ENBREL common questions

Prescribing: What are some important safety considerations when prescribing ENBREL?
A: 

ENBREL suppresses the immune system and has been associated with serious and sometimes fatal infections including TB and other opportunistic infections, malignancies, neurologic events, hematologic events, congestive heart failure, hepatitis B reactivation, allergic reactions, lupus-like syndrome and autoimmune hepatitis.1

Please see the Important Safety Information below and the Prescribing Information and Medication Guide.

Immunity: Does ENBREL affect immunity?
A: 

Anti-tumor necrosis factor (TNF) therapies, including ENBREL, affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 49 RA patients treated with ENBREL, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector cell populations. The impact of treatment with ENBREL on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood.1

The risks and benefits of ENBREL should be carefully considered in patients with chronic or recurrent infection or underlying conditions that may predispose them to infection (such as advanced or poorly controlled diabetes) or a history of opportunistic infections, and with those who have been exposed to tuberculosis or areas of endemic tuberculosis or mycoses (such as histoplasmosis, coccidioidomycosis, or blastomycosis).1

Vaccinations: Can ENBREL patients receive vaccinations?
A: 

In a study of patients with psoriatic arthritis, most patients receiving ENBREL were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccines, but titers in aggregate were moderately lower, and fewer patients had 2-fold rises in titers compared with patients not receiving ENBREL. The clinical significance of this is unknown. Patients receiving ENBREL may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving ENBREL.1

It is recommended that pediatric patients, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines prior to initiating ENBREL therapy.1

Live vaccines are not recommended for patients on ENBREL.1

Geriatrics: How was ENBREL tolerated by geriatric patients?
A: 

A total of 480 RA patients ages 65 years or older have been studied in clinical trials. In plaque psoriasis randomized clinical trials, a total of 138 out of 1,965 subjects treated with ENBREL or placebo were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but the number of geriatric psoriasis subjects is too small to determine whether they respond differently from younger subjects. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating elderly patients.1

Monitoring: Is there a need to monitor patients treated with ENBREL?
A: 

Patients need to be monitored for the development of any side effects, including potentially serious side effects. For example, 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 infection prior to initiating therapy. Stop ENBREL if infection becomes serious.1

Physicians should exercise caution when using ENBREL in patients who also have heart failure, and monitor patients carefully.1

Monitor patients previously infected with hepatitis B virus for reactivation during and several months after therapy. If reactivation occurs, consider stopping ENBREL and beginning anti-viral therapy.

See Prescribing Information for additional warnings and precautions.

Fertility: Does ENBREL affect fertility or mutagenesis?
A: 

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of ENBREL or its effect on fertility. Mutagenesis studies were conducted in vitro and in vivo, and no evidence of mutagenic activity was observed. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Three case reports showed that cord blood levels of etanercept at delivery in infants, born to mothers administered etanercept during pregnancy, were between 3 and 32% of the maternal serum level.1

Pregnancy: Can ENBREL be used in pregnant women?
A: 

ENBREL is classified as Pregnancy Category B. There are no adequate and well controlled studies in pregnant women. Based on limited data, etanercept concentration in cord blood at the time of delivery showed that etanercept crossed the placenta in small amounts. Developmental toxicity studies have been performed in rats and rabbits at doses ranging from 60- to 100-fold higher than the human dose, and have revealed no evidence of harm to fetuses due to ENBREL. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Three case reports showed that cord blood levels of etanercept at delivery in infants, born to mothers administered etanercept during pregnancy, were between 3 and 32% of the maternal serum level.1

There is a Pregnancy Surveillance Program that monitors outcomes in women exposed to ENBREL during pregnancy. Women who become pregnant during ENBREL treatment are encouraged to enroll. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.1

Nursing: Can ENBREL be used in nursing mothers?
A: 

Limited data from published literature show that etanercept is present in low levels in human milk and minimally absorbed by a breastfed infant. Caution should be exercised when ENBREL is administered to a nursing woman. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENBREL and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Women who choose to continue ENBREL treatment while nursing are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.1

Latex: Is there latex content in the SureClick® autoinjector, prefilled syringes, or their components?
A: 

Yes, the needle covers on the SureClick® autoinjector and the single-use prefilled syringes contain dry natural rubber (derivative of latex), which should not be handled by persons sensitive to the substance.1

Contraindications: Are there any contraindications to ENBREL use?
A: 

ENBREL should not be administered to patients with sepsis.1

Dosage: What are the dosage forms and strengths of ENBREL?
A: 

Each single-use prefilled syringe and SureClick® autoinjector contains 50 mg/mL of etanercept in a single-dose syringe with a 27-gauge, 1/2-inch needle.1

ENBREL multiple-use vial is supplied in a carton containing four dose trays. Each dose tray contains one 25-mg vial of etanercept, one diluent syringe (1 mL Sterile Bacteriostatic Water for Injection, USP, containing 0.9% benzyl alcohol), one 27-gauge 1/2-inch needle, one vial adapter, and one plunger. Each carton contains four "Mixing Date:" stickers.1

Administration of one 50-mg prefilled syringe or one SureClick® autoinjector provides a dose equivalent to two 25-mg prefilled syringes or two multiple-use vials of lyophilized ENBREL, when vials are reconstituted and administered as recommended.1

Discontinuation: Are there circumstances that may require discontinuation of ENBREL therapy?
A: 

Serious infections, including patients with pneumonia, sinusitis, abscess, and herpes zoster1

ENBREL should be discontinued if a patient develops a serious infection or sepsis. Consider the risks and benefits carefully prior to initiation of therapy in patients with chronic or recurrent infection. Monitor patients closely for infections during and after treatment, including the possible development of tuberculosis (TB) in patients who tested negative for latent TB prior to therapy initiation.

Hematologic Events

Discontinuation of ENBREL should be considered in patients with confirmed significant hematologic abnormalities.

Allergic Reactions

If an anaphylactic reaction or other serious allergic reaction occurs, administration of ENBREL should be discontinued immediately and appropriate therapy initiated.

Vaccinations, including yellow fever, BCG, rubella, polio, cholera, typhoid, and varicella1

When taking ENBREL, patients may receive concurrent vaccination, except for live vaccines. Patients with significant exposure to varicella virus should temporarily discontinue ENBREL therapy and be considered for prophylactic treatment.

Most PsA patients receiving ENBREL were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower and fewer patients had 2-fold rises in titers compared to patients not receiving ENBREL. The clinical significance of this is unknown. Patients receiving ENBREL may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving ENBREL.

Autoimmunity

If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with ENBREL, treatment should be discontinued and the patient should be carefully evaluated.

Pregnancy or intent to breast-feed1

ENBREL should be used in pregnancy only if clearly needed. For nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug. ENBREL is Pregnancy Category B.

Surgery, including dental surgery or hip replacement1,4

ENBREL can lower the ability of the immune system to fight infections. Patients should consult their physician and be closely monitored for the development of signs and symptoms of infection during and after surgery.

Please see Prescribing Information and Medication Guide.

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:

  • Enbrel® (etanercept) Prescribing Information, Immunex Corporation, Thousand Oaks, Calif. 03/2015.
  • Bauer LA. Clinical pharmacokinetics and pharmacodynamics. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; 2011:1-47.
  • Keystone EC, Schiff MH, Kremer JM, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:353-363.
  • Enbrel® (etanercept) Medication Guide, Immunex Corporation, Thousand Oaks, Calif. 03/2015.
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.