INDICATIONS

ENBREL is indicated for reducing signs and symptoms, keeping joint damage from getting worse, and improving physical function in patients with moderately to severely active rheumatoid arthritis. ENBREL can be taken with methotrexate or used alone. Read More

ENBREL is indicated for reducing signs and symptoms, keeping joint damage from getting worse, and improving physical function...Read More

TEMPO Study

Evaluation of ENBREL + MTX vs MTX in moderate to severe RA patients who had failed ≥1 DMARD other than MTX

TEMPO Study

Evaluation of ENBREL + MTX vs MTX in moderate to severe RA patients who had failed ≥1 DMARD other than MTX

Select Safety Results

Select Safety Results From the TEMPO Study Through Year 31,a

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%)

a Including nonmelanoma skin cancers (MTX 1, ENBREL 2, ENBREL + MTX 2).

Study Design

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The TEMPO Study was a 3-year, multicenter, randomized, double-blind controlled trial of 682 patients in Europe, Australia, and Israel with moderate to severe RA (mean disease duration 7 years) who had failed ≥1 disease-modifying antirheumatic drug (DMARD) other than methotrexate (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.1-5 Use of concomitant corticosteroids and/or NSAIDs was permitted.6

  • Primary endpoints: Numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks and change from baseline in modified total Sharp score (mTSS) at Year 1
  • Select secondary endpoints: ACR 20, ACR 50, ACR 70, C-reactive protein (CRP), health assessment questionnaire (HAQ) score, and disease activity score (DAS) 28 clinical remission

References:

  1. van der Heijde D, Klareskog L, Singh A, et al. Patient reported outcomes in a trial of combination therapy with etanercept and methotrexate for rheumatoid arthritis: the TEMPO trial. Ann Rheum Dis. 2006;65(3):328-334.
  2. ENBREL (etanercept) Prescribing Information. Thousand Oaks, CA: Immunex Corporation; 6/2019.
  3. Landewé R, van der Heijde D, Klareskog L, et al. Disconnect between inflammation and joint destruction after treatment with etanercept plus methotrexate: results from the trial of etanercept and methotrexate with radiographic and patient outcomes. Arthritis Rheum. 2006;54(10):3119-3125.
  4. van der Heijde D, Klareskog L, DeJager J, et al; the TEMPO Trial Investigators. Radiographic outcomes of a double-blind study of etanercept and methotrexate, alone and combined, in active patients with rheumatoid arthritis (the TEMPO trial). Poster presented at: 67th Annual Scientific Meeting of the American College of Rheumatology; October 24-28, 2003; Orlando, FL.
  5. van der Heijde D, Klareskog L, Boers M, et al; TEMPO Investigators. Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results. Ann Rheum Dis. 2005;64(11):1582-1587.
  6. van der Heijde D, Burmester G, Melo-Gomes J, et al; Etanercept Study 400 Investigators. The safety and efficacy of adding etanercept to methotrexate or methotrexate to etanercept in moderately active rheumatoid arthritis patients previously treated with monotherapy. Ann Rheum Dis. 2008;67(2):182-188.

Important Information About Risks

  • Lymphoma: In clinical trials of all TNF inhibitors, 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 inhibitors in the development of malignancies is unknown2-4
  • NMSC: Nonmelanoma skin cancer has been reported in patients treated with TNF antagonists including ENBREL. Among adult psoriasis patients treated with ENBREL (n=1,245) in controlled clinical trials, the observed rate of NMSC was 0.04 events/pt-yr vs 0.01 events/pt-yr among control-treated patients (n=720)2
  • Other malignancies: Other malignancies have been reported during postmarking for ENBREL and other TNF blockers, including cases of acute and chronic leukemia2
  • Serious infection: Infections, including serious infections, some fatal, have been observed in patients treated with ENBREL. Discontinue ENBREL if a patient develops a serious infection or sepsis. Patients are at increased risk for developing serious infections when taking ENBREL that may lead to hospitalization or death. Most patients who developed these serious infections were taking concomitant immunosuppressants2
  • Opportunistic infection: In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis, have been reported2
  • Tuberculosis: Cases of reactivation of TB or new TB infections have been observed in patients receiving ENBREL. Patients should be evaluated for TB risk factors and be tested for latent TB infection prior to initiating ENBREL and during treatment2

ERA Study

Evaluation of ENBREL and MTX in early moderate to severe RA, including an analysis of MTX discontinuation

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

  • The serious infections and malignancy rates in the LRA, COMET, TEMPO, and PsA studies were consistent with the rates shown here5-15
  • In patients receiving TNF-blocking agents, opportunistic infections, including TB, histoplasmosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, pneumocystosis, legionella, and listeriosis, have been reported2

Malignancy Rates Similar to MTX at Year 1 and Consistent Over 10 Years (Events/Patient-Year)5,8,16,a-d

Malignancy Rates Similar to MTX at Year 1 and Consistent Over 10 Years (Events/Patient-Year)

Malignancy Rates Similar to MTX at Year 1 and Consistent Over 10 Years (Events/Patient-Year)

Serious Infection Rates Similar to MTX at Year 1 and Consistent Over 10 Years (Events/Patient-Year)5,7,8,17,a-c

Serious Infection Rates Similar to MTX at Year 1 and Consistent Over 10 Years (Events/Patient-Year)

Serious Infection Rates Similar to MTX at Year 1 and Consistent Over 10 Years (Events/Patient-Year)

  • a 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.
  • b 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.
  • c Includes all patients who received at least 1 dose of ENBREL in the randomized controlled trial (RCT) and/or the open-label extension (OLE).
  • d 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.

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

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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.1,2 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 (n=468). MTX could be continued or started as necessary in the OLE at the investigator's discretion.1-6

  • All statistical analyses conducted during the OLE are considered descriptive and not confirmatory and therefore are not presented in this piece. Consider the following limitations when evaluating OLE results:
    • 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
  • Primary endpoints: Numeric index of the ACR response (ACR-N) area under the curve (AUC) at Month 6 and change from baseline in mTSS at Year 14
  • Baseline patient demographics: Mean age was 50 years, 25% of patients were male, mean disease duration was 11.2 months3,6

The ERA Study5-7,a

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a At the end of Year 2, patients switched to or continued on ENBREL 25 mg BIW.

References:

  1. ENBREL (etanercept) Prescribing Information. Thousand Oaks, CA: Immunex Corporation; 6/2019.
  2. Finck BK. Phase III trial of etanercept vs methotrexate in active, early rheumatoid arthritis. Presented at: 63rd Annual Scientific Meeting of the American College of Rheumatology; November 13-17, 1999; Boston, MA.
  3. Data on file, Amgen; 1623 ERA 5 yr. October 20, 2003.
  4. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343(22):1586-1593.
  5. Genovese MC, Bathon JM, Fleischmann RM, et al. Long-term safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol. 2005;32:1232-1242.
  6. Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum. 2002;46:1443-1450.
  7. Weinblatt ME, Baten JM, Kremer JM, et al. Safety and efficacy of etanercept beyond 10 years of therapy in North American patients with early and longstanding rheumatoid arthritis. Arthritis Care Res (Hoboken). 2011;63(3):373-382.

Important Information About Risks

  • Lymphoma: In clinical trials of all TNF inhibitors, 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 inhibitors in the development of malignancies is unknown2-4
  • NMSC: Nonmelanoma skin cancer has been reported in patients treated with TNF antagonists including ENBREL. Among adult psoriasis patients treated with ENBREL (n=1,245) in controlled clinical trials, the observed rate of NMSC was 0.04 events/pt-yr vs 0.01 events/pt-yr among control-treated patients (n=720)2
  • Other malignancies: Other malignancies have been reported during postmarking for ENBREL and other TNF blockers, including cases of acute and chronic leukemia2
  • Serious infection: Infections, including serious infections, some fatal, have been observed in patients treated with ENBREL. Discontinue ENBREL if a patient develops a serious infection or sepsis. Patients are at increased risk for developing serious infections when taking ENBREL that may lead to hospitalization or death. Most patients who developed these serious infections were taking concomitant immunosuppressants2
  • Opportunistic infection: In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis, have been reported2
  • Tuberculosis: Cases of reactivation of TB or new TB infections have been observed in patients receiving ENBREL. Patients should be evaluated for TB risk factors and be tested for latent TB infection prior to initiating ENBREL and during treatment2

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.

WEGENER’S GRANULOMATOSIS PATIENTS

The use of ENBREL in patients with Wegener’s granulomatosis 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 (RA). 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 (PsA). 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 (PsO) who are candidates for systemic therapy or phototherapy.

ENBREL is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS).

ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients ages 2 and older.

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.