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ENBREL clinical study designs

ENBREL has been evaluated in clinical studies over the past 20 years. Clinical research in RA patients began in 19931. The key clinical studies for the safety and efficacy of ENBREL are detailed below.

The TEMPO Study1-2:
A: 
  • Multi-center, double-blind RCT of 682 patients in Europe, Australia, and Israel with moderate to severe RA (mean disease duration 7 years) who had failed ≥ 1 DMARD other than MTX received either ETN 25 mg BIW + MTX (n=231), ETN 25 mg BIW + placebo (n=223), or placebo + MTX (n=228) over 3 years1,2
  • Use of concomitant corticosteroids and/or nonsteroidal anti-inflammatory drugs (NSAIDs) was permitted2
  • The primary clinical endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks2
  • The primary radiographic endpoint was the change from baseline in TSS at 12 months2

TEMPO References:

  • Enbrel® (etanercept) Prescribing Information, Immunex Corporation, Thousand Oaks, Calif. 03/2015.
  • Klareskog L, van der Heijde D, de Jager JP, et al; for the TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004;363:675-681.
ENBREL Global Psoriasis Pivotal Trial1-3:
A: 
  • Multi-center, double-blind, global phase 3 trial
  • 611 adult patients with active but clinically stable plaque psoriasis involving at least 10% of body surface and a minimum PASI score of 10
  • Patients randomized to receive subcutaneous injections of ENBREL 50 mg, ENBREL 25 mg, or placebo administered BIW over 12 weeks
  • Patients were limited to low- to moderate-strength topical corticosteroids in the axillary, groin, and scalp regions
  • After 12 weeks, patients received open-label ENBREL 25 mg BIW. However, in the open-label portion, physicians and patients remained blinded to the original randomized dosing arm through 6 months

Global Psoriasis Pivotal Trial References:

  • Enbrel® (etanercept) Prescribing Information, Immunex Corporation, Thousand Oaks, Calif. 03/2015.
  • Data on file, Amgen; CSR 1642: October 8, 2003.
  • Papp KA, Tyring S, Lahfa M, et at; for the Etanercept Psoriasis Study Group. A global phase Ill randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005; 152:1304-1312.
ENBREL US Psoriasis Pivotal Trial1-3:
A: 
  • Multi-center, double-blind, US phase 3 trial
  • 672 adult patients with active but clinically stable plaque psoriasis involving at least 10% of body surface and a minimum PASI score of 10
  • Patients randomized to receive subcutaneous injections of ENBREL 50 mg BIW, ENBREL 25 mg BIW, ENBREL 25 mg QW, or placebo for 12 weeks. After 12 weeks, patients in the placebo group began treatment with ENBREL 25 mg BIW in a blinded fashion
  • Patients were limited to low- to moderate-strength topical corticosteroids in the axillary, groin, and scalp regions
  • After 24 weeks, patients were classified as responders (had ≥ 50% improvement from baseline PASI) or incomplete responders (had < 50% improvement from baseline PASI)
  • Responders were entered into the withdraw/retreat portion of the study and were discontinued from treatment and followed until their disease relapsed (loss of ≥ 50% PASI improvement obtained between baseline and Week 24), at which time subjects resumed blinded ENBREL therapy at their dose from weeks 13 to 24

US Psoriasis Pivotal Trial References:

  • Data on file, Amgen; CSR 1639: October 8, 2003.
  • Leonardi Cl, Powers Jl, Matheson RT, et al; for the Etanercept Psoriasis Study Group. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349:2014-2022.
  • Gordon KB, Gottlieb AB, Leonardi CL. et at; for the Etanercept Psoriasis Study Group. Clinical response in psoriasis patients discontinued from and then reinitiated on etanercept therapy. J Dermatolog Treat. 2006;17:9-17.
The Psoriatic Arthritis Pivotal Study1,2:
A: 
  • Multi-center, double-blind, phase 3 study of 205 patients with active PsA1,3,4
  • Mean duration of arthritic disease was about 9.1 years and mean duration of plaque psoriasis was about 19.0 years (with a qualifying target skin lesion)1,4
  • Patients were randomized to receive subcutaneous injections of ENBREL 25 mg (n=101) or placebo (n=104) administered twice weekly over the 24-week blinded treatment period1,3
  • After the 24-week period, patients continued therapy in a maintenance period of up to 6 months until all patients completed double-blind therapy. After the maintenance period, all patients received ENBREL 25 mg twice weekly in an open-label period of 48 weeks1,3
  • Of the 205 patients enrolled in the randomized phase of the study, 169 (88 originally randomized to ENBREL; 81 originally randomized to placebo) entered the open-label extension. Concomitant use of MTX, NSAID, corticosteroids, and topical therapies were permitted at the discretion of the investigator1,2
  • Nonresponder imputation analysis was conducted during the double-blind portion for ACR response and skin lesion clearing, while parameters assessed during the open-label period were analyzed based on the observed population at each time point1
  • The primary efficacy endpoint was ACR 20 at 12 weeks1
  • The primary radiographic endpoint was the annualized rate of change in TSS over 1 year of treatment1

TSS is based on combined scores of joint erosions in the hands and wrists on a scale of 0 to 5 (0=no damage) and joint space narrowing in the hands and wrists on a scale of 0 to 4 (0=no narrowing) and was modified to include an assessment of the distal interphalangeal joints. Data are shown for all patients having a 2-year radiograph (n=141).1,2,5

Psoriatic Arthritis Pivotal Study References:

  • Data on file, Amgen. 1630 PsA 2 yr 08/2004.
  • Mease PJ, Kivitz AJ, Burch FX, et al. Continued inhibition of radiographic progression in patients with psoriatic arthritis following 2 years of treatment with etanercept. J Rheumatol. 2006;33:712-721.
  • Enbrel® (etanercept) Prescribing Information, Immunex Corporation, Thousand Oaks, Calif. 03/2015.
  • Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum. 2004;50:2264-2272.
  • van der Heijde DM. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol. 2000;27:261-263.
The Ankylosing Spondylitis Trial1:
A: 
  • Multi-center, double-blind, randomized, placebo-controlled Phase 3 trial of 277 patients with active AS (mean duration of disease: 10 years) who did not have complete spinal fusion
  • Patients were randomized to receive ENBREL 25 mg (n=138) or placebo (n=139) twice weekly for 24 weeks. NSAIDs and corticosteroids were allowed if doses remained stable for 2 weeks before the study start and throughout the study; MTX, sulfasalazine, or hydroxychloroquine were allowed if doses remained stable for 4 weeks before baseline and throughout the study. Of 277 patients randomized, 44 (32%) of the ENBREL group and 43 (31%) of the placebo group were receiving concomitant MTX, sulfasalazine, or hydroxychloroquine at baseline
  • For the purposes of this study, ASAS 20 response (primary measure of efficacy) was defined as improvement of ≥20% and absolute improvement of ≥10 units (on a scale of 0 to 100) in at least 3 of 4 ASAS domains and absence of deterioration in the remaining domain
  • The 4 ASAS domains included patient global assessment measured on a VAS of “none” to “severe,” pain assessment (the average of nocturnal and total pain scores, both measured on a VAS of “no pain” to “most severe pain”), function (the average of 10 questions on the BASFI) measured on a VAS of “easy” to “impossible,” and inflammation (the average of 2 questions regarding morning stiffness on the BASDAI), measured on a VAS: one (No. 5) of “none” to “very severe”; the other (No. 6) by duration of morning stiffness between “0” and “2” or more hours
  • ASAS 50 and 70 responses indicated ≥50% and ≥70% improvement in 3 of the 4 listed components in addition to the ≥10-point absolute improvement. Deterioration for the remaining domain for each assessment was defined as worsening of ≥20% and a decline of ≥10 units on a 0 to 100 scale. During the course of this study, the official ASAS criteria were revised to eliminate the nocturnal pain assessment
    • One patient in the placebo group had a score of 0 at baseline and was not included in the analysis of % improvement in nocturnal pain assessment from baseline
  • Ankylosing Spondylitis Trial Reference:

    • Data on file, Amgen; CSR 1637: December 20, 2002.
The JIA Trial1,2:
A: 
  • A two-part, multi-center study of 69 patients ages 4 to 17 years with moderate to severe polyarticular-course JIA who were refractory to or intolerant of MTX
  • In part 1, which was open-label, all patients received ENBREL 0.4 mg/kg subcutaneously twice weekly for 90 days
  • Responders (n=51), measured using the JIA definition of improvement defined as JIA 30, continued into part 2, the double-blind portion, and were randomized to receive either ENBREL (n=25) or placebo (n=26) for 4 months or until disease flare occurred
  • The primary efficacy endpoint was the number of patients with disease flare after ENBREL or placebo in part 2
  • At the conclusion of the 7-month trial, 58 of the original 69 patients (from the nonresponder, ENBREL, and placebo groups) were enrolled in a new unblinded, open-label follow-up using ENBREL 0.4 mg/kg twice weekly
  • Pediatric patients received long-term, open-label treatment with a 0.8-mg/kg weekly subcutaneous dose of ENBREL (up to a maximum of 50 mg per week)
  • Concurrent use of NSAIDs, corticosteroids, and/or MTX was permitted during the open-label extension phase

Definition1,2

The definition of improvement used to assess disease response had 6 response variables: global assessment of the severity of disease by the physician, global assessment of overall well-being by the patient or parent, number of “active” joints, number of joints with limitation of motion (LOM), functional ability (CHAQ), and erythrocyte sedimentation rate (ESR). Number of joints with LOM was counted only if LOM was accompanied by pain and/or tenderness.2

JIA 30 response is defined as a ≥30% improvement in at least 3 of the 6 criteria of a modified JIA core set, with no more than 1 of 6 criteria worsening by more than 30%.2

JIA 50 and 70 responses are defined as a ≥50% or ≥70% improvement, respectively, in at least 3 of 6 response criteria, with no more than 1 criterion worsening by more than 30%.2

Disease flare was defined as a ≥30% worsening in 3 of the 6, a ≥30% improvement in not more than 1 of the 6 JIA core set criteria, and a minimum of 2 active joints.1

JIA Trial References:

  • Data on File, Amgen; 1618 LRA 10 yr: September 2008.
  • Lovell DJ, Giannini EH, Reiff A, et al; for the Pediatric Rheumatology Collaborative Study Group. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med. 2000;342:763-769.
THE EARLY RA (ERA) STUDY AND OPEN-LABEL EXTENSION1-6:
A: 
  • Multicenter, double-blind, double-dummy, Phase 3 study1,2
  • 632 MTX-naïve patients with early moderately to severely active RA (≤3 years’ duration) were randomized to receive twice-weekly ENBREL 25 mg (n=207), twice-weekly ENBREL 10 mg (n=208), or MTX (n=217). The mean duration of disease for these patients was 11 to 12 months1,2,3
  • This study became open-label and unblinded after all patients had completed 1 year of evaluation. Patients continued through 1 year of follow-up on the treatment to which they had been randomized. At the end of Year 2, patients switched to or continued twice-weekly ENBREL 25 mg subcutaneously1,2,4,5
  • Subjects could re-enroll in the continuing open-label portion of the study upon meeting specific predefined re-enrollment inclusion criteria2
  • Primary endpoints were area under curve (AUC) for the numeric ACR score over 6 months and modified Total Sharp Score (mTSS) over 12 months3
  • In the OLE of ERA trial, MTX could be added to ETN if, after 1 year in the RCT, there was lack of efficacy6
  • Of the 207 patients initially randomized to receive ENBREL 25 mg BIW at baseline, 79 patients did not receive MTX at any point during the OLE through 5 years6

ERA Study References:

  • Enbrel® (etanercept) Prescribing Information, Immunex Corporation, Thousand Oaks, Calif. 03/2015.
  • Data on File, Amgen. 1623 ERA 5 yr 10/2003.
  • Bathon JM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343:1586-1593.
  • Genovese MC, et al. Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol. 2005;32:1232-1242.
  • Genovese MC, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes Arthritis Rheum 2002;46:1443-1450.
  • Data on File, Amgen. 1623 ERA Final 12/2009.
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 and psoriasis 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 EVENTS

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 EVENTS

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. JIA patients, if possible, should be brought up to date with all immunizations prior to initiating ENBREL. In patients with exposure to varicella virus, consider temporary discontinuation of ENBREL and 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 EVENTS

The most commonly reported adverse events in RA clinical trials were injection site reaction, infection, and headache. In clinical trials of all other adult indications, adverse events were similar to those reported in RA clinical trials.

In a JIA study, adverse reactions in pediatric patients were generally 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 of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ages 2 and older.

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 reducing signs and symptoms in patients with active ankylosing spondylitis.

ENBREL is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

References:

  • Data on file, Amgen. Enbrel RA Clinical Trials Experience, 2012.
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 and psoriasis 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 EVENTS

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 EVENTS

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. JIA patients, if possible, should be brought up to date with all immunizations prior to initiating ENBREL. In patients with exposure to varicella virus, consider temporary discontinuation of ENBREL and 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 EVENTS

The most commonly reported adverse events in RA clinical trials were injection site reaction, infection, and headache. In clinical trials of all other adult indications, adverse events were similar to those reported in RA clinical trials.

In a JIA study, adverse reactions in pediatric patients were generally 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 of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ages 2 and older.

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 reducing signs and symptoms in patients with active ankylosing spondylitis.

ENBREL is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

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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 and psoriasis 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 EVENTS

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 EVENTS

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. JIA patients, if possible, should be brought up to date with all immunizations prior to initiating ENBREL. In patients with exposure to varicella virus, consider temporary discontinuation of ENBREL and 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 EVENTS

The most commonly reported adverse events in RA clinical trials were injection site reaction, infection, and headache. In clinical trials of all other adult indications, adverse events were similar to those reported in RA clinical trials.

In a JIA study, infection, headache, abdominal pain, vomiting, and nausea occurred more frequently than in adult RA patients in placebo-controlled trials. The types of infections reported in JIA patients were generally mild and consistent with those commonly seen in outpatient pediatric populations.

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 of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ages 2 and older.

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 in combination with methotrexate in patients who do not respond adequately to methotrexate alone

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

ENBREL is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

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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.