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Antipsoriatic Monoclonal Antibodies and OthersOther Specific AntirheumaticsTumor Necrosis Factor (TNF) Alpha Inhibitors
Etanercept recipients are at increased risk for developing serious infections that may result in hospitalization and/or death. Patients greater than 65 years of age (geriatric patients), patients with comorbid conditions or immunosuppression, or patients taking concomitant immunosuppressants may be at greater risk of infection. Most patients who developed serious infections were taking concomitant immunosuppressants such as methotrexate or corticosteroid therapy. These infections involve multiple organ systems and include bacterial infection (Legionella and Listeria), mycobacterial infection (disseminated tuberculosis or extrapulmonary tuberculosis), fungal infection (histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, listeriosis, Pneumocystis jiroveci pneumonia), parasitic infection, viral infection (hepatitis B), and other opportunistic infections. Patients with invasive fungal infections (specifically histoplasmosis) may present with disseminated rather than localized disease. Health care providers should be aware that antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Carefully consider the benefits and risks associated with etanercept prior to initiating therapy in patients who have resided or have traveled to histoplasmosis, blastomycosis, or coccidioidomycosis endemic zones. In patients who develop severe systemic illness, consider administering empiric antifungal therapy. Patients need to be evaluated for tuberculosis risk factors and for latent or active tuberculosis infection with a tuberculin skin test both before and during treatment. The possibility of anergy needs to be considered when interpreting the test result. If tuberculin skin testing is performed for latent tuberculosis infection, an induration size of 5 mm or greater should be considered positive even if the patient was vaccinated previously with Bacille Calmette-Guerin. Cases of tuberculosis have occurred in patients who received etanercept; therefore, treatment of latent infection should be started before etanercept initiation. Treatment of latent tuberculosis in patients with a reactive tuberculin test reduces the risk of tuberculosis reactivation. Consider antituberculosis therapy before etanercept initiation in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and in patients who have several or highly significant risk factors for tuberculosis infection (e.g., close contact with infected person or travel to endemic zone) and have a negative test for latent tuberculosis. Some patients who tested negative for latent tuberculosis before etanercept receipt have developed active tuberculosis. Carefully consider the benefits and risks associated with etanercept prior to initiating therapy in patients who have resided or traveled in areas of endemic tuberculosis or who have been exposed to tuberculosis. Do not initiate etanercept in patients with an active infection including clinically important localized infections; etanercept is contraindicated for use by patients with sepsis as increased mortality may occur. Consider the risks and benefits of etanercept receipt before drug initiation in patients with chronic or recurrent infection, with a history of an opportunistic infection, or with underlying conditions that may predispose them to infection such as advanced or poorly controlled diabetes mellitus, immunosuppression, or bone marrow suppression. Also, cautious use is advised for patients who have a previous history of significant hematological disease; hematologic events such as pancytopenia and aplastic anemia have been reported. Tumor necrosis factor has important effects on inflammation and cellular immune responses. Etanercept has not been found to act as a general immunosuppressant. Immunocompetency testing (immunoglobulin level, neutrophil function, and surface markers of T and B lymphocytes) of a subset of patients from rheumatoid arthritis clinical trials revealed no difference between patients receiving etanercept and those receiving placebo. In addition, among 49 patients with rheumatoid arthritis who received etanercept, no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin concentrations, or change in enumeration of effector cell populations was noted. However, immunosuppression due to the patient's underlying disease state may compound the TNF-antagonistic effects of etanercept and increase the risk of developing a serious infection. In September 2011, the FDA issued an alert warning of the association between etanercept and the development of serious infections. In this alert, the FDA recommends evaluating the risks and benefits of etanercept prior to beginning therapy in patients with chronic or recurrent infections or in patients with underlying conditions predisposing them to infection. Health care providers are encouraged to report etanercept-associated adverse events to the MedWatch Safety Information and Adverse Event Reporting Program by telephoning 1-800-332-1088 or by completing the form online.
Lymphoma and other neoplastic disease have been reported in adults and pediatric patients. Etanercept has a black box warning of an increased risk of lymphoma and other neoplastic disease in children and adolescents. Use of etanercept by patients with a history of malignancy or current malignancy may be unadvisable. The effect of TNF inhibition on the development and course of malignancies is not fully understood.
Chimeric fusion protein; consists of the extracellular ligand-binding portion of the p75 TNF receptor linked to the Fc portion of human IgGUsed for in adults for rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis and psoriatic arthritis; used in pediatric patients as young as 4 years for juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA) and plaque psoriasisBoxed warnings for increased risk of developing serious infections and potential for malignancy
Enbrel Subcutaneous Inj Pwd F/Sol: 25mgEnbrel Subcutaneous Inj Sol: 0.5mL, 1mL, 25mg, 50mg
50 mg subcutaneously once weekly. Clinical trials also used 25 mg subcutaneously twice weekly, with doses given every 3 to 4 days. May be used with or without methotrexate. Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, and analgesics may be continued during etanercept treatment. A study of etanercept 50 mg subcutaneous twice weekly suggested a higher incidence of adverse reactions but similar American College of Rheumatology (ACR) response rates; thus, doses more than 50 mg/week are not recommended. Clinical responses were seen within 1 to 2 weeks and nearly always occurred by 3 months during initial trials; durable responses were seen for up to 24 months in patients receiving etanercept consistently. Patients receiving etanercept plus methotrexate had significantly better outcomes than those receiving methotrexate alone. Compared to high-dose methotrexate, etanercept demonstrated equivalence for delaying structural damage and significantly reduced the development of new erosions over 1 year in patients diagnosed with RA less than 3 years. ACR Guidelines recommend a TNF blocker +/- methotrexate as an option for patients with a disease duration less than 6 months and high disease activity with poor prognostic feature presence. For patients with established disease, adding or switching to an anti-TNF biologic is an option for patients with moderate or high disease activity after 3 months of methotrexate monotherapy or DMARD combination therapy. A switch to a different anti-TNF biologic is an option for patients with moderate or high disease activity after 3 months or more of a TNF blocker or with a non-serious adverse event. Also, a switch to an anti-TNF biologic is an option for patients with moderate or high disease activity after 6 months or more of a non-TNF biologic or with a serious or non-serious adverse event to the drug. The goal is low disease activity or remission.
0.8 mg/kg per week subcutaneously (up to 50 mg/week). Pediatric patients weighing 63 kg (138 pounds) or more may receive 50 mg subcutaneously once weekly. For pediatric doses other than 25 mg or 50 mg, use reconstituted etanercept lyophilized powder. Corticosteroids, NSAIDs, and other analgesics may be continued with etanercept but concurrent use of methotrexate or higher doses of etanercept have not been studied. Patients who have responded to etanercept within 3 months may continue to show improvement through 7 months of treatment. Studies have not been done in patients with JRA who did not respond within 3 months of starting etanercept. In a study of children with polyarticular JRA, patients were treated with etanercept for 3 months, and those who responded were randomized to receive either etanercept or placebo. At the end of the open-label treatment, 74% (51 of 69 patients) of patients responded to etanercept. In the double-blind study, 81% (21 of 26 patients) of patients who received placebo withdrew due to disease flare as compared to 28% (7 of 25 patients) of patients receiving etanercept. The median time to disease flare was 28 days with placebo compared to more than 116 days with etanercept. Higher doses of etanercept have not been shown to be effective in patients who do not respond to the recommended dose.
Initially, 50 mg subcutaneously twice weekly (given 3 to 4 days apart) for 3 months. The maintenance dose is 50 mg subcutaneously once weekly. Clinical trials also used a maintenance dose of 25 mg subcutaneously given twice weekly. In addition to the 50 mg twice weekly recommended starting dose, starting doses of 25 mg or 50 mg per week were shown to be efficacious; however, the proportion of responders was related to the initial dosage. In 1 study of patients who had failed previous systemic therapy or phototherapy, a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) after 25 mg subcutaneous twice weekly (n = 57) was achieved by 30% and 56% of patients at 12 and 24 weeks, respectively vs. 2% and 5% of placebo-treated patients (n = 55). In another study, receipt of 50 mg (n = 97) or 25 mg (n = 71) subcutaneous twice weekly for 24 weeks yielded a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) in 59% and 44% of patients, respectively.
0.8 mg/kg subcutaneously once weekly (up to 50 mg/week). Pediatric patients weighing 63 kg (138 pounds) or more may receive 50 mg subcutaneously once weekly. For pediatric doses other than 25 mg or 50 mg, use reconstituted etanercept lyophilized powder.
50 mg subcutaneously once weekly. Etanercept can be used with or without methotrexate. A study of etanercept 50 mg subcutaneous twice weekly suggested a higher incidence of adverse reactions but similar response rates; therefore, doses greater than 50 mg/week are not recommended. At 12 weeks, patients treated with etanercept had experienced a significantly greater improvement in their disease as compared to those treated with placebo. Etanercept-treated psoriatic arthritis patients experienced significant improvement disease symptoms including tender joints, swollen joints, morning stiffness, and disability index. About 25% of the etanercept-treated psoriasis patients achieved a 75% improvement as compared to none of the patients treated with placebo.
50 mg subcutaneously once weekly is recommended. Clinical trials also used a dose of 25 mg subcutaneously twice weekly, with doses given every 3 to 4 days. Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, analgesics, or methotrexate may be continued during etanercept treatment. In clinical trials, patients have responded to etanercept therapy given as 25 mg subcutaneous twice weekly for 4 months. At 4 months, 80% of patients treated with etanercept had a response as compared to 30% treated with placebo. Improvements included improvements in morning stiffness, spinal pain, functioning, quality of life, enthesitis, chest expansion, erythrocyte sedimentation rate, and C-reactive protein. With longer-term treatment, sustained improvements in spinal mobility, physical function, and other signs and symptoms have been reported. Specifically, 78% of patients experienced a 20% improvement in the ASAS 20 score. In addition, 31% of patients achieved a partial remission.
The suggested weight-based dosage is 0.8 mg/kg subcutaneously once weekly (Max: 50 mg/week). One randomized, controlled clinical trial in pediatric patients (n = 41, age 6 years and older) with JSpA suggests that etanercept is effective. Phase 1 of the trial was an open-label, uncontrolled 24-week study period in which all patients were administered etanercept. At week 24, treatment with etanercept resulted in response rates of 93%, 93%, 80%, 56%, and 54% based on the ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria, respectively. A clinical decrease in all disease activity measures was observed (e.g., tender joints, swollen joints, and joints with active arthritis). Physician's global assessment of disease activity, parent's assessment of patient's overall well-being, and the Childhood Health Assessment Questionnaire disability index also improved significantly. The number of tender enthesis sites and total scores for back pain, nocturnal pain, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, and Juvenile Arthritis Disease Activity Score based on 10-joint counts (JADAS10) decreased by 75%, 72%, 81%, 72%, 85%, and 87%, respectively. Patients considered to be treatment responders at week 24 according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement in juvenile arthritis entered the second phase, a 24-week randomized, double-blind, placebo-controlled withdrawal study. In phase 2, 38 patients were randomly assigned to receive placebo (n = 18) or to continue receiving etanercept (n = 20). Up to week 48, 12 disease flares occurred, in 9 patients receiving placebo and 3 patients receiving etanercept (OR 6.0, p = 0.02). There were no serious infections, malignancies, or deaths. A review of published evidence also mentions etanercept, along with other anti-TNF agents, as potentially effective, particularly in children 2 years and older refractory to methotrexate or sulfasalazine. Specific recommendations for juvenile spondyloarthropathy (JSpA) were omitted from 2011 ACR treatment guidelines due to the lack of sufficient supporting evidence at that time.
100 mg/week subcutaneously, not to exceed 50 mg/dose.
0.8 mg/kg/week subcutaneously, not to exceed 50 mg/week subcutaneously.
>= 2 years: 0.8 mg/kg/week subcutaneously, not to exceed 50 mg/week subcutaneously.< 2 years: Use not recommended.
Use not recommended.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
If appropriate, etanercept may be administered by the patient or a caregiver after thorough instruction of proper injection preparation and administration. Assess the patient’s or caregiver’s ability to inject subcutaneously and observe the first injection.Administration of one 50 mg/mL prefilled syringe or autoinjector of etanercept provides a dose equivalent to two, 25 mg prefilled syringes or two, 25 mg vials of lyophilized etanercept when vials are reconstituted and administered as recommended.The needle cap on the prefilled syringe and on the SureClick autoinjector contain dry natural rubber (latex) and should not be handled by persons sensitive to this product.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.The etanercept solution should be clear and colorless, although small white protein particles in solution may be noted in the autoinjector or prefilled syringe. Do not use if the solution is discolored or cloudy, or contains foreign particulate matter.
Etanercept is for subcutaneous administration.Injection sites include front of the thigh; abdomen except the 2 inches around the navel; or outer area of the upper arm (only used if someone besides the patient is administering). For patient self-administration, the front thighs are the preferred sites. Rotate injection sites. Do not administer where skin is tender, bruised, red, or hard. Also, do not inject directly into any raised, thick, red, or scaly skin patches or lesions related to psoriasis. Reconstitution and administration of the Enbrel vialDo not mix or transfer the contents of one vial into another vial. Also, do not filter reconstituted product during preparation or administration. Do not add other medications to solutions containing etanercept. ONLY use the supplied diluent.A vial adaptor is supplied for use when reconstituting the powder; however, the adaptor should not be used if multiple doses are going to be withdrawn from the vial. To reconstitute using the vial adaptor, slide the plunger into the flange end of the syringe. Attach the plunger to the gray rubber stopper in the syringe by turning the plunger clockwise until a slight resistance is felt. Remove the twist-off cap from the prefilled diluent syringe by turning counterclockwise. Once the twist-off cap is removed, twist the vial adapter onto the syringe clockwise until a slight resistance is felt. Place the vial adapter over the top of the vial being careful not to bump or touch the plunger; the plastic spike inside the vial adapter should puncture the gray stopper. Push the plunger down until all the liquid from the syringe is in the vial and gently swirl to dissolve the powder. After the diluent is added, some foaming may occur. Do not shake. Generally, dissolution takes less than 10 minutes; the solution should be clear and colorless. Each reconstituted vial contains 25 mg/mL of etanercept. Turn the vial upside down and slowly pull the plunger down to the unit markings on the side of the syringe that correspond with the needed dose. Gently tap the syringe to make any air bubbles rise to the top of the syringe, and slowly push the plunger up to remove them. Remove the syringe from the vial adapter by turning the syringe counterclockwise and attach the 27 gauge needle.If the vial will be used for multiple doses, use a 25-gauge needle for reconstituting and withdrawing the solution. Insert the 25 gauge needle or the vial adapter straight into the center of the gray stopper. A "pop" will be felt. Inject the diluent very slowly. After the diluent is added, some foaming may occur. Do not shake. Swirl contents gently during dissolution. Generally, dissolution takes less than 10 minutes; the solution should be clear and colorless. Write the mixing date on the supplied sticker and attach to the vial. Each reconstituted vial contains 25 mg/mL of etanercept. Withdraw the correct dose of the solution into the syringe; remove any air bubbles. Remove the 25-gauge needle from the syringe. Attach a 27-gauge needle.Hold the barrel of the syringe with one hand and pull the needle cover straight off.Choose an injection site. Injection sites include front of the thigh; abdomen except the 2 inches around the navel; or outer area of the upper arm. Rotate injection sites. Do not administer where skin is tender, bruised, red, or hard. Also, do not inject directly into any raised, thick, red, or scaly skin patches or lesions related to psoriasis.Hold the syringe in one hand like a pencil and use the other hand to gently pinch a fold of skin at the cleaned injection site. Insert the needle at a 45 degree angle to the skin. Let go of the skin, and hold the syringe near its base to stabilize it. Push the plunger to inject all of the solution at a slow, steady rate. Withdraw the needle at the same angle as insertion. Do NOT rub the site.Administer as soon as possible after reconstitution. Place reconstituted vials for multiple doses in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F) within 4 hours of reconstitution and store there for up to 14 days. DO NOT FREEZE. Product stability and sterility cannot be assured after 14 days. Use of the Enbrel SureClick autoinjectorThe single-use prefilled Enbrel SureClick autoinjector may be allowed to reach room temperature by removing the product from the refrigerator 15 to 30 minutes before use. Do not shake. Immediately before use, remove the needle shield by pulling it straight off; do not twist off or recap.Choose an injection site. Injection sites include front of the thigh; abdomen except the 2 inches around the navel; or outer area of the upper arm. Rotate injection sites. Do not administer where skin is tender, bruised, red, or hard. Also, do not inject directly into any raised, thick, red, or scaly skin patches or lesions related to psoriasis.Stretch the skin under and around the prefilled autoinjector: the skin must be firm and taut to provide enough resistance to fully retract the safety guard and unlock the prefilled autoinjector. Place the open end against the injection site at a 90 degree angle. Without pushing the purple button on top, push the autoinjector firmly against the skin to unlock. Press the purple button on top once and release the button. Listen for the first click. Wait for the second click or wait 15 seconds, and remove the autoinjector from injection site. Do NOT rub the site.Look at the inspection window. If it is not purple, call 1-(888)-436-2735; do not try to reuse the autoinjector. Use of the Enbrel prefilled syringe:The single-use prefilled syringe may be allowed to reach room temperature by removing the product from the refrigerator 15 to 30 minutes before use. Do not shake. Immediately before use, remove the needle shield by pulling it straight off; do not twist off or recap.Check to see if the amount of liquid in the prefilled syringe falls between the two purple fill level indicator lines on the syringe. Hold the prefilled syringe with the covered needle pointing down. If bubbles are seen in the syringe, very gently tap the prefilled syringe to allow any bubbles to rise to the top of the syringe. Turn the syringe so that the purple horizontal lines on the barrel are directly facing you. Do not use if the syringe does not have the right amount of liquid.Hold the barrel of the prefilled syringe with one hand and pull the needle cover straight off. Holding the syringe with the needle pointing up, check the syringe for air bubbles. If there are bubbles, gently tap the syringe with your finger until the air bubbles rise to the top of the syringe. Slowly push the plunger up to force the air bubbles out of the syringe.Choose an injection site. Injection sites include front of the thigh; abdomen except the 2 inches around the navel; or outer area of the upper arm. Rotate injection sites. Do not administer where skin is tender, bruised, red, or hard. Also, do not inject directly into any raised, thick, red, or scaly skin patches or lesions related to psoriasis.Hold the syringe in one hand like a pencil and use the other hand to gently pinch a fold of skin at the cleaned injection site. Insert the needle at a 45 degree angle to the skin. Let go of the skin, and hold the syringe near its base to stabilize it. Push the plunger to inject all of the solution at a slow, steady rate. Withdraw the needle at the same angle as insertion. Do NOT rub the site. Use of the Erelzi Sensoready PenAllow the single-use prefilled Erelzi Sensoready Pen to reach room temperature by removing the product from the refrigerator 15 to 30 minutes before use. Do not shake.Immediately before use, remove the white cap - twist the cap off in the direction of the arrow; do not recap; use the pen within 5 minutes of taking the cap off.Choose an injection site. Injection sites include front of the thigh; abdomen except the 2 inches around the navel; or outer area of the upper arm (only if someone else is giving the patient the injection). Rotate injection sites. Do not administer where skin is tender, bruised, red, or hard. Also, do not inject directly into any raised, thick, red, or scaly skin patches or lesions related to psoriasis.Place the open end of the pen against the injection site at a 90 degree angle.Press the Erelzi Sensoready Pen firmly against the skin to start the injection.The 1st click indicates the injection has started. Keep holding the ERELZI Sensoready Pen firmly against the skin.The green indicator shows the progress of the injection.Listen for the 2nd click. This indicates the injection is almost finished.Check to make sure the green indicator fills the viewing window and has stopped moving.The ERELZI Sensoready Pen can now be removed.Dispose of the used Pen in a proper sharps container.
Enbrel:- Do not freeze- Product must be used within 14 days after removal from refrigeration to room temperature (77 degrees F)- Product stored at controlled room temperature should not be returned to a refrigerator- Protect from light- Refrigerate (between 36 and 46 degrees F)- Store in original package until time of use- Store reconstituted product in refrigerator (36 to 46 degrees F), discard after 14 days
Cautious use of etanercept is advised for patients who are identified as carriers of hepatitis B virus (HBV) and for patients with moderate to severe alcoholic hepatitis. In a study of 48 patients with moderate to severe alcoholic hepatitis, the mortality rate in etanercept recipients was similar to placebo recipients at 1 month but significantly higher after 6 months. For carriers of HBV, receipt of etanercept may lead to reactivation of HBV. Evaluate patients at risk for HBV for prior evidence of HBV before etanercept initiation. Adequate data are unavailable on the safety or efficacy of treating patients who are carriers of HBV with antiviral therapy in conjunction with TNF-blocker therapy to prevent HBV reactivation. If etanercept is used in a patient who is a carrier of HBV, careful monitoring for clinical and laboratory signs of active HBV throughout therapy and for several months after etanercept discontinuation is recommended. If HBV reactivation occurs, consider etanercept discontinuation and antiviral initiation with appropriate supportive treatment. The safety of resuming etanercept after HBV reactivation is controlled is unknown. In this situation, weigh the risks and benefits when considering resumption of etanercept.
Etanercept use by patients with Wegener's granulomatosis, a distinctive granulomatous vasculitis, who are taking immunosuppressive agents is not recommended. As compared with recipients of standard therapy alone, recipients of etanercept plus standard therapy including cyclophosphamide had a higher incidence of non-cutaneous solid malignancies and no improved clinical outcomes.
Use etanercept cautiously in patients with congestive heart failure (CHF), and carefully monitor patients. Post-marketing reports of worsening CHF, with and without precipitating factors, in patients taking etanercept have been received. Also, rare reports of new onset CHF including CHF in patients without known pre-existing cardiovascular disease have been received. Of note, 2 studies evaluating the use of etanercept in the treatment of CHF were terminated early due to a lack of efficacy. Although analysis of data from one of the studies suggested higher mortality of patients treated with etanercept as compared with placebo, specific factors associated with an increased risk of adverse outcomes were not identified by analyses of the data. Instruct patients to report any signs of new or worsening heart failure.
Limited data are available regarding the response to vaccination in patients receiving etanercept. Adult patients may receive vaccinations concurrently with etanercept therapy, with the exception of live virus vaccines. There are no data available regarding the safety and efficacy of live or killed vaccines and toxoids in patients with juvenile rheumatoid arthritis (JRA) treated with etanercept. The manufacturer recommends that all JRA patients be brought up to date with immunizations, if possible, prior to beginning etanercept therapy. Immunosuppressed patients should not be exposed to others who have recently received the oral poliovirus vaccine. Attenuated virus vaccines may also be associated with increased adverse reactions in immunosuppressed patients. There are no data available on secondary transmission of infection by live vaccines in patients receiving etanercept. It is recommended that patients significantly exposed to varicella virus temporarily discontinue etanercept therapy. Treatment with Varicella Zoster Immune Globulin should be considered in these patients. While receiving etanercept, 2 pediatric patients developed varicella infection associated with aseptic meningitis; the infection resolved in these patients without sequelae.
Use caution when considering the use of etanercept in a patient with neurological disease such as pre-existing or recent-onset central or peripheral nervous system demyelinating disorders such as multiple sclerosis. Rare cases of central or peripheral nervous system demyelinating disorders have been reported. New onset seizures or exacerbations of a seizure disorder have also been observed during etanercept therapy.
If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune disease such as autoimmune hepatitis, discontinue etanercept and carefully evaluate the patient. Etanercept receipt may result in the formation of autoantibodies and may rarely result in the development of a lupus-like syndrome or autoimmune hepatitis, which may resolve after etanercept withdrawal.
Available studies with use of etanercept during pregnancy do not reliably support an association between etanercept use during pregnancy and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS) Enbrel Pregnancy Registry in women with rheumatic diseases or psoriasis and a Scandinavian study in pregnant women with chronic inflammatory disease. Both the OTIS Registry and the Scandinavian study showed the proportion of liveborn infants with major birth defects was higher for women exposed to etanercept compared to diseased etanercept unexposed women. However, the lack of pattern of major birth defects is reassuring and differences between exposure groups (e.g., disease severity) may have impacted the occurrence of birth defects.Etanercept crosses the placenta in small amounts. Among 3 babies born to women who received etanercept during pregnancy, cord blood concentrations of etanercept at delivery were 3% to 32% of the maternal serum concentrations. No fetal harm was noted in developmental animal toxicity studies in which animals received doses ranging from 60 to 100 times the human dose. The risk of fetal/neonatal adverse reactions with in utero exposure to etanercept is unknown. Neonates and infants born to women treated with etanercept during their pregnancy may be at increased risk of infection for a period of time after birth. In general, a waiting period of several months following birth is recommended before the administration of any live vaccine to infants exposed in utero to a biologic such as etanercept, or until the drug is considered to be undetectable in the infant. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to neonates and infants exposed to etanercept in utero. Long-term animal studies have not been conducted to evaluate the potential of etanercept to affect fertility.
Limited data from published literature show that etanercept is present in low levels in human milk and minimally absorbed by a breast-fed infant. No data are available on the effects of etanercept on the breast-fed infant or the effects on milk production. The data, along with the high molecular weight of etanercept, suggest that the drug would be poorly absorbed by the infant and that risk, particularly for an older infant, would be unlikely. Etanercept use during lactation may generally be considered compatible. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for etanercept and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition. In a case report describing etanercept use in a lactating mother, drug concentrations in the mothers serum, infants serum, and breast milk at post-delivery week 12 were 2,872 ng/mL, not detected, and 3.5 ng/mL, respectively. Adalimumab and infliximab may be potential alternatives to consider during breast-feeding. However, indication and patient specific factors should be assessed before choosing an alternative agent. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.
The safety and efficacy of etanercept have not been established in children less than 2 years of age. Etanercept has a boxed warning regarding lymphoma and other cancers; these cancers have been reported with the use of TNF blockers in children and adolescents, and etanercept may affect host defenses against infection. No data are available regarding the safety and efficacy of vaccines and toxoids in patients with juvenile rheumatoid arthritis (JRA) treated with etanercept. The manufacturer recommends that all JRA patients be brought up to date with immunizations, if possible, prior to beginning etanercept therapy. Live vaccine administration during etanercept therapy is to be avoided. Immunosuppressed patients should not be exposed to others who have recently received the oral poliovirus vaccine. Attenuated virus vaccines may also be associated with increased adverse reactions in immunosuppressed patients. There are no data available on secondary transmission of infection by live vaccines in patients receiving etanercept. It is recommended that patients significantly exposed to varicella virus temporarily discontinue etanercept therapy. Treatment with Varicella Zoster Immune Globulin should be considered in these patients. While receiving etanercept, 2 pediatric patients developed varicella infection associated with aseptic meningitis; the infection resolved in these patients without sequelae.
Allergic reactions have been reported with etanercept. The needle cap on the SureClick autoinjector and the needle cap on the prefilled syringe contain dry natural rubber (latex) that may cause allergic reactions in persons with latex hypersensitivity.
myelitis / Delayed / 0-0.1Guillain-Barre syndrome / Delayed / 0-0.1optic neuritis / Delayed / 0-0.1seizures / Delayed / 0-0.1lupus-like symptoms / Delayed / 0-0.1aplastic anemia / Delayed / 0-0.1pancytopenia / Delayed / 0-0.1heart failure / Delayed / 0-0.1aseptic meningitis / Delayed / Incidence not knownangioedema / Rapid / Incidence not knownvasculitis / Delayed / Incidence not knowntoxic epidermal necrolysis / Delayed / Incidence not knownStevens-Johnson syndrome / Delayed / Incidence not knownerythema multiforme / Delayed / Incidence not knownuveitis / Delayed / Incidence not known
antibody formation / Delayed / 6.0-15.0erythema / Early / 7.0-7.0neutropenia / Delayed / 2.0-2.0hepatitis / Delayed / 0-0.1bleeding / Early / Incidence not knownpsoriasis / Delayed / Incidence not knowncandidiasis / Delayed / Incidence not knownelevated hepatic enzymes / Delayed / Incidence not knownthrombocytopenia / Delayed / Incidence not knownanemia / Delayed / Incidence not knownlymphadenopathy / Delayed / Incidence not knownleukopenia / Delayed / Incidence not knownsecondary malignancy / Delayed / Incidence not knownchest pain (unspecified) / Early / Incidence not knownpsoriaform rash / Delayed / Incidence not known
infection / Delayed / 27.0-81.0influenza / Delayed / 17.0-65.0pharyngitis / Delayed / 17.0-65.0sinusitis / Delayed / 17.0-65.0injection site reaction / Rapid / 7.0-43.0diarrhea / Early / 3.0-16.0rash (unspecified) / Early / 1.0-13.0pruritus / Rapid / 1.0-5.0fever / Early / 2.0-3.0urticaria / Rapid / 1.0-2.0paresthesias / Delayed / 0-0.1ecchymosis / Delayed / Incidence not known
Abatacept: (Severe) Do not administer abatacept with tumor necrosis factor (TNF) modifiers. The combination may increase the risk of infections and serious infections without an important enhancement of efficacy with concomitant administration. In controlled clinical trials, patients receiving concomitant abatacept and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) as compared with patients treated with only TNF antagonists (43% and 0.8%, respectively). These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of abatacept with a TNF antagonist. Monitor patients for signs of infection during the transition from TNF antagonist therapy to abatacept therapy. Adalimumab: (Severe) Do not use etanercept in combination with other tumor necrosis factor (TNF) modifier therapy, including adalimumab, due to the potential for additive effects and drug toxicity. It is unknown if any adverse effects would occur if etanercept is used concomitantly with adalimumab. A potential exists for increased risk of infection or an impact on the development of malignancies from increased activity toward TNF. Anakinra: (Severe) Concurrent use of anakinra and tumor necrosis factor (TNF) modifiers is not recommended. Data suggest a higher rate of serious infections when anakinra and etanercept are used in combination (7%) compared with anakinra given alone (3%) or etanercept alone (0%). In a combination study, neutropenia (neutrophil count <= 1000/mm3) was observed in 2% of patients. In addition, the use of anakinra and etanercept in combination did not yield any additional clinical benefit as compared to the use of etanercept alone. In a 24-week trial of anakinra plus etanercept, the ACR(50) response rate in patients receiving anakinra plus etanercept was 31% as compared to 41% in patients receiving etanercept alone. It is recommended that anakinra not be used in combination with tumor necrosis factor inhibitors because of the increased risk of infection or other adverse events with no additional clinical benefit. Canakinumab: (Severe) The concomitant administration of tumor necrosis factor (TNF) modifiers with other drugs that block interleukin (IL)-1, such as canakinumab, has not been studied; however, an increased incidence of serious infections and an increased risk of neutropenia have been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Based upon the potential for similar interactions, concomitant administration of TNF inhibitors and canakinumab is not recommended. Certolizumab pegol: (Severe) Do not use certolizumab in combination with other tumor necrosis factor (TNF) modifier therapy, including etanercept, due to the potential for additive effects and drug toxicity. It is unknown if any adverse effects would occur if certolizumab is used concomitantly with etanercept. A potential exists for increased risk of infection or an impact on the development of malignancies from increased activity toward TNF. Cyclophosphamide: (Major) The concurrent use of cyclophosphamide and etanercept is not recommended. Patients with severe Wegener's granulomatosis who received cyclophosphamide, etanercept, and corticosteroids had more non-cutaneous solid malignancies as compared with patients who received only cyclophosphamide and corticosteroids. Also, concurrent use of myelosuppressive anti-rheumatic agents has been associated with pancytopenia, including aplastic anemia, in some patients treated with etanercept. Golimumab: (Severe) Do not use golimumab in combination with other tumor necrosis factor (TNF) modifier therapy, including etanercept, due to the potential for additive effects and drug toxicity. It is unknown if any adverse effects would occur if golimumab is used concomitantly with etanercept. A potential exists for increased risk of infection or an impact on the development of malignancies from increased activity toward TNF. Infliximab: (Severe) The combination of infliximab with other biologics used to treat the same conditions as infliximab is not recommended. Both infliximab and etanercept block the actions of TNF-alpha. It is unknown if any adverse effects would occur if infliximab was used concomitantly with etanercept. A potential exists for an increased risk for serious infection or an impact on the development of malignancies from increased activity toward TNF. Live Vaccines: (Severe) Etanercept has not been found to act as a general immunosuppressant; however, the patient's underlying disease state may result in the immunosuppression. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune syste Natalizumab: (Major) Natalizumab for Crohn's disease should not be used in combination with tumor necrosis factor (TNF) modifiers. Coadministration may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy and other opportunistic infections. Ordinarily, patients with mulitple sclerosis who are receiving chronic TNF-modifier therapy should not be treated with natalizumab. Rabies Vaccine: (Major) Etanercept has not been found to act as a general immunosuppressant; however, the patient's underlying disease state may result in the immunosuppression of the patient, thereby, impairing the immunologic response to the rabies vaccine. If possible, administration of etanercept should be avoided during use of the rabies vaccine for postexposure prophylaxis. When etanercept must be administered to persons also receiving the rabies vaccine for postexposure prophylaxis, a serum rabies antibody titer should be obtained on day 14 (day of the 4th vaccination) to ensure an acceptable antibody response has been induced. Rilonacept: (Severe) Concurrent use of rilonacept and tumor necrosis factor (TNF) modifiers is not advised, as the risk of serious infections may be increased. Although concurrent use has not been evaluated in clinical trials, an increased incidence of serious infections and neutropenia has been associated with administration of another drug that blocks IL-1 in combination with TNF inhibitors. Rituximab: (Major) The concomitant use of rituximab with etanercept, a tumor necrosis factor inhibitor, may result in additive immunosuppression and an increased risk of infection. Combination therapy has been reported in published open-label trials for patients refractory to rituximab alone, but further study is needed to establish an increased clinical benefit and impact on side effects, including immunosuppression and infection rates. Higher rates of serious infection were observed in patients with rheumatoid arthritis treated with rituximab who received subsequent treatment with a TNF inhibitor in controlled clinical trials. Monitor patients receiving this combination closely for signs or symptoms of infection. Rituximab; Hyaluronidase: (Major) The concomitant use of rituximab with etanercept, a tumor necrosis factor inhibitor, may result in additive immunosuppression and an increased risk of infection. Combination therapy has been reported in published open-label trials for patients refractory to rituximab alone, but further study is needed to establish an increased clinical benefit and impact on side effects, including immunosuppression and infection rates. Higher rates of serious infection were observed in patients with rheumatoid arthritis treated with rituximab who received subsequent treatment with a TNF inhibitor in controlled clinical trials. Monitor patients receiving this combination closely for signs or symptoms of infection. Sarilumab: (Major) Avoid using sarilumab with biological DMARDs because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of sarilumab with biological DMARDs such as tumor necrosis factor (TNF) modifiers has not been studied. Sulfasalazine: (Moderate) The combined use of etanercept and sulfasalazine may cause neutropenia. Carefully monitor patients who receive etanercept and sulfasalazine concurrently. Tocilizumab: (Major) Tocilizumab has not been studied and its use should be avoided in combination with biologic DMARDs because of the possibility of increased immunosuppression and increased infection risk. Tocilizumab has not been studied in combination with biologi DMARDs such as tumor necrosis factor (TNF) antagonists. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives. Tofacitinib: (Severe) Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) modifiers,because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking tofacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids. Tuberculin Purified Protein Derivative, PPD: (Moderate) Etanercept has not been found to act as a general immunosuppressant; however, the patient's underlying disease state may result in immunosuppression. Patients receiving ertanercept may have a decreased immunologic response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of ertanercept therapy. Vedolizumab: (Major) Vedolizumab should not be used in combination with tumor necrosis factor (TNF) modifiers because of the potential for increased risk of progressive multifocal leukoencephalopathy and other infections. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with vedolizumab.
Etanercept inhibits tumor necrosis factor (TNF). TNF, a cytokine produced by macrophages and activated T-cells, plays an important role in rheumatoid arthritis by mediating cytokines that cause inflammation and joint destruction. TNF is elevated in rheumatoid synovial fluids in patients with severe disease or a high white blood cell count in the synovial fluid. There are two types of TNF receptors (TNFRs); both are located on cell surfaces and in the plasma as a soluble form. They are a 55 kD protein (p55) and a 75 kD protein (p75). The activity of TNF is dependent upon binding to 2—3 of these cell surface receptors. The soluble TNFRs act as a signaling receptor for inflammatory responses (p55) or as an antagonist to TNF (p75). As a recombinant TNFR p75 bound to the Fc fragment of the human IgG1, etanercept binds to and inactivates TNF but does not affect TNF production or serum levels. Etanercept has a higher binding affinity for TNF and is a more potent inhibitor of TNF activity in vitro and in animal models than the natural soluble TNFR p75. Cells that express transmembrane TNF that is bound to etanercept are not lysed in vitro in the presence or absence of complement. Etanercept may also modulate other biologic responses that are induced or regulated by TNF such as expression of adhesion molecules, other serum cytokines and serum matrix metalloproteinase-3 (MMP-3 or stromelysin). Advanced heart failure is correlated with a progressive increase in peripheral circulating levels of TNF. It is thought after myocardial injury, cytokines, including TNF, play a role in initiating and integrating the homeostatic response leading to cardiac repair. Overexpression of TNF in the myocardium may be one of several maladaptive mechanisms responsible for the progressive cardiac decompensation and remodeling that occurs in advanced heart failure. TNF binding to cell surface TNFRs produces a negative inotropic effect; it is not known which receptor acts as the signaling receptor on myocytes. In vitro studies have shown that myocytes treated with a neutralizing anti-TNF antibody prevents the negative inotropic effects of TNF.
Etanercept is administered subcutaneously. Some placental transfer of etanercept appears to occur based on limited data. After single doses, the mean etanercept half-life in adult patients with rheumatoid arthritis is 102 +/- 30 hours with a mean clearance of 160 +/- 80 mL/hour. Affected Cytochrome P40 *CYP450) enzymes and drug transporters: None known.
The maximum serum concentration (Cmax) of etanercept was 1.1 +/- 0.6 mcg/mL, and the time to the maximum serum concentration (Tmax) was 69 +/- 34 hours after a single subcutaneous injection of 25 mg to patients with rheumatoid arthritis (RA). After 6 months of etanercept 25 mg twice weekly, the mean Cmax was 2.4 +/- 1 mcg/mL, and an approximate four-fold increase in the systemic exposure (range, 1 to 17 fold) was noted. At steady state, the mean Cmax, Cmin, and partial AUC were similar with a 50 mg subcutaneously weekly dose as compared with a 25 mg subcutaneously twice weekly dose. After 25 mg subcutaneously twice weekly, the mean Cmax was 2.6 +/- 1.2 mcg/mL, and the mean Cmin was 1.4 +/- 0.7 mcg/mL. After 50 mg subcutaneously weekly, the mean Cmax was 2.4 +/- 1.5 mcg/mL, and the mean Cmin was 1.2 +/- 0.7 mcg/mL. The pharmacokinetic parameters of etanercept in patients with plaque psoriasis were similar to those seen in patients with RA.