Version May 2024
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. Test patients for latent TB before etanercept use and during therapy. Initiate treatment for latent infection 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. Consider empiric antifungal therapy 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.
Monitor patients closely 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 : In Canada, Brenzys and Erelzi are approved as biosimilars to Enbrel (etanercept).
Graft-versus-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) (Ref) or 25 mg twice weekly (in combination with corticosteroids) for 4 weeks (Ref). 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) (Ref).
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 (Ref).
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) (Ref).
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 (Ref).
Once-weekly dosing: SUBQ: 50 mg once weekly (with or without methotrexate) (Ref); maximum dose: 50 mg/week.
Twice-weekly dosing: SUBQ: 25 mg twice weekly (with or without methotrexate) (Ref).
Stevens-Johnson syndrome/toxic epidermal necrolysis (off-label use): SUBQ: 25 mg (for weight ≤65 kg) or 50 mg (for weight >65 kg) twice weekly in combination with glucocorticoids; discontinue when skin lesions heal or glucocorticoids are able to be tapered (Ref).
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).
Refer to adult dosing.
(For additional information see "Etanercept (including biosimilars available in Canada): Pediatric drug information")
Note: In Canada, Brenzys and Erelzi are approved as biosimilars to Enbrel (etanercept); approved uses and ages may vary; consult product labeling.
Familial Mediterranean fever (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 (Ref); a case series in adult patients (n=5, age range: 20 to 40 years) reported either no further attacks (80%) or a decrease in attack frequency (20%) with etanercept (25 mg twice weekly) therapy (Ref). Note: Trials performed with Enbrel product.
Juvenile idiopathic arthritis:
Children ≥2 years and Adolescents <18 years:
Once-weekly dosing:
Weight <63 kg: Enbrel: SUBQ: 0.8 mg/kg/dose once weekly; maximum dose: 50 mg/dose.
Weight ≥63 kg: Enbrel: SUBQ: 50 mg once weekly.
Twice-weekly dosing: Enbrel: SUBQ: 0.4 mg/kg/dose twice weekly, given 72 to 96 hours apart; maximum dose: 25 mg/dose (Ref).
Juvenile psoriatic arthritis:
Children ≥2 years and Adolescents <18 years:
Weight <63 kg: Enbrel: SUBQ: 0.8 mg/kg/dose once weekly; maximum dose: 50 mg/dose.
Weight ≥63 kg: Enbrel: SUBQ: 50 mg once weekly.
Kawasaki disease; acute, adjunct therapy: Limited data available; efficacy results for IV immunoglobulin (IVIG) resistance variable by ages (Ref).
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 (Ref). 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 (Ref). Note: Trials performed with Enbrel product.
Plaque psoriasis:
Children ≥4 years and Adolescents <18 years: Note: Results of a long-term study (264 weeks) showed efficacy maintained and therapy generally well-tolerated (Ref).
Weight <63 kg: Enbrel: SUBQ: 0.8 mg/kg/dose once weekly; maximum dose: 50 mg/dose.
Weight ≥63 kg: Enbrel: SUBQ: 50 mg once weekly.
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).
Autoantibody development may occur with the use of tumor necrosis factor (TNF) alpha inhibitors, including etanercept. Most frequently, autoantibodies include antinuclear antibody and anti–double-stranded DNA; less frequently, anti–extractable nuclear antigen, antihistone antibody, and anticardiolipin antibody (Ref). Frequency of autoantibody development varies depending on underlying disease, specific TNF alpha inhibitor medication, and the duration of use; the clinical significance of asymptomatic antibody positivity is unclear (Ref). Antibody positivity may rarely result in the development of an autoimmune disorder, such as lupus-like syndrome (Ref). Symptoms may include arthralgia, myalgia, mucocutaneous symptoms (eg, skin rash), cytopenia, fatigue, fever, serositis, and kidney injury (Ref). Development of an autoimmune disorder is associated with a poor treatment response of the original disease to TNF alpha inhibitor therapy (Ref). It is unclear if the development of an autoimmune disorder is a TNF alpha inhibitor class effect; several reports of rechallenge with the same TNF alpha inhibitor or a different TNF alpha inhibitor after treatment of the initial autoimmune disorder did not result in a recurrence (Ref).
Mechanism: Unknown; postulated mechanisms include bystander activation of autoreactive lymphocytes due to drug-specific immunity, nonspecific activation of lymphocytes, direct cytotoxicity with release of autoantigens, and disruption of central T-cell tolerance (Ref).
Risk factors:
• Longer disease duration (Ref)
• Females (Ref)
• Ulcerative colitis (Ref).
New-onset or exacerbation of central and peripheral nervous system demyelinating disease, such as multiple sclerosis, optic neuritis, acute transverse myelitis, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy, may occur with tumor necrosis factor (TNF) alpha inhibitors, although causality has not been proven (Ref). Symptomatic CNS demyelination associated with TNF alpha inhibitors may be monophasic and/or clinically isolated (Ref). Partial or complete resolution may occur after discontinuation of TNF alpha inhibitors (Ref); however, approximately one-third of TNF alpha inhibitors associated demyelinating episodes evolve into clinically definite multiple sclerosis (Ref).
Mechanism: Unknown; several mechanisms have been postulated, including the following: May trigger CNS demyelination directly by immune activation in genetically and/or immunologically predisposed individuals (Ref); may inhibit remyelination via TNF type-2 receptor (TNFR2) (Ref); may increase ingress of auto-reactive T cells in the CNS; may alter downstream cytokine responses; may neutralize TNF systemically but not within the CNS, creating an artificially high local concentration of brain TNF (known as sponge effect); may permit latent CNS viral infection; or may promote anti-drug antibodies and immune complexes that are contributory to demyelination events (Ref).
Onset: Varied; mean time of exposure to TNF alpha inhibitors before onset of symptoms: 18 months (Ref).
Risk factors:
• Preexisting or recent onset of central or peripheral nervous system demyelinating disease
Various cutaneous eruptions have been reported with etanercept, including psoriasiform eruption (either new onset or exacerbation), hidradenitis suppurativa, lupus-like syndrome, eczematous rash, erythema nodosum, bullous pemphigoid, lichenoid eruption, and Henoch-Schönlein purpura (Ref).
Mechanism: Psoriasiform eruptions: Non–dose-related; possibly related to cytokine imbalance or imbalance between tumor necrosis factor (TNF) alpha and interferon-alpha (Ref). Lupus-like syndrome: Non–dose-related; possibly related to cytokine imbalance; development of autoantibodies typically associated with lupus may occur without clinical symptoms in patients treated with etanercept and other TNF alpha inhibitors (Ref).
Onset: Psoriasiform eruptions: Delayed; ~10 months (range: 2 to 62 months) (Ref).
Risk factors:
• Females (psoriatic lesions) (Ref)
• Males (palmoplantar pustulosis) (Ref)
• Cross-reactivity data among TNF alpha inhibitors in patients who develop psoriatic lesions are conflicting (Ref)
New-onset heart failure (HF) and worsening of HF have been reported with tumor necrosis factor (TNF) alpha inhibitors, including etanercept; however, data are conflicting, and risk is unclear (Ref). Rheumatoid arthritis (RA) may be a risk factor for HF development (Ref). Some data suggest that TNF alpha inhibitors may reduce the risk of HF in the RA population by improving inflammation, lowering disease activity, and improving surrogate markers of cardiovascular disease (Ref).
Mechanism: Not clearly established; postulated mechanisms include pro-inflammatory cytokine activation, accelerated atherosclerosis, and reduced physical activity related to the underlying rheumatologic disease (Ref). “Reverse signaling” may occur, leading to cardiotoxic effects; TNF on cardiomyocytes of the failing heart may act as receptors, activating intracellular signaling pathways, potentiating the toxic effect of the cytokine (Ref).
Onset: Varied; median 8.5 months (range: 5 to 17 months [data with infliximab]) (Ref).
Risk factors:
• Preexisting HF
• Higher disease activity (inflammation) (eg, disease activity score [DAS28], C-reactive protein, erythrocyte sedimentation rate) (Ref)
Reactivation of hepatitis B virus (HBV) may occur with immunosuppressive or biologic therapy, including tumor necrosis factor (TNF) alpha inhibitors (Ref). Reactivation of HBV may occur in patients who are HBsAg-positive and in patients who are HBsAg-negative/HBcAb-positive with detectable HBV DNA (Ref). Criteria for HBV reactivation includes (1) a rise in HBV DNA compared to baseline (or an absolute level of HBV DNA when a baseline is unavailable) and (2) reverse seroconversion (seroreversion) from HBsAg-negative to HBsAg-positive for patients who are HBsAg-negative and anti-HBc–positive (Ref).
Mechanism: Inhibit stimulation of HBV-specific T lymphocytes, promoting reactivation (Ref).
Onset: Varied; 2 weeks after initiation, up to a year after discontinuation (Ref).
Risk factors:
• Males (Ref)
• Older age (Ref)
• Presence of cirrhosis (Ref)
• High baseline HBV DNA level (Ref)
• HBeAg or HBsAg seropositivity (Ref)
• Absence of anti-HBs among patients with resolved HBV infection (Ref)
• Chronic HBV (Ref).
• Non-A HBV genotype (Ref).
• Hepatitis C, hepatitis D, or HIV co-infection (Ref).
Etanercept has been associated with increased serum transaminases and hepatotoxicity (Ref). Cholestatic hepatitis, reactivation of hepatitis B virus (HBV), exacerbation of hepatitis E virus infection, and autoimmune hepatitis have been reported with etanercept and other tumor necrosis factor (TNF) alpha inhibitors (Ref). Elevated aminotransferases between 2 to 3 times the upper limit of normal may occur that are usually transient and asymptomatic (Ref). Resolution of symptoms in patients who develop an autoimmune hepatitis may require initiation of corticosteroid therapy (Ref). Immunomodulatory use, in particular methotrexate, may decrease the risk of hepatotoxicity associated with TNF alpha inhibitors (Ref). Patients often tolerate a different TNF alpha inhibitor (Ref); although, hepatotoxicity may recur with an alternative agent in some cases (Ref). Hepatotoxicity is more commonly associated with infliximab compared to etanercept and other TNF alpha inhibitors (Ref).
Mechanism: Unknown; idiosyncratic (Ref) or autoimmunity due to development of autoantibodies (Ref).
Onset: Varied; ranges from 2 weeks to several years (Ref). Autoimmune hepatitis has a longer latency period than non-immune cases (16 weeks vs 10 weeks, respectively) (Ref).
Risk factors:
• Higher body mass index (elevated liver enzymes) (Ref)
Tumor necrosis factor (TNF) alpha inhibitors may be associated with infection, including serious infection. In clinical trials, serious infections were numerically higher among patients treated with TNF alpha inhibitors than among patients who received placebo. Meta-analyses and observational studies have reported inconsistency in risk. One study reported an increase in serious infection in patients treated with TNF alpha inhibitors (Ref). Another study found no increase in risk (Ref). An observational study did not demonstrate an increased infection risk among patients receiving TNF alpha inhibitors vs comparators (Ref). Infections may present as disseminated (rather than local) disease. Tuberculosis disease (including reactivation of tuberculosis infection), invasive fungal infection (including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and pneumocystosis), and bacterial infection, viral infection, or other opportunistic infections (including legionellosis and listeriosis) have been reported.
Mechanism: Dose-related; TNF alpha is important in the immune response against infections, suggesting that medications that inhibit TNF alpha may increase the risk of infections (Ref).
Risk factors:
• Higher doses (Ref)
• Older age (Ref)
• Chronic lung or kidney disease (Ref)
• Concurrent immunosuppressants (eg, corticosteroids, methotrexate) (Ref)
• History of an opportunistic infection
• Chronic or recurrent infection
• Conditions that predispose to infections (eg, advanced or poorly controlled diabetes)
• Residence/travel in areas of endemic tuberculosis or mycoses (blastomycosis, coccidioidomycosis, histoplasmosis)
Etanercept is associated with injection-site reactions; recall reactions (local reactions at the site of previous injections) may also occur (Ref). Irritative reactions do not require discontinuation and resolve spontaneously over time (Ref). Cross-reactivity between tumor necrosis factor (TNF) alpha inhibitors is not well described. Etanercept has been tolerated in patients with previous infusion reactions with infliximab (Ref). In contrast, there are reports of patients who developed hypersensitivity reactions to etanercept and at least one other TNF alpha inhibitor (Ref). There is a decreased risk with concurrent immunomodulator therapy (eg, methotrexate, cyclosporine) (Ref).
Mechanism: Unknown; T-cell mediated (Ref) or IgE mediated (Ref). Irritative reactions may result from improper injection technique or excipients (Ref).
Onset: Varied; reactions generally occur on the fourth injection, with an onset 1 to 2 days after injection and last 2 to 3 days (Ref).
Risk factors:
• Younger age (Ref)
• Increased pain associated with etanercept single-use syringes vs etanercept in vials (Ref)
Malignant lymphoma and other malignant neoplasms (some fatal) have been reported in children and adolescents receiving tumor necrosis factor (TNF) alpha inhibitors, including etanercept. Half of the malignancies reported in children and adolescents were lymphomas (Hodgkin lymphoma and non-Hodgkin lymphoma), while other cases varied and included rare malignancies usually associated with immunosuppression and malignancies not typically observed in this population. Most patients were receiving concomitant immunosuppressants.
Long-term observational studies and meta-analyses indicate no association between TNF alpha inhibitor therapy and an overall increased risk of cancer (Ref). One study reported a significant increase in lymphomas in patients with rheumatoid arthritis (RA) receiving TNF alpha inhibitors compared to the general population. However, there was no significant increased risk of lymphomas in patients receiving TNF alpha inhibitors compared to those receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or with dose, increasing time since initiation, or cumulative duration (Ref). Another study reported no difference in the risk of solid tumors in patients with RA receiving TNF alpha inhibitors compared to those receiving csDMARDs (Ref). Other studies reported no increased risk of malignancy recurrence in patients receiving TNF alpha inhibitors (Ref).
Mechanism: May contribute to pro-tumor activity and suppress the anti-tumor response (Ref).
Onset: Delayed; median 30 months (range: 1 to 84 months).
Adult and pediatric patients treated with tumor necrosis factor (TNF) alpha inhibitors are at risk for developing tuberculosis (TB) disease (including reactivated tuberculosis) (Ref). A meta-analysis of randomized controlled trials (RCTs) of TNF alpha inhibitors vs control and registry/longitudinal cohort studies of TNF alpha inhibitors vs other disease-modifying antirheumatic drugs (DMARDs) found a significant increase in TB risk in patients with rheumatoid arthritis treated with TNF alpha inhibitors. In the non-RCTs, incidence rates with adalimumab were higher than etanercept. Preventive treatment for latent TB infection reduced TB risk (Ref). In the RCTs, no difference in TB rates were found; however, the failure to detect a difference in TB rates between the 2 groups may be due to a short observational period (Ref).
Mechanism: TNF alpha inhibitors interfere with TNF alpha induction of the granuloma, which is a crucial defense mechanism in controlling TB (Ref). TNF alpha inhibitors modulate T-cell number, function, and cytokine signaling, important for the control of TB infection (Ref).
Onset: Varied; median 3 to ~73 months (Ref).
Risk factors:
• Residence in an area with high TB prevalence (Ref)
• Known TB exposure or ongoing risk factors for TB exposure (eg, travel to areas with high TB prevalence; residence in correctional facilities, long-term care facilities, or homeless shelters; certain healthcare workers) (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Dermatologic: Skin rash (1% to 13%) (table 1)
|
Drug (Etanercept) |
Comparator (Methotrexate) |
Placebo |
Population |
Indication |
Number of Patients (Etanercept) |
Number of Patients (Methotrexate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
1% |
N/A |
1% |
Adults |
Plaque psoriasis |
876 |
N/A |
359 |
|
13% |
19% |
N/A |
Adults |
Rheumatoid arthritis |
415 |
217 |
N/A |
|
3% |
N/A |
2% |
Adults |
Rheumatoid arthritis |
349 |
N/A |
152 |
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: 27% to 81%) (table 2)
|
Drug (Etanercept) |
Comparator (Methotrexate) |
Placebo |
Population |
Indication |
Number of Patients (Etanercept) |
Number of Patients (Methotrexate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
27% |
N/A |
28% |
Adults |
Plaque psoriasis |
876 |
N/A |
359 |
|
81% |
86% |
N/A |
Adults |
Rheumatoid arthritis |
415 |
217 |
N/A |
|
50% |
N/A |
39% |
Adults |
Rheumatoid arthritis |
349 |
N/A |
152 |
Local: Injection-site reaction (children and adolescents: 7%; adults: 15% to 43%; mild to moderate; usually decreases with subsequent injections) (table 3)
|
Drug (Etanercept) |
Comparator (Methotrexate) |
Placebo |
Population |
Indication |
Number of Patients (Etanercept) |
Number of Patients (Methotrexate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
7% |
N/A |
N/A |
Children and adolescents |
Plaque psoriasis |
N/A |
N/A |
N/A |
|
15% |
N/A |
6% |
Adults |
Plaque psoriasis |
876 |
N/A |
359 |
|
43% |
18% |
N/A |
Adults |
Rheumatoid arthritis |
415 |
217 |
N/A |
|
37% |
N/A |
11% |
Adults |
Rheumatoid arthritis |
349 |
N/A |
152 |
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: Heart 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, malignant melanoma, skin carcinoma
Gastrointestinal: Gastroenteritis
Hematologic & oncologic: Malignant neoplasm
Infection: Abscess, influenza, opportunistic infection, sepsis
Neuromuscular & skeletal: Osteomyelitis, septic arthritis
Renal: Pyelonephritis
Respiratory: Bronchitis, pneumonia, reactivated tuberculosis, sinusitis
Postmarketing:
Cardiovascular: Chest pain, vasculitis (Pérez-De-Lis 2017)
Dermatologic: Alopecia (Havmose 2017), bullous pemphigoid (Shmidt 2012), cutaneous lupus erythematosus, eczematous rash (Lee 2007), erythema multiforme, erythema nodosum (Kurokami 2023), lichenoid eruption (Havmose 2017), Merkel cell carcinoma (de Giorgi 2011), psoriasiform eruption (Shmidt 2012), psoriasis (including palmoplantar) (Shmidt 2012), psoriasis flare (Shmidt 2012), pustular psoriasis (Shmidt 2012), Stevens-Johnson syndrome, subcutaneous nodule, toxic epidermal necrolysis
Gastrointestinal: Inflammatory bowel disease (van Dijken 2011)
Hematologic & oncologic: Anemia, hematologic abnormality (macrophage activation syndrome), Henoch-Schönlein purpura (Shmidt 2012), Hodgkin lymphoma, leukopenia, lymphadenopathy, neutropenia (Pérez-De-Lis 2017), non-Hodgkin lymphoma, thrombocytopenia (Pérez-De-Lis 2017)
Hepatic: Cholestatic hepatitis (Shah 2020), hepatotoxicity (Chalasani 2021), increased serum transaminases (Shah 2020)
Hypersensitivity: Angioedema (Sendur 2009), hypersensitivity angiitis (Ramos-Casals 2010)
Immunologic: Sarcoidosis (Pérez-De-Lis 2017)
Infection: Aspergillosis, atypical mycobacterial infection, blastomycosis, candidiasis, coccidioidomycosis, herpes zoster infection, histoplasmosis, protozoal infection
Nervous system: Guillain-Barré syndrome, headache, multiple sclerosis, paresthesia, seizure, transverse myelitis (Havmose 2017)
Ophthalmic: Optic neuritis (Ramos-Casals 2010), scleritis (Sassa 2012), uveitis (Pérez-De-Lis 2017)
Respiratory: Interstitial lung disease (Pérez-De-Lis 2017), 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. Tuberculosis (TB) disease (including reactivation of TB infection [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]: TB disease (active TB) (disseminated or extrapulmonary), including reactivation of TB infection (latent TB), has been reported in patients receiving etanercept. Evaluate patients for TB risk factors and TB infection (with a tuberculin skin test) prior to and during therapy. Treatment for TB infection 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 TB infection or disease or with risk factors despite negative skin test. Some patients who tested negative prior to therapy have developed active infection; tests for 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.
• Patients with rheumatic musculoskeletal disease undergoing hip or knee replacement surgery: Hold biologic disease-modifying antirheumatic drugs (DMARDs) prior to surgery and plan surgery after the next dose is due. Surgery can occur after holding medication for 1 full dosing cycle (eg, for medications administered every 4 weeks, schedule surgery 5 weeks from last administered dose); therapy can be restarted once surgical wound shows evidence of healing (eg, no swelling, erythema, or drainage), sutures/staples are removed, and no ongoing nonsurgical site infections (typically ~14 days to reduce infection risk). Decisions to withhold therapy should be based on shared decision making; ensure the patient and their provider weigh risks of interrupting therapy and disease control versus risks of continuing therapy and surgical complications (ACR/AAHKS [Goodman 2022]).
• 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). Note: As of June 2023, the Enbrel prescribing information states that the devices are no longer made with 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 patients with juvenile idiopathic arthritis, rare inflammatory bowel disease has been reported (van Dijken 2011); monitor and discontinue therapy if symptoms develop.
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.
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 (1 mL)
Solution Cartridge, Subcutaneous [preservative free]:
Enbrel Mini: 50 mg/mL (1 mL)
Solution Prefilled Syringe, Subcutaneous [preservative free]:
Enbrel: 25 mg/0.5 mL (0.5 mL); 50 mg/mL (1 mL)
Solution Reconstituted, Subcutaneous:
Enbrel: 25 mg (1 ea [DSC]) [contains benzyl alcohol]
No
Solution (Enbrel Subcutaneous)
25 mg/0.5 mL (per 0.5 mL): $1,110.27
Solution Auto-injector (Enbrel SureClick Subcutaneous)
50 mg/mL (per mL): $2,220.55
Solution Cartridge (Enbrel Mini Subcutaneous)
50 mg/mL (per mL): $2,220.55
Solution Prefilled Syringe (Enbrel Subcutaneous)
25 mg/0.5 mL (per 0.5 mL): $1,110.27
50 mg/mL (per mL): $2,220.55
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
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 ([DSC]) [contains benzyl alcohol, tromethamine]
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.
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 administered 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 (≥30 minutes for autoinjector). Note: If the prescriber determines that it is appropriate, patients or caregivers may self-inject or inject, respectively, 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): 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.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103795s5594lbl.pdf#page=35, must be dispensed with this medication.
Ankylosing spondylitis: Reducing signs and symptoms in patients with active ankylosing spondylitis.
Juvenile psoriatic arthritis: Treatment of active juvenile psoriatic arthritis in pediatric patients ≥2 years of age.
Plaque psoriasis: Treatment of patients ≥4 years of age with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
Polyarticular juvenile idiopathic arthritis: Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ≥2 years of age.
Psoriatic arthritis: Reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in adults with psoriatic arthritis. Etanercept can be used with or without methotrexate.
Rheumatoid arthritis: 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. Etanercept can be initiated in combination with methotrexate or used alone.
Note: In Canada, Brenzys and Erelzi are approved as biosimilars to Enbrel (etanercept); refer to Canadian product monograph(s) for biosimilar-specific indication details.
Acute graft-vs-host disease (treatment); Nonradiographic axial spondyloarthritis; Stevens-Johnson syndrome/toxic epidermal necrolysis
Enbrel may be confused with Levbid
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.
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
Antithymocyte Globulin (Equine): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
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). Management: Consider alternatives to the use of belimumab with other biologic therapies. Monitor closely for increased toxicities related to additive immunosuppression (ie, infection, malignancy) if combined. Risk D: Consider therapy modification
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
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
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
Chikungunya Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). 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
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
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
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Mumps- 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 Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
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
Ritlecitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
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
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
Ublituximab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
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): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Live). 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]).
Females 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]).
Etanercept is present in breast milk.
A case report describes use of SubQ etanercept 25 mg twice weekly starting 4 weeks' postpartum. In samples obtained 1 day after the fifth maternal dose (postpartum day 45), concentrations of etanercept in the breast milk and maternal serum were 75.4 ng/mL and 2,057.6 ng/mL, respectively. The infant was not breastfed (Ostensen 2004). SubQ etanercept was initiated 3 months' postpartum in a woman who was already breastfeeding her infant. Peak breast milk concentrations (7.5 ng/mL) occurred 72 hours after a 50 mcg once weekly dose (Keeling 2010). A third case report describes maternal use of etanercept 25 mg SubQ once weekly beginning the second trimester of pregnancy and continuing postpartum while breastfeeding her infant. Breast milk concentrations on postpartum day 41 (1 day after a maternal dose) were 3 ng/mL, increasing to 5 ng/mL on postpartum day 43, then decreasing to <2 ng/mL prior to the next maternal dose (postpartum day 47). Etanercept in the infant serum was less than the limit of detection (<4 ng/mL) when sampled on days 42 through 43 postpartum (Berthelsen 2010).
According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. However, tumor necrosis factor alpha (TNFα) blocking agents are considered compatible with breastfeeding (AAD-NPF [Menter 2019]; ACOG 776 2019).
CBC with differential (baseline); complete metabolic panel (baseline); tuberculosis (TB) screening prior to initiating and during therapy (chest X-ray if TB positive); hepatitis B virus (HBV)/hepatitis C virus screening prior to initiating (all patients), HBV carriers (during and for several months following therapy); HIV screening (baseline) (AAD-NPF [Menter 2019]); signs/symptoms of infection, heart failure, hypersensitivity reaction, lupus-like syndrome, or malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss). Monitor improvement of symptoms and physical function assessments.
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.
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