score | ||||||
| Baseline | ||||||
| Mean | 36 | 34 | 31 | 3.0 | 2.9 | 2.9 |
| Median | 26 | 29 | 24 | 1.0 | 1.0 | 1.0 |
| Change from baseline | ||||||
| Mean | 2.9 | 1.1 | 0.0 | 0.6 | 0.1 | 0.2 |
| Median | 1.5 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
Physical Function Response
Physical function and disability were assessed using the Health Assessment Questionnaire (HAQ-DI) and the general health-related quality of life questionnaire SF-36.
In Study RA I, all doses/schedules of infliximab + MTX showed significantly greater improvement from baseline in HAQ-DI and SF-36 physical component summary score averaged over time through Week 54 compared to placebo + MTX, and no worsening in the SF-36 mental component summary score. The median (interquartile range) improvement from baseline to Week 54 in HAQ-DI was 0.1 (-0.1, 0.5) for the placebo + MTX group and 0.4 (0.1, 0.9) for infliximab + MTX (p<0.001). Both HAQ-DI and SF-36 effects were maintained through Week 102. Approximately 80% of patients in all doses/schedules of infliximab + MTX remained in the trial through 102 weeks.
In Study RA II, both infliximab treatment groups showed greater improvement in HAQ-DI from baseline averaged over time through Week 54 compared to MTX alone; 0.7 for infliximab + MTX vs. 0.6 for MTX alone (P≤0.001). No worsening in the SF-36 mental component summary score was observed.
Clinical Response
Treatment with infliximab resulted in improvement in signs and symptoms, as assessed by the ACR criteria, with 58% of infliximab-treated patients achieving ACR 20 at Week 14, compared with 11% of placebo-treated patients (P < 0.001). The response was similar regardless of concomitant use of methotrexate. Improvement was observed as early as Week 2. At 6 months, the ACR 20/50/70 responses were achieved by 54%, 41%, and 27%, respectively, of patients receiving infliximab compared to 16%, 4%, and 2%, respectively, of patients receiving placebo. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and spondylitis with peripheral arthritis subtypes.
Compared to placebo, treatment with infliximab resulted in improvements in the components of the ACR response criteria, as well as in dactylitis and enthesopathy (Table 11). The clinical response was maintained through Week 54. Similar ACR responses were observed in an earlier randomized, placebo-controlled study of 104 psoriatic arthritis patients, and the responses were maintained through 98 weeks in an open-label extension phase.
| Placebo | Infliximab 5 mg/kg P<0.001 for percent change from baseline in all components of ACR 20 at Week 24, P<0.05 for % of patients with dactylitis, and P=0.004 for % of patients with enthesopathy at Week 24 | |||
|---|---|---|---|---|
| Patient randomized | (n = 100) | (n = 100) | ||
| Baseline | Week 24 | Baseline | Week 24 | |
| Parameter (medians) | ||||
| No. of Tender Joints Scale 0-68 | 24 | 20 | 20 | 6 |
| No. of Swollen Joints Scale 0-66 | 12 | 9 | 12 | 3 |
| Pain Visual Analog Scale (0=best, 10=worst) | 6.4 | 5.6 | 5.9 | 2.6 |
| Physician's Global Assessment | 6.0 | 4.5 | 5.6 | 1.5 |
| Patient's Global Assessment | 6.1 | 5.0 | 5.9 | 2.5 |
| Disability Index (HAQ-DI) Health Assessment Questionnaire, measurement of 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities (0=best, 3=worst) | 1.1 | 1.1 | 1.1 | 0.5 |
| CRP (mg/dL) Normal range 0-0.6 mg/dL | 1.2 | 0.9 | 1.0 | 0.4 |
| % Patients with 1 or more digits with dactylitis | 41 | 33 | 40 | 15 |
| % Patients with enthesopathy | 35 | 36 | 42 | 22 |
Improvement in Psoriasis Area and Severity Index (PASI) in psoriatic arthritis patients with baseline body surface area (BSA) ≥ 3% (n = 87 placebo, n = 83 infliximab) was achieved at Week 14, regardless of concomitant methotrexate use, with 64% of infliximab-treated patients achieving at least 75% improvement from baseline vs. 2% of placebo-treated patients; improvement was observed in some patients as early as Week 2. At 6 months, the PASI 75 and PASI 90 responses were achieved by 60% and 39%, respectively, of patients receiving infliximab compared to 1% and 0%, respectively, of patients receiving placebo. The PASI response was generally maintained through Week 54. [See also Clinical Studies (14.8)].
Radiographic Response
Structural damage in both hands and feet was assessed radiographically by the change from baseline in the van der Heijde-Sharp (vdH-S) score, modified by the addition of hand DIP joints. The total modified vdH-S score is a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing (JSN) in the hands and feet. At Week 24, infliximab-treated patients had less radiographic progression than placebo-treated patients (mean change of -0.70 vs. 0.82, P < 0.001). infliximab-treated patients also had less progression in their erosion scores (-0.56 vs 0.51) and JSN scores (-0.14 vs 0.31).
The patients in the infliximab group demonstrated continued inhibition of structural damage at Week 54. Most patients showed little or no change in the vdH-S score during this 12-month study (median change of 0 in both patients who initially received infliximab or placebo). More patients in the placebo group (12%) had readily apparent radiographic progression compared with the infliximab group (3%).
Physical Function
Physical function status was assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. infliximab-treated patients demonstrated significant improvement in physical function as assessed by HAQ-DI (median percent improvement in HAQ-DI score from baseline to Week 14 and 24 of 43% for infliximab-treated patients vs 0% for placebo-treated patients).
During the placebo-controlled portion of the trial (24 weeks), 54% of infliximab-treated patients achieved a clinically meaningful improvement in HAQ-DI (≥0.3 unit decrease) compared to 22% of placebo-treated patients. infliximab-treated patients also demonstrated greater improvement in the SF-36 physical and mental component summary scores than placebo-treated patients. The responses were maintained for up to 2 years in an open-label extension study.
Immunosuppression
Inform patients that RENFLEXIS may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctors if they develop any symptoms of an infection, including tuberculosis and reactivation of hepatitis B virus infections. Patients should be counseled about the risk of lymphoma and other malignancies while receiving RENFLEXIS.
Other Medical Conditions
Advise patients to report any signs of new or worsening medical conditions such as heart disease, neurological disease, or autoimmune disorders. Advise patients to report any symptoms of a cytopenia such as bruising, bleeding or persistent fever.
