Patients treated with etanercept 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.
Etanercept should be discontinued if a patient develops a serious infection or sepsis.
Reported infections include:
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 etanercept use and during therapy. Treatment for latent infection should be initiated prior to etanercept use.
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.
Bacterial, viral, and other infections caused by opportunistic pathogens, including Legionella and Listeria.
The risks and benefits of treatment with etanercept should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with etanercept, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor blockers, including etanercept.
Note: Erelzi (etanercept-szzs) and Eticovo (etanercept-ykro) are approved as biosimilars to Enbrel. Approved uses for biosimilar agents may vary (consult product labeling).
Juvenile idiopathic arthritis: Children ≥2 years and Adolescents:
Once-weekly dosing:
Weight <63 kg: Enbrel: SubQ: 0.8 mg/kg/dose once weekly; maximum dose: 50 mg/dose. Note: Although FDA approved in patients ≥2 years of age, Erelzi does not have a dosage form that would allow for dosing in patients <63 kg.
Weight ≥63 kg: Enbrel, Erelzi: SubQ: 50 mg once weekly.
Twice-weekly dosing: SubQ: 0.4 mg/kg/dose twice weekly, given 72 to 96 hours apart; maximum dose: 25 mg/dose (Lovell 2006); Note: Trials performed with Enbrel product.
Kawasaki disease; acute, adjunct therapy: Limited data available; efficacy results for IV immunoglobulin (IVIG) resistance variable by ages (AHA [McCrindle 2017]; Portman 2019).
Infants ≥2 months, Children, and Adolescents: SubQ: 0.8 mg/kg/dose for 3 doses; administer first dose immediately after completion of IVIG (day 0), then next 2 doses administered weekly (ie, the second dose at day 7, and third dose at day 14); maximum dose: 50 mg/dose; in all trials, patients also received standard aspirin therapy (Choueiter 2010; Portman 2011; Portman 2019). Dosing based on a multi-center, phase 3, double-blind, placebo-controlled trial (EATAK) including 201 pediatric patients (n=100 etanercept treatment group; mean age: 3.77 ± 2.67 years [infant subgroup: n=15]) which showed that overall, etanercept did not significantly lower IVIG resistance compared to placebo (13% vs 22%, [p=0.1]). However, subgroup analysis demonstrated significantly lower IVIG resistance in patients >1 year of age compared to placebo. Etanercept significantly reduced coronary z-scores in subjects with and without baseline dilatation, and coronary dilation progression compared to placebo (Portman 2019). Note: Trials performed with Enbrel product.
Mediterranean fever; familial (FMF) (intolerance or resistance to colchicine): Very limited data available; efficacy results variable: Children ≥11 years and Adolescents: SubQ: 0.8 mg/kg once weekly; maximum dose: 50 mg/dose; dosing based on a case series (n=3); results showed fewer attacks with treatment, median duration of therapy was 3 months and all patients continued colchicine therapy if able; over time, therapy was eventually changed to anakinra due to clinician determined unsatisfactory response (Akgul 2012; Özen 2011; Sakallioglu 2006; Soriano 2013); a case series in adult patients (n=5, age range: 20 to 40 years) reported no further attacks (80%) or decrease frequency (20%) with etanercept (25 mg twice weekly) therapy (Bilgen 2011). Note: Trials performed with Enbrel product.
Plaque psoriasis:
Children and Adolescents 4 to 17 years Enbrel: SubQ: 0.8 mg/kg/dose once weekly; maximum dose: 50 mg/dose; results of a long-term study (264 weeks) showed efficacy maintained and therapy generally well-tolerated (Paller 2008; Paller 2010; Paller 2016; Siegfried 2010); Note: Studies performed with Enbrel product.
Adolescents ≥18 years: Enbrel: SubQ: Initial: 50 mg twice weekly administered 72 to 96 hours apart for 3 months; Note: Initial doses of 25 mg or 50 mg per week were also shown to be efficacious; maintenance dose: 50 mg once weekly.
Psoriatic arthritis: Adolescents ≥18 years: Enbrel:
Once-weekly dosing: SubQ: 50 mg once weekly.
Twice-weekly dosing: SubQ: 25 mg twice weekly (individual doses should be separated by 72 to 96 hours) (Mease 2000; Mease 2004).
Rheumatoid arthritis, ankylosing spondylitis: Adolescents ≥18 years: Enbrel, Erelzi:
Once-weekly dosing: SubQ: 50 mg once weekly.
Twice-weekly dosing: SubQ: 25 mg twice weekly (individual doses should be separated by 72 to 96 hours) (Bathon 2000; Calin 2004; Davis 2003; Genovese 2002).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
(For additional information see "Etanercept (including biosimilars available in Canada): Drug information")
Note : In Canada, Brenzys and Erelzi are approved as biosimilars to Enbrel (etanercept).
Ankylosing spondylitis or nonradiographic axial spondyloarthritis (off-label use):
Note: Patients with an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs) (Ward 2019).
Once-weekly dosing: SUBQ: 50 mg once weekly (Dougados 2014; Maksymowych 2016; van der Heijde 2006).
Twice-weekly dosing: SUBQ: 25 mg twice weekly (Calin 2004; Davis 2003; Yu 2021).
Graft-vs-host disease (treatment) (off-label use):
Acute graft-vs-host disease, treatment:
Initial treatment (alternative therapy): SUBQ: 0.4 mg/kg (maximum: 25 mg/dose) twice weekly for 8 weeks (in combination with methylprednisolone) (Levine 2008) or 25 mg twice weekly (in combination with corticosteroids) for 4 weeks (Alousi 2009). Note: Guidelines recommend methylprednisolone or prednisolone be used alone for the initial treatment of acute graft-vs-host disease; current data are unable to determine which patients might benefit from intensified treatment (ie, the addition of an immunosuppressive agent, such as etanercept, with glucocorticoid therapy) (ASBMT [Martin 2012]).
Plaque psoriasis, moderate to severe: SUBQ:
Initial: 50 mg twice weekly for 3 months (starting doses of 25 or 50 mg once weekly have also been used successfully).
Maintenance dose: 50 mg once weekly. Note: Some patients may require 50 mg twice weekly (AAD-NPF [Menter 2019]).
Psoriatic arthritis:
Once-weekly dosing: SUBQ: 50 mg once weekly (with or without concomitant methotrexate).
Twice-weekly dosing: SUBQ: 25 mg twice weekly (with or without concomitant methotrexate) (Mease 2000; Mease 2004; Mease 2006).
Rheumatoid arthritis:
Note: For use as an alternative to methotrexate in disease-modifying antirheumatic drug–naive patients with moderate to high disease activity, or as adjunctive therapy in patients who have not met treatment goals despite maximally tolerated methotrexate therapy (ACR [Fraenkel 2021]).
Once-weekly dosing: SUBQ: 50 mg once weekly (with or without methotrexate) (Emery 2010); maximum dose: 50 mg/week.
Twice-weekly dosing: SUBQ: 25 mg twice weekly (with or without methotrexate) (Bathon 2000; Genovese 2002).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Subcutaneous [preservative free]:
Enbrel: 25 mg/0.5 mL (0.5 mL)
Solution Auto-injector, Subcutaneous [preservative free]:
Enbrel SureClick: 50 mg/mL (0.98 mL [DSC], 1 mL)
Solution Cartridge, Subcutaneous [preservative free]:
Enbrel Mini: 50 mg/mL (0.98 mL [DSC], 1 mL)
Solution Prefilled Syringe, Subcutaneous [preservative free]:
Enbrel: 25 mg/0.5 mL (0.5 mL, 0.51 mL [DSC]); 50 mg/mL (0.98 mL [DSC], 1 mL)
Solution Reconstituted, Subcutaneous:
Enbrel: 25 mg (1 ea [DSC]) [contains benzyl alcohol]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Auto-injector, Subcutaneous:
Brenzys: 50 mg/mL (0.98 mL)
Erelzi: 50 mg/mL (1 mL)
Solution Prefilled Syringe, Subcutaneous:
Brenzys: 50 mg/mL (0.98 mL)
Enbrel: 50 mg/mL (0.98 mL)
Erelzi: 25 mg/0.5 mL (0.5 mL); 50 mg/mL (1 mL)
Solution Reconstituted, Subcutaneous:
Enbrel: 25 mg (4 ea) [contains benzyl alcohol, tromethamine]
Erelzi (etanercept-szzs): FDA approved August 2016; anticipated availability is currently unknown. Erelzi is approved as biosimilar to Enbrel, but not as an interchangeable product.
Eticovo (etanercept-ykro): FDA approved April 2019; anticipated availability is currently unknown. Eticovo is approved as biosimilar to Enbrel, but not as an interchangeable product.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/103795s5574s5577lbl.pdf#page=35, must be dispensed with this medication.
Administer subcutaneously into front of the thigh (preferred), abdomen (avoiding the area around the navel [2 inches in adults]), or outer area of the upper arm. Rotate injection sites. New injections should be given at least 1 inch from an old site and never into areas where the skin is tender, bruised, red, or hard or into any raised thick, red, or scaly skin patches or lesions. For a more comfortable injection, autoinjectors, prefilled syringes, and dose trays may be allowed to reach room temperature by removing from the refrigerator 15 to 30 minutes prior to injection. Note: If the prescriber determines that it is appropriate, patients may self-inject after proper training in injection technique.
Multiple-use vial (Enbrel): Visually inspect for particulate matter and discoloration prior to administration; solution should not be used if cloudy, discolored, or if particulate is present. Do not administer >25 mg at a single injection site if the multiple-use vial is used to prepare the dose; use a 27-gauge needle for injection.
Single-dose vial (Enbrel): Do not remove vial cap while allowing to reach room temperature. Visually inspect for particulate matter and discoloration prior to administration; solution may have small white particles of protein, which is normal for a proteinaceous solution; solution should not be used if cloudy, discolored, or if foreign matter is present. Use a 22-gauge needle for withdrawing solution from vial(s); the same syringe may be used if more than 1 vial is required for the dose; use a 27-gauge needle for injection.
Single-use prefilled syringe or autoinjector (Enbrel, Erelzi): Do not remove needle cover or needle shield (syringe) or purple cap (autoinjector) while allowing to reach room temperature. Visually inspect for particulate matter and discoloration prior to administration; solution may have small white particles of protein, which is normal for a proteinaceous solution; solution should not be used if cloudy, discolored or if foreign matter is present.
SUBQ: Administer subcutaneously. Rotate injection sites; may inject into the thigh (preferred), abdomen (avoiding the 2-inch area around the navel), or outer areas of upper arm. New injections should be given at least 1 inch from an old site and never into areas where the skin is tender, bruised, red, or hard; any raised thick, red, or scaly skin patches or lesions; or areas with scars or stretch marks. For a more comfortable injection, allow autoinjectors, prefilled syringes, single-dose vials, and dose trays to reach room temperature for 15 to 30 minutes (≥30 minutes for autoinjector) prior to injection; do not remove the needle cover while allowing product to reach room temperature. There may be small white particles of protein in the solution; this is not unusual for proteinaceous solutions. Note: If the health care provider determines that it is appropriate, patients may self-inject after proper training in injection technique.
Additional formulation-specific administration information:
Single-dose vials: Withdraw contents from vial using a 22-gauge 1½ inch needle attached to a 1 mL syringe; after withdrawing vial contents, remove needle and replace with 27-gauge ½ inch needle to administer the injection. Use the same syringe if 2 vials are needed to achieve the total dose.
Store intact product at 2°C to 8°C (36°F to 46°F). Do not shake. Do not freeze or store in extreme heat or cold. Store in the original carton to protect from light or physical damage.
Individual autoinjectors, prefilled syringes, dose trays (containing multiple-dose vials and diluent syringes), single-dose vials, or prefilled pens may be stored between 20°C and 25°C (68°F and 77°F) for a maximum single period of 28 days (Erelzi), 30 days (Enbrel), or 60 days (Brenzys [Canadian product]) with protection from light and sources of heat and humidity. Once an autoinjector, prefilled syringe, dose tray, single-dose vial, or prefilled pen has been stored at room temperature, it should not be placed back into the refrigerator; discard after 28 days (Erelzi), 30 days (Enbrel), or 60 days (Brenzys [Canadian product]).
Once the multiple-dose vial has been reconstituted, use the reconstituted solution immediately or refrigerate at 2°C to 8°C (36°F to 46°F); do not store at room temperature. Reconstituted solution must be discarded after 14 days.
Treatment of moderately to severely active polyarticular juvenile idiopathic arthritis (Enbrel, Erelzi: FDA approved in ages ≥2 years); treatment of chronic (moderate to severe) plaque psoriasis in patients who are candidates for systemic therapy or phototherapy (Enbrel FDA approved in ages ≥4 years and adults); treatment of psoriatic arthritis (Enbrel: FDA approved in ages ≥18 years and adults); treatment of moderately to severely active rheumatoid arthritis (RA) (Enbrel, Erelzi: FDA approved in adults); treatment of symptoms of active ankylosing spondylitis (Enbrel, Erelzi: FDA approved in adults); has also been used as adjunctive therapy for Kawasaki disease and for treatment of familial Mediterranean fever (colchicine refractory or colchicine intolerant).
Note: Biosimilar agents (eg, Erelzi [etanercept-szzs], Eticovo [etanercept-ykro]) have been approved; uses may vary (consult product labeling).
Enbrel may be confused with Levbid
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Dermatologic: Skin rash (3% to 13%)
Gastrointestinal: Diarrhea (3% to 16%)
Hematologic & oncologic: Positive ANA titer (11%)
Immunologic: Antibody development (non-neutralizing; 4% to 16%)
Infection: Infection (including bacterial infection, fungal infection, serious infection, viral infection: 50% to 81%)
Local: Injection site reaction (adults: 15% to 43%; children: 7%; mild to moderate; usually decreases with subsequent injections)
Respiratory: Respiratory tract infection (21% to 54%), upper respiratory tract infection (38% to 65%)
1% to 10%:
Dermatologic: Pruritus (2% to 5%), urticaria (1% to 2%)
Hypersensitivity: Hypersensitivity reaction (≤1%)
Miscellaneous: Fever (2% to 3%)
<1%:
Cardiovascular: Cardiac failure
Hematologic & oncologic: Aplastic anemia, leukemia, malignant lymphoma, pancytopenia
Hepatic: Autoimmune hepatitis
Infection: Reactivation of HBV, varicella zoster infection
Nervous system: Aseptic meningitis, demyelinating disease of the central nervous system
Neuromuscular & skeletal: Lupus-like syndrome
Respiratory: Tuberculosis (including pulmonary and extrapulmonary)
Frequency not defined:
Dermatologic: Cellulitis
Gastrointestinal: Gastroenteritis
Hematologic & oncologic: Malignant melanoma, malignant neoplasm, skin carcinoma
Infection: Abscess, influenza, opportunistic infection, sepsis
Neuromuscular & skeletal: Osteomyelitis, septic arthritis
Renal: Pyelonephritis
Respiratory: Bronchitis, pneumonia, sinusitis
Postmarketing:
Cardiovascular: Chest pain, hypersensitivity angiitis, vasculitis
Dermatologic: Cutaneous lupus erythematosus, erythema multiforme, psoriasis (including palmoplantar), psoriasis flare, pustular psoriasis, Stevens-Johnson syndrome, subcutaneous nodule, toxic epidermal necrolysis
Gastrointestinal: Inflammatory bowel disease
Hematologic & oncologic: Anemia, hematologic abnormality (macrophage activation syndrome), leukopenia, lymphadenopathy, Merkel cell carcinoma, neutropenia, sarcoidosis, thrombocytopenia
Hepatic: Hepatotoxicity (Chalasani 2014), increased serum transaminases
Hypersensitivity: Angioedema
Infection: Aspergillosis, atypical mycobacterial infection, blastomycosis, candidiasis, coccidioidomycosis, herpes zoster infection, histoplasmosis, protozoal infection
Nervous system: Guillain-Barré syndrome, headache, paresthesia, seizure, transverse myelitis
Neuromuscular & skeletal: Multiple sclerosis
Ophthalmic: Optic neuritis, scleritis, uveitis
Respiratory: Interstitial pulmonary disease, pneumonia due to Pneumocystis jirovecii
Sepsis
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to etanercept or any component of the formulation; patients at risk of sepsis syndrome (eg, immunocompromised, HIV positive)
Concerns related to adverse effects:
• Anaphylaxis/hypersensitivity reactions: Allergic reactions may occur, if an anaphylactic reaction or other serious allergic reaction occurs, administration should be discontinued immediately and appropriate therapy initiated.
• Antibody formation: Formation of neutralizing anti-drug antibodies may occur with biologic tumor necrosis factor (TNF) inhibitors and may be associated with loss of efficacy (AAD-NPF [Menter 2019]).
• Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome or autoimmune hepatitis, have been reported; monitor and discontinue if symptoms develop.
• Demyelinating CNS disease: Rare cases of new-onset or exacerbation of CNS demyelinating disorders have occurred; may present with mental status changes and some may be associated with permanent disability. Optic neuritis, transverse myelitis, multiple sclerosis, Guillain-Barré syndrome, and other peripheral demyelinating neuropathies have been reported. Use with caution in patients with preexisting or recent-onset CNS demyelinating disorders.
• Heart failure: Worsening and new-onset heart failure has been reported, including in patients without known preexisting cardiovascular disease. Use with caution in patients with heart failure or decreased left ventricular function. In a scientific statement from the American Heart Association, TNF blockers have been determined to be agents that may either cause direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).
• Hematologic disorders: Rare cases of pancytopenia and aplastic anemia have been reported (some fatal). Patients must be advised to seek medical attention if they develop signs and symptoms suggestive of blood dyscrasias; discontinue if significant hematologic abnormalities are confirmed. Use with caution in patients with a history of significant hematologic abnormalities.
• Hepatitis B: Rare reactivation of hepatitis B (HBV) has occurred in chronic carriers of the virus, usually in patients receiving concomitant immunosuppressants (has been fatal); evaluate for HBV prior to initiation in all patients. Monitor during and for several months following discontinuation of treatment in HBV carriers; consider interruption of therapy if reactivation occurs and treat appropriately with antiviral therapy. If resumption of therapy is deemed necessary, exercise caution and monitor patient closely.
• Infections: [US Boxed Warning]: Patients receiving etanercept are at increased risk for serious infections which may result in hospitalization and/or fatality; infections usually developed in patients receiving concomitant immunosuppressive agents (eg, methotrexate, corticosteroids) and may present as disseminated (rather than local) disease. Active tuberculosis [TB] (including reactivation of latent TB), invasive fungal (including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and pneumocystosis) and bacterial, viral, or other opportunistic infections (including Legionellosis and Listeriosis) have been reported. Monitor closely for signs/symptoms of infection during and after treatment. Discontinue for serious infection or sepsis. Consider risks versus benefits prior to initiating therapy in patients with chronic or recurrent infection. Consider empiric antifungal therapy in patients who are at risk for invasive fungal infections who develop severe systemic illness. Caution should be exercised when considering use in elderly patients, patients with chronic or recurrent infections, patients exposed to TB, patients with a history of an opportunistic infection, in patients with conditions that predispose them to infections (eg, advanced or poorly controlled diabetes), residence/travel from areas of endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), or with latent infections. Do not initiate etanercept therapy in patients with an active infection, including clinically important localized infection. Patients who develop a new infection while undergoing treatment should be monitored closely.
• Malignancy: [US Boxed Warning]: Lymphoma and other malignancies (some fatal) have been reported in children and adolescents receiving TNF-blocking agents, including etanercept. Half of the malignancies reported in children and adolescents were lymphomas (Hodgkin and non-Hodgkin) while other cases varied and included rare malignancies usually associated with immunosuppression and malignancies not typically observed in this population. The impact of etanercept on the development and course of malignancy is not fully defined. Compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis alone has been previously associated with an increased rate of lymphoma and leukemia. Lymphomas and other malignancies were also observed (at rates higher than expected for the general population) in adult patients receiving etanercept. Hepatosplenic T-cell lymphoma, a rare T-cell lymphoma, has also been associated with TNF-blocking agents, primarily reported in adolescent and young adult males with Crohn disease or ulcerative colitis. Melanoma, nonmelanoma skin cancer, and Merkel cell carcinoma have been reported. Perform periodic skin examinations in all patients during therapy, particularly those at increased risk of skin cancer.
• Tuberculosis: [US Boxed Warning]: Active TB (disseminated or extrapulmonary), including reactivation of latent TB, has been reported in patients receiving etanercept. Evaluate patients for TB risk factors and latent TB infection (with a tuberculin skin test) prior to and during therapy. Treatment for latent TB should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for TB during and after treatment. Consider antituberculosis treatment if an adequate course of treatment cannot be confirmed in patients with a history of latent or active TB or with risk factors despite negative skin test. Some patients who tested negative prior to therapy have developed active infection; tests for latent TB infection may be falsely negative while on etanercept therapy. Use with caution in patients who have traveled to or resided in regions where TB is endemic. Monitor for signs and symptoms of TB in all patients.
Disease-related concerns:
• Alcoholic hepatitis: Use with caution in patients with moderate to severe alcoholic hepatitis. Compared to placebo, the mortality rate in patients treated with etanercept was similar at 1 month but significantly higher after 6 months.
• Granulomatosis with polyangiitis: Use is not recommended in patients with granulomatosis with polyangiitis who are receiving immunosuppressive therapy due to higher incidence of noncutaneous solid malignancies.
• HIV: Use with caution in HIV-positive patients; TNF-α inhibitors may be appropriate in patients receiving highly active antiretroviral therapy, provided they have normal CD4 counts, no viral load, and no recent opportunistic infections (AAD-NPF [Menter 2019]).
• Seizure disorders: Use with caution in patients with a history of seizures; new-onset or exacerbation of seizures have been reported.
Special populations:
• Older adult: Infection has been reported at a higher incidence; use caution in elderly patients.
• Pediatric: Malignancies have been reported among children and adolescents.
• Varicella virus exposure: Patients with a significant exposure to varicella virus should temporarily discontinue therapy; treatment with varicella zoster immune globulin should be considered.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Diluent for injection may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
• Latex: Some dosage forms may contain dry natural rubber (latex).
Other warnings/precautions:
• Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Live vaccines should not be given concurrently; there is no data available concerning secondary transmission of live vaccines in patients receiving therapy.
In an analysis of children and adolescents who had received TNF-blockers (etanercept and infliximab), the FDA identified 48 cases of malignancy. Of the 48 cases, ~50% were lymphomas (eg, Hodgkin and non-Hodgkin lymphoma) and other malignancies, such as leukemia, melanoma, and solid organ tumors, were also reported; malignancies rarely seen in children (eg, leiomyosarcoma, hepatic malignancies, and renal cell carcinoma) were also observed. Overall, in pediatric patients, the median onset of malignancy was after 30 months of therapy (range: 1 to 84 months); most of these cases (88%) were receiving other immunosuppressive medications (eg, azathioprine and methotrexate). As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma. The role of TNF-blockers in the development of malignancies in children cannot be excluded. The FDA also reviewed 147 postmarketing reports of leukemia (including acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) in patients (children and adults) using TNF-blockers. Average onset time to development of leukemia was within the first 1 to 2 years of TNF blocker initiation. Although most patients were receiving other immunosuppressive agents, the role of TNF blockers in the development of leukemia could not be excluded. The FDA concluded that there is a possible association with the development of leukemia and the use of TNF-blockers. Patients should be monitored closely for signs and symptoms suggestive of malignancy, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation.
In JIA patients, rare inflammatory bowel disease has also been reported (van Dijken 2011); monitor and discontinue therapy if symptoms develop.
Reactivation of TB has been reported in pediatric patients receiving biologic response modifiers (infliximab and etanercept); prior to therapy, patients with no TB risk factors should be screened for latent TB infection (LTBI) with an age appropriate test (ie, <5 years of age: tuberculin skin test, and ≥5 years of age: IGRA [interferon gamma release assay]); if any TB risk factors are present or symptoms, both LTBI screening tests should be performed (AAP [Davies 2016])
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program
Abatacept: Anti-TNF Agents may enhance the immunosuppressive effect of Abatacept. Risk X: Avoid combination
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Anifrolumab: Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) may enhance the immunosuppressive effect of Anifrolumab. Risk X: Avoid combination
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Belimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combination
Biologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Risk X: Avoid combination
Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Risk X: Avoid combination
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
Cyclophosphamide: Etanercept may enhance the adverse/toxic effect of Cyclophosphamide. An increased risk of solid cancer development may be present. Risk X: Avoid combination
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination
Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Thiopurine Analogs: Anti-TNF Agents may enhance the adverse/toxic effect of Thiopurine Analogs. Specifically, the risk for T-cell non-Hodgkin's lymphoma (including hepatosplenic T-cell lymphoma) may be increased. Risk C: Monitor therapy
Tocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Vedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
The American Academy of Dermatology considers tumor necrosis factor alpha (TNFα) blocking agents for the treatment of psoriasis to be compatible for use in male patients planning to father a child (AAD-NPF [Menter 2019]).
Women with well-controlled psoriasis planning a pregnancy who wish to avoid fetal exposure can consider discontinuing etanercept 15 days prior to attempting pregnancy (Rademaker 2018).
Etanercept crosses the placenta.
Following in utero exposure, etanercept concentrations in the newborn at delivery are 3% to 32% of the maternal serum concentration. A case report describes maternal use of subcutaneous etanercept 25 mg twice weekly throughout pregnancy. Maternal concentrations remained stable throughout each trimester. Maternal and cord blood concentrations at delivery were 2,239 ng/mL and 81 ng/mL, respectively. Etanercept concentrations in the neonate were 21 ng/mL, 1 week after delivery and not detectable 12 weeks later even though the child was breastfed and etanercept was present in breast milk (3.5 ng/mL) (Murashima 2009).
Outcome information following maternal use of etanercept in pregnancy is available. Information related to this class of medications is emerging, but based on available data, tumor necrosis factor alpha (TNFα) blocking agents are considered to have low to moderate risk when used in pregnancy (ACOG 776 2019).
The risk of immunosuppression may be increased following third trimester maternal use of TNFα blocking agents; the fetus, neonate/infant should be considered immunosuppressed for 1 to 3 months following in utero exposure (AAD-NPF [Menter 2019]).
Use of immune modulating therapies in pregnancy should be individualized to optimize maternal disease and pregnancy outcomes (ACOG 776 2019). The American Academy of Dermatology considers TNFα blocking agents for the treatment of psoriasis to be compatible with pregnancy (AAD-NPF [Menter 2019]).
Monitor improvement of symptoms and physical function assessments (eg, joint swelling, pain, and tenderness; ESR or C-reactive protein level). Latent TB screening prior to initiating and during therapy; signs/symptoms of infection (prior to, during, and following therapy); CBC with differential; signs/symptoms/worsening of heart failure; LFTs at baseline; HBV screening prior to initiating (all patients), HBV carriers (during and for several months following therapy); signs and symptoms of hypersensitivity reaction; symptoms of lupus-like syndrome; signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss).
Etanercept is a recombinant DNA-derived protein composed of tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. Etanercept binds tumor necrosis factor (TNF) and blocks its interaction with cell surface receptors. TNF plays an important role in the inflammatory processes and the resulting joint pathology of rheumatoid arthritis (RA), polyarticular-course juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), and plaque psoriasis.
Onset of action: ~2 to 3 weeks; RA: 1 to 2 weeks, weeks, with maximum effect at 3 months; Psoriasis: Response best determined after 3 to 4 months (AAD-NPF [Menter 2019]).
Absorption: Absorbed slowly after SUBQ injection.
Bioavailability: SUBQ: 60%.
Half-life elimination: SUBQ: Children ≥4 years and Adolescents (JIA): Mean range: 70 to 94.8 hours (range: 31.2 to 104.8 hours) (Yim 2005); Adults (RA): 102 ± 30 hours.
Time to peak: RA: SUBQ: 69 ± 34 hours.
Clearance: Children and Adolescents 4 to 17 years: 46 mL/hour/m2 (Enbrel prescribing information 1998); Adults: 160 ± 80 mL/hour.
Solution (Enbrel Subcutaneous)
25 mg/0.5 mL (per 0.5 mL): $984.55
Solution Auto-injector (Enbrel SureClick Subcutaneous)
50 mg/mL (per mL): $1,969.09
Solution Cartridge (Enbrel Mini Subcutaneous)
50 mg/mL (per mL): $1,969.09
Solution Prefilled Syringe (Enbrel Subcutaneous)
25 mg/0.5 mL (per 0.5 mL): $984.55
50 mg/mL (per mL): $1,969.09
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