Review ENBREL’s extensive safety profile, including 10 years of continuous safety data, in treating patients with moderate to severe rheumatoid arthritis (RA).
SEAM-RA Study
Evaluation of etanercept and methotrexate in combination or as monotherapy in subjects with moderate to severe RA
Adverse Event Rates
During the double-blind period, rates for treatment-emergent adverse events, serious adverse events, and events leading to discontinuation were similar across all three treatment groups.1
No new safety signals were observed regarding the use of ENBREL or MTX1
| Treatment-Emergent Adverse Events1 |
MTX MonotherapyMono- therapy (n=100) | ENBREL MonotherapyMono- therapy (n=99) | ENBREL + MTX (n=53) |
|---|---|---|---|
| All treatment-emergent adverse events, n (%) | 63 (63.0) | 55 (55.6) | 33 (62.3) |
| Serious adverse events | 4 (4.0) | 4 (4.0) | 3 (5.7) |
| Adverse events leading to discontinuation of investigational product | 3 (3.0) | 2 (2.0) | 0 (0.0) |
| Fatal adverse events | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Treatment-Emergent Adverse Events Occurring in ≥5% of Patients, n (%)1,2 | MTX MonotherapyMono- therapy (n=100) | ENBREL MonotherapyMono- therapy (n=99) | ENBREL + MTX (n=53) |
|---|---|---|---|
| Infections | 28 (28.0) | 31 (31.3) | 14 (26.4) |
| Musculoskeletal and connective tissue disorder | 33 (33.0) | 19 (19.2) | 11 (20.8) |
| Injury, poisoning, and procedural complications | 10 (10.0) | 9 (9.1) | 3 (5.7) |
| Respiratory, thoracic, and mediastinal disorders | 6 (6.0) | 4 (4.0) | 3 (5.7) |
| Gastrointestinal disorders | 4 (4.0) | 6 (6.1) | 2 (3.8) |
| Nervous system disorders | 5 (5.0) | 4 (4.0) | 2 (3.8) |
Serious adverse events included:
The SEAM-RA Study was a multicenter, randomized, withdrawal, double-blind controlled study that enrolled 371 patients with moderate to severe RA on ENBREL + MTX who had good disease control for 6 months before study entry. The study consisted of a 30-day screening period, a 24-week open-label run-in period, a
48-week double-blind treatment period, and a 30-day safety follow-up period.1 Eligible patients (n=253) who were in SDAI remission (SDAI ≤3.3) were randomized to receive ENBREL + MTX combination therapy (n=51), ENBREL monotherapy (n=101), or MTX monotherapy (n=101).2
Primary endpoint:1
Select secondary endpoints:1
*During the double-blind phase, patients with disease-worsening could receive rescue therapy with weekly ENBREL + MTX (ie, reestablished or continued combination therapy using the same doses received at study enrollment) in an attempt to recapture remission. Patients were considered to have disease-worsening if they had an increased SDAI score >3.3 and ≤11 on two consecutive visits at least 2 weeks apart, or SDAI >3.3 and ≤11 at any time on three or more separate visits, or SDAI >11 at any time.
Important Information About Risks
EOS, end of study; MTX, methotrexate; QW, every week; SEAM-RA, study of etanercept and methotrexate in combination or as monotherapy in subjects with rheumatoid arthritis; SDAI, simple disease activity index; TNF, tumor necrosis factor.
TEMPO Study
Evaluation of ENBREL + MTX vs MTX in moderate to severe RA patients who had failed ≥1 disease-modifying antirheumatic drug (DMARD) other than MTX
Select Safety Results
Significant adverse events, medically important infections, and malignancy rates were similar across all 3 treatment arms6
| MTX (n=228) | ENBREL (n=223) | ENBREL + MTX (n=231) | |
|---|---|---|---|
| Treatment-emergent adverse events | 201 (88.2%) | 206 (92.4%) | 210 (90.9%) |
| Discontinuation due to adverse events | 52 (22.8%) | 39 (17.5%) | 35 (15.2%) |
| Serious adverse events | 43 (18.9%) | 51 (22.9%) | 54 (23.4%) |
| Serious infections | 19 (8.3%) | 15 (6.7%) | 17 (7.4%) |
| Malignancies | 4 (1.8%) | 6 (2.7%) | 5 (2.2%) |
| Death | 1 (0.5%) | 2 (1%) | 2 (1%) |
*Including nonmelanoma skin cancers (MTX, ENBREL, ENBREL + MTX).
The TEMPO Study was a 3-year, multicenter, double-blind, randomized, controlled trial (RCT) of 682 patients in Europe, Australia, and Israel with moderate to severe RA (mean disease duration of 6.6 years) who had failed ≥1 DMARD other than MTX. Patients received either ENBREL 25 mg biweekly (BIW) + MTX (n=231), ENBREL 25 mg BIW + placebo (n=223), or placebo + MTX (n=228) over 3 years. Use of concomitant corticosteroids and/or NSAIDs was permitted.3,6,7
Important Information About Risks
ACR, American College of Rheumatology; ACR 20/50/70, American College of Rheumatology (20/50/70) percent response; CRP, C-reactive protein; DAS 28, disease activity score in 28 joints; HAQ, Health Assessment Questionnaire; mTSS, modified total Sharp score; TEMPO, Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes.
ERA Study
Evaluation of ENBREL and MTX in early moderate to severe RA, including an analysis of MTX discontinuation
10 Years of Continuous Safety Data
Malignancy rates and serious infection rates were similar to MTX at Year 1 and consistent over 10 years10,11
*In the controlled portion, event rates were based on the definition of medically important infections (infections associated with hospitalization or intravenous antibiotics). For long-term therapy, serious infections were defined as all serious adverse events that were infectious.8
†Observed on study or within 30 days after the last ENBREL dose. The population for each year reflects all adult patients at the time of analysis who received at least 1 dose of study drug.8
‡Includes all patients who received at least 1 dose of ENBREL in the randomized controlled trial (RCT) and/or the open-label extension (OLE).19
§Data are from clinical studies and include all Surveillance, Epidemiology, and End Results (SEER)-defined cancers (excluding nonmelanoma skin cancers, in situ carcinomas except bladder, and recurrent cancers), and comparisons are based on age and sex-matched cohorts.8
SIR = standardized incidence ratio, which is an estimate of the occurrence of the specified condition in the ENBREL population relative to what might be expected in a larger comparison population designated as normal or average, such as the general population.
Study Design
The Early RA (ERA) Study was a 1-year, multicenter, randomized, double-blind study of 632 patients with early moderately to severely active RA (≤3 years' duration) with mean disease duration of 11.2 months. In Year 1 of the study, patients were randomized to receive ENBREL 10 mg BIW (n=208), ENBREL 25 mg BIW (n=207), or MTX (up to 20 mg/week, n=217). At Year 2, patients continued in an open-label treatment period. At Year 3, patients switched to or continued ENBREL 25 mg BIW for an open-label extension (OLE) (n=468). MTX could be continued or started as necessary in the OLE at the investigator's discretion.3,8,10
– There is no concurrent control arm, limiting the estimate of treatment effect
– Data are based only on patients who continued taking ENBREL at each year. Reasons for discontinuation included lack of tolerability, lack of efficacy, and loss to follow-up. Response rates may represent an enriched proportion of patients with continued efficacy and tolerability
*At the end of Year 2, patients switched to or continued on ENBREL 25 mg BIW.
Important Information About Risks
BIW, biweekly (twice a week); COMET, comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis; ERA, early rheumatoid arthritis; LRA, late rheumatoid arthritis; PsA, psoriatic arthritis.
Prescription Enbrel® (etanercept) is administered by injection.
IMPORTANT SAFETY INFORMATION AND INDICATIONS
SERIOUS INFECTIONS
Patients treated with ENBREL 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 or were predisposed to infection because of their underlying disease. ENBREL should not be initiated in the presence of sepsis, active infections, or allergy to ENBREL or its components. ENBREL should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: 1) Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before ENBREL use and periodically during therapy. Treatment for latent infection should be initiated prior to ENBREL use, 2) 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 antifungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness, and 3) Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.
The risks and benefits of treatment with ENBREL should be carefully considered prior to initiating therapy in patients 1) with chronic or recurrent infection, 2) who have been exposed to TB, 3) who have resided or traveled in areas of endemic TB or endemic mycoses, or 4) with underlying conditions that may predispose them to infections such as advanced or poorly controlled diabetes. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ENBREL, including the possible development of TB in patients who tested negative for latent TB prior to initiating therapy.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including ENBREL.
In adult clinical trials of all TNF blockers, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients. The role of TNF blocker therapy in the development of malignancies is unknown.
Cases of acute and chronic leukemia have been reported in association with postmarketing TNF blocker use in RA and other indications. The risk of leukemia may be higher in patients with RA (approximately 2-fold) than the general population.
Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF blockers, including ENBREL. Periodic skin examinations should be considered for all patients at increased risk for skin cancer.
Pediatric Patients
In patients who initiated therapy at ≤18 years of age, approximately half of the reported malignancies were lymphomas (Hodgkin's and non-Hodgkin's lymphoma). Other cases included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants.
NEUROLOGIC REACTIONS
Treatment with TNF-blocking agents, including ENBREL, has been associated with rare (<0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barré syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with ENBREL therapy. Prescribers should exercise caution in considering the use of ENBREL in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.
CONGESTIVE HEART FAILURE
Cases of worsening congestive heart failure (CHF) and, rarely, new-onset cases have been reported in patients taking ENBREL. Caution should be used when using ENBREL in patients with CHF. These patients should be carefully monitored.
HEMATOLOGIC REACTIONS
Rare cases of pancytopenia, including aplastic anemia, some fatal, have been reported. The causal relationship to ENBREL therapy remains unclear. Exercise caution when considering ENBREL in patients who have a previous history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs or symptoms of blood dyscrasias or infection. Consider discontinuing ENBREL if significant hematologic abnormalities are confirmed.
HEPATITIS B REACTIVATION
Reactivation of hepatitis B has been reported in patients who were previously infected with hepatitis B virus (HBV) and received concomitant TNF-blocking agents, including ENBREL. Most reports occurred in patients also taking immunosuppressive agents, which may contribute to hepatitis B reactivation. Exercise caution when considering ENBREL in these patients.
ALLERGIC REACTIONS
Allergic reactions associated with administration of ENBREL during clinical trials have been reported in <2% of patients. If an anaphylactic reaction or other serious allergic reaction occurs, administration of ENBREL should be discontinued immediately and appropriate therapy initiated.
IMMUNIZATIONS
Live vaccines should not be administered to patients on ENBREL. Pediatric patients, if possible, should be brought up to date with all immunizations prior to initiating ENBREL. In patients with exposure to varicella virus, temporarily discontinue ENBREL and consider prophylactic treatment with Varicella Zoster Immune Globulin.
AUTOIMMUNITY
Autoantibodies may develop with ENBREL, and rarely lupus-like syndrome or autoimmune hepatitis may occur. These may resolve upon withdrawal of ENBREL. Stop ENBREL if lupus-like syndrome or autoimmune hepatitis develops.
USE IN GRANULOMATOSIS WITH POLYANGIITIS PATIENTS
The use of ENBREL in patients with granulomatosis with polyangiitis receiving immunosuppressive agents (eg, cyclophosphamide) is not recommended.
MODERATE TO SEVERE ALCOHOLIC HEPATITIS
Based on a study of patients treated for alcoholic hepatitis, exercise caution when using ENBREL in patients with moderate to severe alcoholic hepatitis.
ADVERSE REACTIONS
The most commonly reported adverse reactions in RA clinical trials were injection site reaction and infection. In clinical trials of all other adult indications, adverse reactions were similar to those reported in RA clinical trials.
In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients. The types of infections reported in pediatric patients were generally mild and consistent with those commonly seen in the general pediatric population.
DRUG INTERACTIONS
The use of ENBREL in patients receiving concurrent cyclophosphamide therapy is not recommended. The risk of serious infection may increase with concomitant use of abatacept therapy. Concurrent therapy with ENBREL and anakinra is not recommended. Hypoglycemia has been reported following initiation of ENBREL therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.
Please see Prescribing Information and Medication Guide.
INDICATIONS
ENBREL is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. ENBREL can be initiated in combination with methotrexate (MTX) or used alone.
ENBREL is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis. ENBREL can be used with or without MTX.
ENBREL is indicated for the treatment of patients 4 years or older with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
ENBREL is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ages 2 and older.
Prescription Enbrel® (etanercept) is administered by injection.
IMPORTANT SAFETY INFORMATION AND INDICATIONS
SERIOUS INFECTIONS
Patients treated with ENBREL 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 or were predisposed to infection because of their underlying disease. ENBREL should not be initiated
Patients treated with ENBREL are at increased risk for developing serious infections that may lead to
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