(et a NER sept)
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)
Solution Prefilled Syringe, Subcutaneous [preservative free]:
Enbrel: 25 mg/0.5 mL (0.51 mL); 50 mg/mL (0.98 mL)
Solution Reconstituted, Subcutaneous [preservative free]:
Enbrel: 25 mg (1 ea) [contains benzyl alcohol, tromethamine]
Brand Names: U.S.
- Enbrel SureClick
- Antirheumatic, Disease Modifying
- Tumor Necrosis Factor (TNF) Blocking Agent
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.
Absorbed slowly after SubQ injection
Vd: 1.78 to 3.39 L/m2
Clearance: Children and Adolescents 4 to 17 years: 46 mL/hour/m2; 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
RA: SubQ: Children: 70 to 94.8 hours; Adults: 102 ± 30 hours
Use: Labeled Indications
Ankylosing spondylitis: Reducing signs and symptoms in patients with active ankylosing spondylitis.
Plaque psoriasis: Treatment of patients ≥4 years (Enbrel) or ≥18 years (Erelzi) 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.
Psoriatic arthritis: 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.
Treatment of acute graft-versus-host disease (GVHD).
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to etanercept or any component of the formulation.
Note: Erelzi is approved as biosimilar to Enbrel.
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 2002)
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
Acute graft-versus-host disease (GVHD), treatment (off-label use): SubQ: 0.4 mg/kg (maximum: 25 mg/dose) twice weekly for 8 weeks (in combination with methylprednisolone) (Levine 2008)
Refer to adult dosing.
Note: Erelzi is approved as biosimilar to Enbrel.
Juvenile idiopathic arthritis: Children ≥2 years and Adolescents: SubQ: Note: May continue glucocorticoids, NSAIDs, or analgesics during etanercept therapy.
<63 kg: 0.8 mg/kg (maximum: 50 mg/dose) once weekly. Note: There is no dosage form for Erelzi that allows weight-based dosing for pediatric patients <63 kg.
≥63 kg: 50 mg once weekly.
Twice-weekly dosing (off-label dose): 0.4 mg/kg (maximum: 25 mg/dose) twice weekly (Lovell 2006).
Plaque psoriasis (Enbrel only): Children ≥4 years and Adolescents: SubQ:
<63 kg: 0.8 mg/kg (maximum: 50 mg/dose) once weekly.
≥63 kg: 50 mg once weekly
Acute graft-versus-host disease (GVHD), treatment (off-label use): Children ≥1 year and Adolescents: SubQ: Refer to adult dosing.
Dosing: Renal Impairment
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Dosing: Hepatic Impairment
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
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.
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.
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) or 28 days (Erelzi) 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) or 28 days (Erelzi).
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.
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: Etanercept may enhance the adverse/toxic effect of Belimumab. 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
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
InFLIXimab: Etanercept may enhance the immunosuppressive effect of InFLIXimab. Avoid combination
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
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
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. 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
Tocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Avoid combination
Tofacitinib: Anti-TNF Agents may enhance the adverse/toxic effect of Tofacitinib. Avoid combination
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. 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. Avoid combination
Vedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Avoid combination
Central nervous system: Headache (17% to 19%)
Dermatologic: Skin rash (3% to 13%)
Gastrointestinal: Abdominal pain (5%; children 19%), diarrhea (3% to 16%), vomiting (3%; children 13%)
Infection: Infection (50% to 81%; children 62%)
Local: Injection site reaction (14% to 43%; bleeding, bruising, erythema, itching, pain, or swelling)
Respiratory: Upper respiratory tract infection (38% to 65%), respiratory tract infection (21% to 54%), rhinitis (12%)
Miscellaneous: Antibody development (positive antidouble-stranded DNA antibodies 15% by RIA, 3% by Crithidia luciliae assay), positive ANA titer (11%)
≥3% to 10%:
Central nervous system: Dizziness (7%)
Dermatologic: Pruritus (2% to 5%)
Gastrointestinal: Nausea (children 9%), dyspepsia (4%)
Neuromuscular & skeletal: Weakness (5%)
Respiratory: Pharyngitis (7%), cough (6%), respiratory distress (5%), sinusitis (3%)
Miscellaneous: Fever (2% to 3%)
<3% (Limited to important or life-threatening): Abscess, adenopathy, anemia, angioedema, anorexia, aplastic anemia, appendicitis, aseptic meningitis, aspergillosis, autoimmune hepatitis, blood coagulation disorder, bursitis, cardiac failure, cerebral ischemia, cerebrovascular accident, cholecystitis, cutaneous lupus erythematous, deep vein thrombosis, demyelinating disease of the central nervous system (suggestive of multiple sclerosis, transverse myelitis, or optic neuritis), depression, dermal ulcer, erythema multiforme, gastritis, gastroenteritis, gastrointestinal hemorrhage, glomerulopathy (membranous), hepatotoxicity (idiosyncratic) (Chalasani, 2014), herpes zoster, hydrocephalus (with normal pressure), hypersensitivity, hypersensitivity reaction, hypertension, hypotension, inflammatory bowel disease, interstitial pulmonary disease, intestinal perforation, ischemic heart disease, leukemia, leukopenia, lupus-like syndrome, lymphadenopathy, malignant lymphoma, malignant melanoma, malignant neoplasm, Merkel cell carcinoma, myocardial infarction, multiple sclerosis, nephrolithiasis, neutropenia, optic neuritis, oral mucosa ulcer, pancreatitis, pancytopenia, pneumonia due to Pneumocystis carinii, polymyositis, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), pulmonary disease, pulmonary embolism, reactivation of HBV, sarcoidosis, scleritis, seizure, skin carcinoma, Stevens-Johnson syndrome, subcutaneous nodule, thrombocytopenia, thrombophlebitis, toxic epidermal necrolysis, tuberculosis, tuberculous arthritis, urinary tract infection, uveitis, varicella zoster infection, vasculitis (cutaneous and systemic), weight gain
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.
• 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.
• 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).
• 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.
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 Risk Factor
Adverse events have not been observed in animal reproduction studies. Etanercept crosses the placenta. Following in utero exposure, concentrations in the newborn at delivery are 3% to 32% of the maternal serum concentration.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience headache, diarrhea, rhinitis, rhinorrhea, or pharyngitis. Have patient report immediately to prescriber signs of infection, signs of lupus (rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, angina or shortness of breath, or swelling in the arms or legs), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of heart problems (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, bruising, bleeding, severe loss of strength and energy, pale skin, eczema, night sweats, weight loss, skin growths or lumps, mole changes, or severe injection site irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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- Drug class: antirheumatics
Other brands: Enbrel