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.

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PsA Pivotal Study

ENBREL vs placebo in psoriatic arthritis (PsA)

PsA Pivotal Study

ENBREL vs placebo in psoriatic arthritis (PsA)

Select Safety Results

  • During the controlled portion of the study, injection site reactions were reported in 36% of ENBREL subjects, compared with 9% of placebo subjects (P<0.001) 1

Serious Adverse Event Rates

Serious Adverse Event Rates Were Similar to Control in the PsA Pivotal Study 2

Placebo
(n=104)
ENBREL
(n=101)
Serious infections 1.0% (n=1) 0.0% (n=0)
Malignancies 0.0% (n=0) 0.0% (n=0)
Any adverse events 68.0% (n=65) 65.0% (n=64)
Any infections 43.0% (n=41) 40.0% (n=40)

Study Design

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The PsA Pivotal Study was a 24-week, multicenter, double-blind study of 205 patients with active PsA who had a mean duration of arthritic disease of 9.1 years and mean duration of plaque psoriasis of 19 years (with a qualifying target skin lesion). Patients were randomized to receive ENBREL 25 mg biweekly (BIW, n=101) or placebo BIW (n=104). The 24-week, double-blind period was followed by a maintenance period of up to 24 weeks to allow all patients to complete the double-blind study. At Week 48, the maintenance period was followed by an open-label extension (OLE, n=168). Concomitant use of methotrexate (MTX), NSAID, corticosteroids, and topical therapies were permitted in the OLE at the discretion of the investigator. 1

  • Primary endpoints: ACR 20 at Week 12, change in mTSS at Year 1 1
  • Select secondary endpoints: PASI 75 at Week 24, sPGA of clear or almost clear at Week 12 2
ENBREL PsA Pivotal Study
ENBREL PsA Pivotal Study

* Patients were stratified by MTX use at baseline for equal distribution between treatment arms. Patients on MTX therapy at enrollment (stable for 2 months) could continue at a stable dose of 25 mg/week MTX. 2

Stable use of corticosteroids and/or NSAIDs allowed. 2

81 from placebo group; 87 from ENBREL group. 1

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 unknown 3-5
  • 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) 3
  • Other malignancies: Other malignancies have been reported during postmarketing for ENBREL and other TNF blockers, including cases of acute and chronic leukemia 3
  • 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 immunosuppressants 3
  • Opportunistic infection: In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis, have been reported 3
  • 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 treatment 3

SEAM PsA Study

ENBREL + MTX vs ENBREL monotherapy vs MTX monotherapy in PsA

SEAM-PsA Study

ENBREL + MTX vs ENBREL monotherapy vs MTX monotherapy in PsA

Adverse Event Rates

Adverse events 6 MTX (n=282) ENBREL (n=282) ENBREL + MTX (n=284)
All adverse events, n (%) 212
(75.2%)
191
(67.7%)
216
(76.1%)
Serious adverse events, n (%) 16
(5.7%)
19
(6.7%)
17
(6.0%)
DC due to adverse event, n (%) 19
(6.7%)
16
(5.7%)
20
(7.0%)
Adverse events occurring in ≥5%
of subjects, n (%) 6
MTX (n=282) ENBREL (n=282) ENBREL + MTX (n=284)
Nausea 37
(13.1%)
18
(6.4%)
41
(14.4%)
Nasopharyngitis 22
(7.8%)
21
(7.4%)
27
(9.5%)
Upper respiratory tract infection 21
(7.4%)
18
(6.4%)
23
(8.1%)
Diarrhea 17
(6.0%)
13
(4.6%)
14
(4.9%)
Headache 15
(5.3%)
12
(4.3%)
17
(6.0%)
Bronchitis 9
(3.2%)
14
(5.0%)
19
(6.7%)
Vomiting 15
(5.3%)
7
(2.5%)
10
(3.5%)

DC = discontinued.

Study Design

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The Study of Etanercept and Methotrexate (SEAM) PsA Study was a 48-week, multicenter, randomized, double-blind controlled study of 851 subjects with active PsA naïve to biologics and with no prior use of MTX for the treatment of PsA. Eligible patients were randomized to receive ENBREL + MTX combination therapy (n=283), ENBREL monotherapy (n=284), or MTX monotherapy (n=284). 6

  • Primary endpoint: ACR 20 at Week 24 6
  • Key secondary endpoint: Minimal disease activity (MDA) at Week 24 6
  • Select secondary endpoints: ACR 50 at Week 24, ACR 70 at Week 24, change in modified total Sharp score (mTSS), change in body surface area (BSA), percentage of patients achieving static Physician's Global Assessment (sPGA) of clear or almost clear, dactylitis improvement from baseline, enthesitis improvement from baseline, nail disease improvement from baseline 6
  • At or after Week 24, subjects who had an inadequate response received rescue therapy with ENBREL plus MTX until the end of the treatment period. Inadequate response was defined as having <20% improvement in their tender joint count (TJC) and <20% in their swollen joint count (SJC) from baseline at or after Week 24 6
ENBREL SEAM-PsA Study Design
ENBREL SEAM-PsA Study Design

* Rescue option = ENBREL 50 mg per week + MTX 20 mg per week if inadequate response (<20% improvement in TJC and SJC from baseline) at or after 24 weeks. 6

Select Baseline Demographics/Characteristics 6

Demographic/
Characteristics
MTX
Monotherapy (n=284)
ENBREL
Monotherapy (n=284)
ENBREL
+ MTX (n=283)
Mean age in years (SD) 48.7
(13.1)
48.5
(13.5)
48.1
(12.7)
% female 56.3% 46.8% 49.1%
Mean years disease duration (SD) 3.6
(6.8)
3.1
(6.0)
3.0
(6.0)
Mean years mTSS (SD) 2.76
(0.12)
2.97
(0.13)
2.70
(0.12)
% dactylitis (LDI) 34.5% 33.8% 31.8%
% enthesitis (SPARCC) 67.3% 66.5% 69.3%
% nail disease (mNAPSI) 65.1% 72.5% 69.6%
Mean tender joint count (SD) 20.9
(15.0)
18.8
(14.5)
20.0
(15.3)
Mean swollen joint count (SD) 12.9
(9.9)
11.5
(9.6)
11.2
(9.1)
Mean % BSA 12.7% 10.8% 10.7%
Mean sPGA (SD) 2.6%
(1.1)
2.6%
(1.0)
2.5%
(1.0)

LDI = Leeds Dactylitis Index; mNAPSI = modified Nail Psoriasis Severity Index; SD = standard deviation; SPARCC = Spondyloarthritis Research Consortium of Canada.

Selected Inclusion/Exclusion Criteria 6,7

Inclusion criteria

  • Diagnosis of PsA by the Classification Criteria for Psoriatic Arthritis (CASPAR) criteria
  • ≥3 tender and ≥3 swollen joints (as part of a 66/68 joint count) at screening and at baseline
  • Active psoriatic skin lesion ≥2 cm in diameter
  • Naïve to etanercept and any other biologic for the treatment for PsA or psoriasis
  • No prior use of methotrexate for PsA (allowed if indicated for psoriasis as long as discontinuation was not due to toxicity or intolerance and treatment discontinued ≥6 months prior to initiation of etanercept)

Exclusion criteria

  • Prior or current use of cyclophosphamide, chlorambucil, nitrogen mustard, or any other alkylating agent
  • Use of any of the following ≤3 months prior to screening: abatacept, anakinra, azathioprine, cyclosporine, gold, mycophenolate mofetil, prosorba column, tacrolimus, apremilast
  • Use of leflunomide ≤12 weeks prior to screening
  • Use of any of the following ≤4 weeks prior to screening: sulfasalazine; intraarticular, intramuscular, or intravenous corticosteroids, including adrenocorticotropic hormone; intraarticular hyaluronic acid injections; live vaccines

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 unknown 3-5
  • 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) 3
  • Other malignancies: Other malignancies have been reported during postmarking for ENBREL and other TNF blockers, including cases of acute and chronic leukemia 3
  • 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 immunosuppressants 3
  • Opportunistic infection: In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis, have been reported 3
  • 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 treatment 3

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.

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.