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Etanercept

Pronunciation

Pronunciation

(et a NER sept)

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)

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
  • Enbrel SureClick

Pharmacologic Category

  • Antirheumatic, Disease Modifying
  • Tumor Necrosis Factor (TNF) Blocking Agent

Pharmacology

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.

Absorption

Absorbed slowly after SubQ injection

Distribution

Vd: 1.78-3.39 L/m2

Excretion

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

Half-Life Elimination

RA: SubQ: Children: 70-94.8 hours; Adults: 102 ± 30 hours

Use: Labeled Indications

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

Plaque psoriasis: Treatment of adults ≥18 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 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: Unlabeled

Treatment of acute graft-versus-host disease (GVHD).

Contraindications

Sepsis

Dosing: Adult

Ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis: SubQ: Note: Methotrexate, glucocorticoids, salicylates, NSAIDs, or analgesics may be continued during etanercept therapy: 50 mg once weekly or 25 mg given twice weekly (off-label dose; Bathon, 2000; Calin, 2004; Davis, 2003; Genovese, 2002; Mease, 2000; Mease, 2002); maximum dose (rheumatoid arthritis): 50 mg weekly

Plaque psoriasis: SubQ:

Initial: 50 mg twice weekly; maintain initial dose 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)

Dosing: Geriatric

SubQ: Refer to adult dosing.

Dosing: Pediatric

Juvenile idiopathic arthritis: Children ≥2 years and Adolescents: SubQ: Note: Glucocorticoids, NSAIDs, or analgesics may be continued during etanercept therapy: 0.8 mg/kg (maximum: 50 mg/dose) once weekly or 0.4 mg/kg (maximum: 25 mg/dose) twice weekly (off-label dose; Lovell, 2006)

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).

Reconstitution

Reconstitute lyophilized powder aseptically with 1 mL sterile bacteriostatic water for injection, USP (supplied); swirl gently, do not shake. Do not filter reconstituted solution during preparation or administration.

Administration

Administer subcutaneously. Rotate injection sites; may inject into the thigh (preferred), abdomen (avoiding the 2-inch area around the navel), or upper arm. New injections should be given at least one 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, 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 freeze. Do not store in extreme heat or cold. Store in the original carton to protect from light or physical damage.

Individual autoinjectors, prefilled syringes, or dose trays (containing multi-use vials and diluent syringes) may be stored at room temperature for a maximum single period of 14 days with protection from light and sources of heat, and humidity. Once an autoinjector, prefilled syringe or dose tray has been stored at room temperature, it should not be placed back into the refrigerator; discard after 14 days.

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). Reconstituted solution must be used within 14 days; discard 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: 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

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

Adverse Reactions

>10%:

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

ALERT: U.S. Boxed Warning

Serious infections:

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.

Discontinue etanercept if a patient develops a serious infection or sepsis.

Reported infections include the following:

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.

Carefully consider the risks and benefits of treatment with etanercept prior to initiating therapy in patients with long-term or recurrent infections.

Closely monitor patients 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.

Malignancies:

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including etanercept.

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, other peripheral demyelinating neuropathies, and new-onset or exacerbation of seizures 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.

• Hematologic disorders: Rare cases of pancytopenia and and aplastic anemia have been reported with etanercept. 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; evaluate for HBV prior to initiation in all patients. Monitor during and for several months following discontinuation of treatment in HBV carriers; interrupt 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 or corticosteroids) and may present as disseminated (rather than local) disease. Active tuberculosis (or 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 in patients receiving TNF-blocking agents, including etanercept. Monitor closely for signs/symptoms of infection. Discontinue for serious infection or sepsis. Consider risks versus benefits prior to use in patients with a history of chronic or recurrent infection. Consider empiric antifungal therapy in patients who are at risk for invasive fungal infection and develop severe systemic illness. Caution should be exercised when considering use in the elderly or in patients with conditions that predispose them to infections (eg, diabetes) or residence/travel from areas of endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), or with latent or localized infections. Do not initiate etanercept therapy with clinically important active infection. Patients who develop a new infection while undergoing treatment should be monitored closely.

• Malignancy: [US Boxed Warning]: Lymphoma and other malignancies have been reported in children and adolescent patients receiving TNF-blocking agents, including etanercept. Half of the malignancies reported in children were lymphomas (Hodgkin and non-Hodgkin) while other cases varied and included 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. 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 in patients receiving TNF-blocking agents, including etanercept. Perform periodic skin examinations in all patients during therapy, particularly those at increased risk of skin cancer.

• Tuberculosis: [US Boxed Warning]: Tuberculosis (disseminated or extrapulmonary) has been reported in patients receiving etanercept; both reactivation of latent infection and new infections have been reported. Patients should be evaluated for tuberculosis risk factors and for latent tuberculosis infection with a tuberculin skin test prior to starting therapy. Treatment of latent tuberculosis should be initiated before etanercept therapy; consider antituberculosis treatment if 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. 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.

• Wegener's granulomatosis: Use is not recommended in patients with Wegener's granulomatosis who are receiving immunosuppressive therapy due to higher incidence of noncutaneous solid malignancies.

Concurrent drug therapy issues:

• Anakinra: Due to a higher incidence of serious infections, concomitant use with anakinra is not recommended.

• Antidiabetic agents: Hypoglycemia has been reported in patients receiving concomitant therapy with etanercept and antidiabetic medications; dose reduction of antidiabetic medication may be necessary. Use with caution in patient with diabetes; monitor blood glucose as clinically necessary.

Special populations:

• 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 Risk Factor

B

Pregnancy Considerations

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.

A pregnancy registry has been established to monitor outcomes of women exposed to etanercept during pregnancy (800-772-6436).

Patient Education

• 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, rhinitis, rhinorrhea, or pharyngitis. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), burning or numbness feeling, severe weakness, seizures, vision changes, dizziness, shortness of breath, excessive weight gain, swelling of arms or legs, loss of strength and energy, pale skin, skin eczema, rash exacerbated by sun exposure, 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 healthcare 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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