Etanercept

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Auto-injector, Subcutaneous [preservative free]:

Enbrel SureClick: 50 mg/mL (0.98 mL, 1 mL)

Solution Cartridge, Subcutaneous [preservative free]:

Enbrel Mini: 50 mg/mL (0.98 mL, 1 mL)

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Enbrel: 25 mg/0.5 mL (0.5 mL, 0.51 mL); 50 mg/mL (0.98 mL, 1 mL)

Solution Reconstituted, Subcutaneous:

Enbrel: 25 mg (1 ea) [contains benzyl alcohol]

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Absorption

Absorbed slowly after SubQ injection

Excretion

Clearance: Children and Adolescents 4 to 17 years: 46 mL/hour/m² (Enbrel prescribing information 1998); Adults: 160 ± 80 mL/hour

Onset of Action

~2 to 3 weeks; RA: 1 to 2 weeks; Maximum effect: RA: Full effect is usually seen within 3 months

Time to Peak

RA: SubQ: 69 ± 34 hours

Half-Life Elimination

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

Use: Labeled Indications

Ankylosing spondylitis: Reducing signs and symptoms in patients with active ankylosing spondylitis.

Plaque psoriasis (Enbrel): 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 (Enbrel): Reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients 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 (RA). Etanercept can be initiated in combination with methotrexate or used alone.

Use: Off Label

Acute graft-versus-host disease (treatment)b

Data from a small pilot/phase 2 study support the use of etanercept (in combination with methylprednisolone) for initial treatment of acute graft-versus-host disease (GVHD) Levine 2008. In a phase 2 study, etanercept (in combination with corticosteroids) demonstrated responses in the initial treatment of acute GVHD Alousi 2009. Data from another small study suggest that etanercept may be of benefit in the management of steroid-refractory acute GVHD Busca 2007. A retrospective study also suggests the utility of etanercept (in combination with tacrolimus and antithymocyte globulin with or without mycophenolate) in the treatment of steroid-refractory acute GVHD Kennedy 2006.

Chronic graft-versus-host disease, refractory (treatment)cyes

Data from a small study support the use of etanercept (in combination with corticosteroids and/or immunosuppressive therapy) in the management of corticosteroid-dependent chronic GVHD following allogeneic bone marrow transplant Chiang 2002. Data from another small study suggest that etanercept may be of benefit in the management of steroid-refractory chronic GVHD Busca 2007. Clinical experience also suggests that etanercept may be of benefit in managing refractory cases of chronic GVHD following allogeneic stem cell transplant Flowers 2015.

Based on the American Society for Blood and Marrow Transplant consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic graft-versus-host disease, etanercept may be a treatment option for steroid-refractory chronic GVHD in select patients with GI or cutaneous manifestations.

Pyoderma gangrenosum (refractory)c

Data from case reports and a small retrospective analysis suggest that etanercept may have some benefit in patients with refractory pyoderma gangrenosum Charles 2007, Roy 2006.

Contraindications

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)

Dosage and Administration

Dosing: Adult

Ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis: SubQ: Note: May continue methotrexate, glucocorticoids, salicylates, NSAIDs, or analgesics during etanercept therapy.

Once-weekly dosing: 50 mg once weekly; maximum dose (rheumatoid arthritis): 50 mg/week.

Twice-weekly dosing (off-label dose): 25 mg twice weekly (Bathon 2000; Calin 2004; Davis 2003; Genovese 2002; Mease 2000; Mease 2004).

Graft-versus-host disease (treatment) (off-label use):

Acute graft-versus-host disease, treatment: SubQ:

Initial treatment: 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).

Steroid refractory: 25 mg twice weekly for 4 weeks, followed by 25 mg once weekly for 4 weeks (Busca 2007) or 0.4 mg/kg (maximum: 25 mg/dose) twice weekly for 4 weeks, followed by 0.4 mg/kg (maximum: 25 mg/dose) once weekly for 4 weeks (in combination with tacrolimus and antithymocyte globulin ± mycophenolate; initiate etanercept within 2 weeks of beginning antithymocyte globulin) (Kennedy 2006).

Chronic graft-versus-host disease (refractory), treatment: SubQ: 25 mg twice weekly for 4 weeks, followed by 25 mg once weekly for 4 weeks (in combination with corticosteroids and/or immunosuppressive therapy) (Chiang 2002) or 25 mg twice weekly for 4 weeks, followed by 25 mg once weekly for 4 weeks (Busca 2007; Wolff 2011).

Plaque psoriasis: 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.

Pyoderma gangrenosum, refractory (off-label use; based on limited data): SubQ: 25 to 50 mg subcutaneously twice weekly; some dosages were administered as 50 mg subcutaneously once per week (Charles 2007; Roy 2006).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Erelzi (etanercept-szzs) is approved as a biosimilar 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 (AHA [McCrindle 2017]): Infants ≥6 months and Children <6 years: SubQ: 0.8 mg/kg/dose for 3 doses; administer first dose within 24 hours after completion of IV immunoglobulin (day 0), the second dose at day 7, and third dose at day 14; maximum dose: 50 mg/dose. Dosing based on an open-labeled pilot trial of 15 pediatric patients (mean age: 2.6 years); all patients also received standard aspirin therapy; no patients required retreatment or rescue therapy for signs/symptoms of Kawasaki disease (Choueiter 2010). A large double-blind, placebo-controlled trial is ongoing [EATAK trial (NCT00841789)] utilizing the same dosage regimen; results pending (Portman 2011). 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: Studies 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)

Reconstitution

Enbrel: Reconstitute lyophilized powder with 1 mL sterile bacteriostatic water for injection (supplied). Swirl gently, do not shake (some foaming is normal); dissolution takes <10 minutes. Use vial adaptor (supplied) when reconstituting (do not use adaptor if multiple doses are to be withdrawn). If the vial is used for multiple doses, use a 25-gauge needle for reconstituting and withdrawing of solution; use a 27-gauge needle for injection. Do not filter reconstituted solution during preparation or administration.

Administration

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, 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.

Storage

Refrigerate 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 multi-use vials and diluent syringes), or prefilled pens may be stored between 20°C and 25°C (68°F and 77°F) for a maximum single period of 14 days (Enbrel), 28 days (Erelzi), or 60 days (Brenzys [Canadian product]) with protection from light and sources of heat and humidity. Once an autoinjector, prefilled syringe, dose tray, or prefilled pen has been stored at room temperature, it should not be placed back into the refrigerator; discard after 14 days (Enbrel), 28 days (Erelzi), or 60 days (Brenzys [Canadian product]).

Once the multi-use 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.

Drug Interactions

Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. 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. Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

Biologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). 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. Avoid combination

Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Cyclophosphamide: Etanercept may enhance the adverse/toxic effect of Cyclophosphamide. An increased risk of solid cancer development may be present. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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. Monitor therapy

Tocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Vedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Avoid combination

Adverse Reactions

>10%:

Dermatologic: Skin rash (3% to 13%)

Gastrointestinal: Diarrhea (3% to 16%)

Infection: Infection (50% to 81%)

Local: Injection site reaction (adults: 15% to 43%; children: 7%; bleeding, bruising, erythema, itching, pain, or swelling; mild to moderate and usually decreases with subsequent injections)

Respiratory: Upper respiratory tract infection (38% to 65%), respiratory tract infection (21% to 54%)

Miscellaneous: Antibody development (non-neutralizing; 4% to 16%), positive ANA titer (11%)

1% to 10%:

Dermatologic: Pruritus (2% to 5%), urticaria ( 2%)

Hypersensitivity: Hypersensitivity reaction (1%)

Miscellaneous: Fever (2% to 3%)

Frequency not defined:

Dermatologic: Cellulitis

Gastrointestinal: Gastroenteritis

Infection: Abscess, influenza, sepsis

Neuromuscular & skeletal: Osteomyelitis, septic arthritis

Renal: Pyelonephritis

Respiratory: Bronchitis, pneumonia, sinusitis

<1%, postmarketing, and/or case reports: Anemia, angioedema, aplastic anemia, aseptic meningitis, aspergillosis, autoimmune hepatitis, cardiac failure, chest pain, cutaneous lupus erythematous, demyelinating disease of the central nervous system, erythema multiforme, fungal infection (including histoplasmosis), Guillain-Barré syndrome, hepatotoxicity (idiosyncratic) (Chalasani 2014), herpes zoster, increased serum transaminases, inflammatory bowel disease, interstitial pulmonary disease, leukemia, leukopenia, lupus-like syndrome, lymphadenopathy, malignant lymphoma, malignant melanoma, malignant neoplasm, Merkel cell carcinoma, multiple sclerosis, neutropenia, optic neuritis, pancytopenia, paresthesia, pneumonia due to Pneumocystis carinii, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), reactivation of HBV, sarcoidosis, scleritis, seizure, skin carcinoma, Stevens-Johnson syndrome, subcutaneous nodule, thrombocytopenia, toxic epidermal necrolysis, transverse myelitis, tuberculosis (including pulmonary and extrapulmonary), uveitis, varicella zoster infection, vasculitis (cutaneous and systemic)

Warnings/Precautions

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.
• 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 (including reactivation of latent tuberculosis), 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 tuberculosis, 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 (HSTCL), 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 tuberculosis (disseminated or extrapulmonary), including reactivation of latent tuberculosis, has been reported in patients receiving etanercept. Evaluate patients for tuberculosis risk factors and latent tuberculosis infection (with a tuberculin skin test) prior to and during therapy. Treatment for latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis 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 tuberculosis or with risk factors despite negative skin test. Some patients who tested negative prior to therapy have developed active infection; tests for latent tuberculosis infection may be falsely negative while on etanercept therapy. Use with caution in patients who have traveled to or resided in regions where tuberculosis is endemic. Monitor for signs and symptoms of tuberculosis 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 one month but significantly higher after 6 months.
• Seizure disorders: Use with caution in patients with a history of seizures; new-onset or exacerbation of seizures have been reported.
• Wegener granulomatosis: Use is not recommended in patients with Wegener granulomatosis who are receiving immunosuppressive therapy due to higher incidence of noncutaneous solid malignancies.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: 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 suggests 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.

Monitoring Parameters

Monitor improvement of symptoms and physical function assessments. 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; 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).

Pregnancy

Pregnancy Considerations

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]).

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).

Patient Education

What is this drug used for?

• It is used to treat some types of arthritis.
• It is used to treat ankylosing spondylitis.
• It is used to treat plaque psoriasis.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Injection site irritation
• Headache
• Diarrhea
• Common cold symptoms

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Aplastic anemia like fever, sore throat, mouth sores, infections, bruising, or purple skin splotches.
• Lupus like rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out.
• Burning or numbness feeling
• Severe weakness
• Seizures
• Vision changes
• Dizziness
• Pale skin
• Eczema
• Swollen glands
• Night sweats
• Shortness of breath
• Unintentional weight loss
• Skin growths or lumps
• Skin changes
• Mole changes
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.