Etanercept is a subcutaneously administered tumor necrosis factor (TNF) blocker that is a soluble TNF receptor. Like other TNF blockers, etanercept is useful in a variety of inflammatory disorders. In adults with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) the drug improves clinical signs and symptoms, inhibits the radiographic progression of structural joint damage, and improves physical function; in adults with ankylosing spondylitis (AS), the drug improves clinical signs and symptoms of active disease. For adult RA, PsA, or AS, etanercept may be used as monotherapy; the drug may also be used with other disease-modifying antirheumatic agents (DMARDs). The ideal combination of therapy for individual patients with inflammatory arthritis conditions is determined by treat to target strategies and severity of disease. For PsA, TNF-blockers are considered a first-line treatment, even in treatment-naive patients. In pediatric patients 2 years and older, etanercept is approved for active juvenile psoriatic arthritis (JPsA) and moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA). The drug reduces signs and symptoms of moderately to severely active pJIA in patients intolerant or refractory to methotrexate. Etanercept is also beneficial for adult and pediatric patients 4 years or older with chronic moderate to severe plaque psoriasis; TNF-blockers may be used as first-line systemic treatments alone or in combination with other therapies. Etanercept does not appear to be effective for granulomatosis with polyangiitis. Etanercept is not effective for treating inflammatory bowel diseases (IBD); cases of new IBD have been reported with etanercept use. As with other TNF-blockers, etanercept product labels include boxed warnings regarding the risk of tuberculosis, other infections, and malignancy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-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. Do not use if the solution is discolored or cloudy, or contains foreign particulate matter.
Subcutaneous Administration
-Etanercept is for subcutaneous administration.
-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.
-Injection sites include front of the thigh; abdomen except for 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.
-Do not administer where the 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.
-Rotate injection sites.
Reconstitution and administration of the Enbrel single-dose vial
-Remove the correct number of single-dose vials from the carton; 1 vial for a dose that is 25 mg or less and 2 vials for a dose greater than 25 mg. Leave at room temperature for at least 30 minutes; do not remove vial caps during this time period. Keep out of direct sunlight.
-Remove the vial cap and use an alcohol swab to wipe the gray stopper clean.
-Withdraw the necessary dose from the vial utilizing a 1-mL Luer-Lock syringe with a 22-gauge, 1.5-inch needle. If 2 vials are needed, use the same syringe for each vial. Discard any unused solution, as it does not contain a preservative.
-Pull the needle plunger back to 0.5 mL. Insert the needle into the vial and slowly push 0.5 mL of air into the vial. Tilt the vial and slowly withdraw all the solution. Remove the needle from the vial. 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. If a second vial is needed, repeat these steps.
-Next, push the plunger down to achieve the needed dose of medication.
-Place the needle cap on a flat surface. Using one hand, slide the needle into the cap and scoop upwards to cap the needle. Do not use your other hand to recap the needle. Twist off the long needle and twist on a short, 27-gauge, half-inch needle.
-Choose an injection site; clean the site with alcohol.
-Hold the barrel of the syringe with 1 hand and pull the needle cover straight off.
-Hold the syringe in 1 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. Push the plunger to inject all the solution at a slow, steady rate. Withdraw the needle at the same angle as insertion.
-Do NOT rub the site. If blood is observed at the injection site, press a cotton ball onto the site until bleeding stops. An adhesive bandage may be applied if needed.
-Dispose of the used needles, syringe, and vials into a proper sharps container.
-Storage: Store single-dose vials in the original carton to protect from light or damage. Store vials in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). If needed, the single-dose vial may be stored at room temperature between 20 and 25 degrees C (68 to 77 degrees F), with protection for light and sources of heat, for up to 30 days. Once a vial has reached room temperature, do not refrigerate. Throw away any vials that have been stored at room temperature for more than 30 days.
Reconstitution and administration of the Enbrel lyophilized powder multi-dose vial
-Do not mix or transfer the contents of 1 vial into another vial. Also, do not filter the 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 corresponds 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 to the syringe.
-Choose an injection site. Clean the injection site with alcohol.
-Hold the barrel of the syringe with 1 hand and pull the needle cover straight off.
-Hold the syringe in 1 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 the solution at a slow, steady rate. Withdraw the needle at the same angle as insertion.
-Do NOT rub the site. If blood is observed at the injection site, press a cotton ball onto the site until bleeding stops. An adhesive bandage may be applied if needed.
-Storage of reconstituted solution: 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; may store refrigerated for up to 14 days. Do NOT freeze. Product stability and sterility cannot be assured after 14 days.
-Storage for individual dose trays: Store an individual dose tray containing a multiple dose vial and diluent syringe in original carton to protect from light. Store trays in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). If needed, the tray may be stored at room temperature between 20 and 25 degrees C (68 to 77 degrees F), with protection form light, sources of heat, and humidity, for up to 14 days. Once a tray has reached room temperature, do not refrigerate. Throw away any trays that have been stored at room temperature for more than 14 days.
Use of the Enbrel SureClick Autoinjector
-The single-use prefilled Enbrel SureClick autoinjector may be allowed to reach room temperature by removing the product from the refrigerator at least 30 minutes before use. Do not warm using a heat source, such as a microwave or hot water. Once it has reached room temperature, do not return to the refrigerator. Do not shake.
-SureClick autoinjector should not be used for children weighing less than 63 kg (138 pounds).
-Choose an injection site. Clean the injection site with alcohol.
-Immediately before use, remove the needle shield (white cap) by pulling it straight off; do not twist off or recap.
-Firmly stretch or pinch a 2-inch area of skin: the skin must be firm and taut to provide enough resistance to retract the safety guard fully 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'. The injection should take approximately 15 seconds to complete. Wait for the second 'click' and the window to turn from clear to yellow, indicating that the injection is complete. Remove the autoinjector from the injection site, and the needle will be automatically covered.
-Do NOT rub the site.
-After removing the autoinjector from the skin, if the window has not turned yellow or if it looks like the medicine is still injecting, this means you have not received a full dose. Do not try to reuse the autoinjector. Call the health care provider immediately. For more information, call 1-888-4Enbrel.
-Dispose of the used Enbrel SureClick autoinjector in an appropriate sharps container.
-Storage: Store SureClick autoinjectors in the original carton to protect from light or damage. Store autoinjectors in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). If needed, the autoinjector may be stored at room temperature between 20 and 25 degrees C (68 to 77 degrees F), with protection for light and sources of heat, for up to 30 days. Once an autoinjector has reached room temperature, do not refrigerate. Throw away any autoinjectors that have been stored at room temperature for more than 30 days.
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.
-Choose an injection site. Clean the injection site with alcohol.
-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 1 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.
-Hold the syringe in 1 hand like a pencil and use the other hand to gently pinch a fold of skin at the cleaned injection site.
-With a quick, dart-like motion, 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 the solution at a slow, steady rate. Withdraw the needle at the same angle as insertion.
-Do NOT rub the site.
-Dispose of the used Enbrel prefilled syringe in a proper sharps container.
-Storage: Store prefilled syringes in the original carton to protect from light or damage. Store prefilled syringes in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). If needed, the prefilled syringe may be stored at room temperature between 20 and 25 degrees C (68 to 77 degrees F), with protection for light and sources of heat, for up to 30 days. Once a prefilled syringe has reached room temperature, do not refrigerate. Throw away any prefilled syringes that have been stored at room temperature for more than 30 days.
AutoTouch reusable Autoinjector with Enbrel Mini single-use cartridge
-The single-use prefilled Enbrel Mini cartridge may be allowed to reach room temperature by removing the product from the refrigerator 30 minutes before use. Do not shake.
-Choose an injection site. Clean the injection site with alcohol.
-Hold Enbrel Mini single-use cartridge with the label side facing out and slide into the door of the AutoTouch autoinjector. Close door. Remove the purple cap. Only remove the purple cap after the cartridge is placed into the autoinjector. Do not remove the cap more than 5 minutes before the injection.
-Place and hold on the skin. The injector end should be completely in contact with the skin. The status button turns green upon contact with the skin.
-To start injection, press and release the green status button. The hidden needle within the cartridge will activate to begin the injection. The status button should flash as the injection begins.
-The injection is finished with you hear a chime, and all lights are turned off. The needle will not be visible at any time during or after the injection; once all medicine is delivered, the needle retracts from the skin.
-After removing the AutoTouch from the skin, if the status button has turned red, call 1-888-4Enbrel immediately for help. If it looks like the medicine is still injecting, or there is still fluid in the Enbrel Mini, the patient has not received a full dose.
-After the injection is complete, the door of the AutoTouch injector will open automatically.
-Discard the used single-use Enbrel Mini cartridge in an appropriate sharps container.
-Care of the Autoinjector: Clean the injection end of AutoTouch before and after injections with alcohol; do not clean with water, household cleanser, or soap. Do not immerse AutoTouch in water.
-Storage: AutoTouch is stored at room temperature; Enbrel Mini cartridges are stored in the refrigerator between 2 and 8 degrees C (36 to 46 degrees F). If needed, the Enbrel Mini cartridge may be stored at room temperature between 20 and 25 degrees C (68 to 77 degrees F), with protection for light and sources of heat, for up to 30 days. Once it has reached room temperature, do not refrigerate. Throw away any doses that have been stored at room temperature for more than 30 days.
Reconstitution and administration of the Erelzi lyophilized powder multi-dose vial
-Product supplied in a carton containing 4 dose trays. Each dose tray contains:
--One 25 mg vial of etanercept lyophilized power
-One prefilled diluent syringe (1 mL sterile Bacteriostatic Water for Injection, USP)
-One 27-gauge 0.5 inch needle
-One vial adapter
-One plunger
-Four Mixing Date stickers
-Do not mix or transfer the contents of 1 vial into another vial. Also, do not filter the reconstituted product during preparation or administration. Do not add other medications to solutions containing etanercept. ONLY use the supplied diluent.
-The dose may be prepared as follows:
--Vial Adaptor Method: 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 corresponds 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.
-Free-Hand Method: If the vial will be used for multiple doses, use the Free-Hand Method and label the reconstituted vial with the provided "Mixing Date" stickers. For this Method, a 25-gauge needle (obtained from care team) is used for mixing and withdrawing the reconstituted solution and a 27-gauge needle is used to inject the dose. 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 a 25-gauge needle onto the top of the syringe until it fits snugly. Insert the needle straight down through the center ring of the gray vial 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 attached sticker. 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 and attach the 27-gauge needle.
-Additional doses from an already reconstituted vial: New needles and syringes will be need for each additional dose; DO NOT reuse the needles and syringes supplied with the dose tray. Removed the reconstituted vial from the refrigerator and check the Mixing Date sticker to ensure it is within the 14-day use window. Using a sterile syringe with a 25-gauge needle attached, insert the needle straight through the center ring of the gray stopper. A "pop" will be felt. Withdraw the correct dose of the solution into the syringe; remove any air bubbles. Remove the 25-gauge needle from the syringe and attach the 27-gauge needle.
-Choose an injection site. Clean the injection site with alcohol.
-Hold the barrel of the syringe with 1 hand and pull the needle cover straight off.
-Hold the syringe in 1 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 the solution at a slow, steady rate. Withdraw the needle at the same angle as insertion.
-Do NOT rub the site. If blood is observed at the injection site, press a cotton ball onto the site until bleeding stops. An adhesive bandage may be applied if needed.
-Storage for individual dose trays: Store an individual dose tray containing a multiple dose vial and diluent syringe in original carton to protect from light. Store trays in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). If needed, the tray may be stored at room temperature between 20 and 25 degrees C (68 to 77 degrees F), with protection form light, sources of heat, and humidity, for up to 31 days. Once a tray has reached room temperature, do not refrigerate. Throw away any trays that have been stored at room temperature for more than 31 days.
-Storage of reconstituted solution: Once the lyophilized powered in a vial has been reconstituted, the solution must be used immediately or may be refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 14 days. Do NOT freeze. Product stability and sterility cannot be assured after 14 days.
Use of the Erelzi Sensoready Pen
-Allow 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 warm using a heat source, such as a microwave or hot water. Once it has reached room temperature, do not return to the refrigerator. Do not shake. Do not use if dropped on a hard surface.
-If dropped, do not use if the pen appears damaged or cap had been removed prior to being dropped.
-Choose an injection site. Clean the injection site with alcohol.
-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. Do not reattach the cap. NOTE: The internal needle cover within the cap of the Erelzi Sensoready Pen contains dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex.
-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 first '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 second 'click' that 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 ERELZI Sensoready Pen in a proper sharps container.
-Storage: Store Sensoready Pen in the original carton to protect from light or damage. Store pens in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). If needed, the pen may be stored at room temperature between 20 and 25 degrees C (68 to 77 degrees F), with protection from light and sources of heat, for up to 28 days. Once a pen has reached room temperature, do not refrigerate. Throw away any Sensoready Pens that have been stored at room temperature for more than 28 days.
Use of the Erelzi prefilled syringe
-The single-use prefilled syringe may be allowed to reach room temperature by removing the product from the refrigerator for at least 15 to 30 minutes before use. Do not warm using a heat source, such as a microwave or hot water. Once it has reached room temperature, do not return to the refrigerator. Do not shake.
-Choose an injection site. Clean the injection site with alcohol.
-Immediately before use, remove the needle shield by pulling it straight off; do not twist off or recap. NOTE: The needle cap of the Erelzi prefilled syringe contains dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex.
-Hold the barrel of the prefilled syringe with 1 hand and pull the needle cover straight off.
-Hold the syringe in 1 hand like a pencil and use the other hand to gently pinch a fold of skin at the cleaned injection site.
-With a quick, dart-like motion, insert the needle at a 45-degree angle to the skin. Push the plunger to inject all of the solution at a slow, steady rate while the syringe is held in place for 5 seconds. Continue to fully press the plunger down and withdraw the needle at the same angle as insertion.
-Once the needle is removed, slowly release the plunger and allow the needle guard to automatically cover the needle.
-Do NOT rub the site.
-Dispose of the used Erelzi prefilled syringe in a proper sharps container.
-Storage: Store prefilled syringe in the original carton to protect from light or damage. Store syringes in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). If needed, the syringe may be stored at room temperature between 20 and 25 degrees C (68 to 77 degrees F), with protection from light and sources of heat, for up to 28 days. Once a syringe has reached room temperature, do not refrigerate. Throw away any prefilled syringes that have been stored at room temperature for more than 28 days.
Use of the Eticovo prefilled syringe
-The single-use prefilled syringe may be allowed to reach room temperature by removing the product from the refrigerator for at least 30 minutes before use. Do not warm using a heat source, such as a microwave or hot water. Once it has reached room temperature, do not return to the refrigerator. Do not shake. Do not use if dropped on a hard surface.
-Choose an injection site. Clean the injection site with alcohol.
-Immediately before use, remove the needle shield by pulling it straight off; do not twist off or recap.
-Hold the barrel of the prefilled syringe with 1 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.
-Hold the syringe in 1 hand like a pencil and use the other hand to gently pinch a fold of skin at the cleaned injection site.
-With a quick, dart-like motion, 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 the solution at a slow, steady rate. Withdraw the needle at the same angle as insertion.
-Do NOT rub the site.
-Dispose of the used Eticovo prefilled syringe in a proper sharps container.
-Storage: Store prefilled syringe in the original carton to protect from light or damage. Store syringes in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). If needed, the syringe may be stored at room temperature between 23 and 27 degrees C (73 to 81 degrees F), with protection from light and sources of heat, for up to 14 days. Once a syringe has reached room temperature, do not refrigerate. Throw away any prefilled syringes that have been stored at room temperature for more than 14 days.
In general, the adverse reactions to etanercept reported in pediatric patients were similar in frequency and type to those seen in adult patients during clinical trials.
One of the most common adverse reactions reported with etanercept is an injection site reaction, which occurred in 15% to 43% of adult patients and 7% of pediatric patients in clinical trials. The injection site reactions, lasting a mean of 3 to 5 days, were usually mild to moderate and consisted of local erythema, itching, pain, and swelling. Localized injection site bleeding and ecchymosis have also been reported. Most reactions occurred during the first month of therapy with etanercept and subsequently decreased in frequency. A few patients (7%) developed erythema at a previous injection site when subsequent injections were given.
Among etanercept recipients in clinical trials, 2% to 3% experienced a fever. In clinical trials, 27% to 81% of patients experienced an infection such as a bacterial, viral, or fungal infection. The most common types of infections were upper respiratory infections like naso-pharyngitis, influenza, sinusitis (17% to 65%) and lower respiratory tract infections (12% to 54%). Discontinue etanercept if a patient develops a serious infection or sepsis; patients who receive etanercept are at an increased risk for developing serious infections that may lead to hospitalization or death. Infections including active tuberculosis, invasive fungal infections, and other opportunistic bacterial and viral infections have been reported in patients receiving etanercept. Reported serious infections include pyelonephritis, bronchitis, septic arthritis, cellulitis, osteomyelitis, pneumonia, abscess, gastroenteritis, and sepsis. Two pediatric patients with juvenile idiopathic arthritis developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae. The most commonly reported opportunistic infections were tuberculosis, histoplasmosis, coccidioidomycosis, listeriosis, aspergillosis, candidiasis, and pneumocystosis. In clinical studies, tuberculosis (pulmonary and extrapulmonary) was observed in approximately 0.006% to 0.02% of patients. Atypical mycobacterial infection, herpes zoster, aspergillosis pneumonia, pneumocystitis pneumonia, and protozoal infections have also been reported with postmarketing use of etanercept. Although infections have been reported in patients who received etanercept alone, most patients who developed serious infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Closely monitor patients who develop a new infection during etanercept therapy and evaluate them for appropriate antimicrobial treatment. Complete a diagnostic workup appropriate for an immunocompromised patient, and consider empiric therapy while the workup is being performed. Patients with opportunistic infections may present with disseminated, rather than localized, disease. For patients who reside or travel to regions where mycoses are endemic and who develop severe systemic illness, invasive fungal infection should be suspected. If possible, make the decision to administer empiric antifungal therapy in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections. Evaluate for latent tuberculosis infection and for tuberculosis risk factors before etanercept initiation and during treatment. Initiate treatment for latent tuberculosis before beginning etanercept treatment. Monitoring for active tuberculosis infection is needed even in patients who test negative for latent tuberculosis infection, as some patients who tested negative for latent tuberculosis before etanercept initiation have developed active tuberculosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection.
In clinical trials of etanercept, diarrhea was noted in 3% to 16% of patients. Rare (less than 0.1%) cases of inflammatory bowel disease (IBD) have been reported with etanercept therapy in patients with juvenile idiopathic arthritis. IBD has also been reported with postmarketing use of etanercept.
Postmarketing cases of pancytopenia (less than 0.1%), anemia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, and aplastic anemia (less than 0.01%) have been reported; some cases were fatal. Among patients who received etanercept and anakinra, 2% developed an absolute neutrophil count (ANC) less than 1,000/mcL; one patient developed cellulitis while neutropenic. Although no high-risk group has been identified and the causal relationship of etanercept and cytopenias is unclear, cautious use of etanercept is advised for patients who have a previous history of significant hematologic abnormalities. Instruct patients to get immediate medical attention for any symptoms suggestive of blood dyscrasias or infection such as bruising, bleeding, persistent fever, or pallor. Consider etanercept discontinuation for patients with confirmed significant hematologic abnormalities.
Congestive heart failure (CHF) has been reported during the postmarketing use of etanercept. Reports include worsening of CHF with and without identifiable precipitating factors. Also, rare (less than 0.1%) reports of new onset CHF including CHF in patients without known preexisting cardiovascular disease have been received. Some of these patients have been under 50 years of age. Cautious use of etanercept by patients who have heart failure is advised. Chest pain (unspecified) has been reported with postmarketing use of etanercept.
Cautiously consider the use of etanercept in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders. Rare cases (less than 0.1%) of new onset or exacerbation of CNS demyelinating disorders and with peripheral nervous system demyelinating disorders have been reported in patients receiving etanercept. Some CNS demyelinating disorders have presented with mental status changes and some have been associated with permanent disability. During the postmarketing period, transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barre syndrome, other peripheral demyelinating neuropathies, paresthesias, headache, and new onset of seizures or exacerbation of seizure disorders have been reported.
Allergic reactions associated with etanercept administration during clinical trials have been reported in less than 2% of patients. Patients receiving etanercept reported rash (unspecified) (1% to 13%), pruritus (1% to 5%), urticaria (1% to 2%), and hypersensitivity (1%). During the postmarketing period, angioedema has been reported. Instruct patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. If an anaphylactic reaction or other serious allergic reaction occurs, immediately discontinue etanercept and initiate appropriate therapy.
During the postmarketing period, cutaneous lupus erythematosus, cutaneous vasculitis including leukocytoclastic vasculitis, systemic vasculitis, macrophage activation syndrome, interstitial lung disease, subcutaneous nodule, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. Twenty cases of leukocytoclastic vasculitis were identified after etanercept administration by examination of reports to the U.S. FDA Adverse Events Reporting System. Thirteen of the 20 reports were biopsy-proven cases, and the other patients had skin lesions that were clinically typical for leukocytoclastic vasculitis. The median time from etanercept initiation to the onset or worsening of vasculitic skin lesions was 28 weeks (range, 2 to 103 weeks). Thirteen of the 20 patients had complete or marked improvement of skin lesions upon etanercept cessation. If a patient develops leukocytoclastic vasculitis while taking etanercept, etanercept discontinuation and other possible etiologies should be considered. A cautious rechallenge with etanercept may be warranted.
During post-marketing use of etanercept, cases of new or worsening psoriasis of all subtypes including pustular and palmoplantar have been noted. Cases of new onset psoriasis including pustular psoriasis and palmoplantar psoriasis have occured in patients using TNF blockers for the treatment of autoimmune and rheumatic conditions other than psoriasis and psoriatic arthritis. The development of psoriasis during TNF blocker receipt occurred from weeks to years after drug initiation. Most patients had psoriasis improvement after TNF blocker discontinuation. None of the patients reported pre-existing psoriasis before TNF blocker initiation. Monitor patients for the emergence of or worsening of psoriasis during TNF blocker receipt. Etanercept has also been reported to cause keratoderma blenorrhagicum, a psoriaform rash that occurs primarily on the palms and soles in some patients with reactive arthritis and is grossly and histologically indistinguishable from pustular psoriasis. Keratoderma blenorrhagicum has also been noted in patients who have received other TNF blockers.
Ocular inflammation, such as uveitis and scleritis, has been reported with the use of etanercept postmarketing.
Reactivation of hepatitis B virus and elevated hepatic enzymes have occurred with etanercept use. In patients who are chronic carriers of hepatitis B virus (HBV), viral reactivation can lead to hepatitis B exacerbation, which may be fatal; hepatitis B reactivation been noted among etanercept recipients (less than 0.01%). Most reports of HBV reactivation were in patients concomitantly receiving other medications that suppress the immune system. Evaluate patients at risk for prior evidence of HBV infection before initiating etanercept. In patients who develop HBV reactivation, 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 etanercept resumption. Treatment with etanercept may result in antibody formation, the development of autoantibodies, and, rarely (less than 0.1%), in the development of a autoimmune hepatitis or lupus-like symptoms, which may resolve after withdrawal of etanercept. Autoimmune hepatitis may lead to hepatic failure or death. Etanercept use has been associated with the development of lupus-like symptoms or systemic lupus erythematosus (SLE). Discontinue etanercept and carefully evaluate the patient if a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis. New positive antinuclear antibodies (ANA) developed in 11% of adult patients treated with etanercept versus 5% in placebo-treated patients. In pediatric plaque psoriasis studies, approximately 10% of patients developed non-neutralizing antibodies to etanercept by week 48 and approximately 16% of subjects developed antibodies to etanercept by week 264. The number of adult patients with new positive anti-double stranded DNA antibodies who got etanercept (15%) as compared with placebo (4%) was also higher by radioimmunoassay and by Crithidia luciliae assay (3% and 0%, respectively). The proportion of patients treated with etanercept who developed anti cardiolipin antibodies was similarly increased. Compared with patients who received methotrexate instead of etanercept, no pattern of increased autoantibody development was seen among patients who received etanercept. In addition to autoantibody formation, antibody formation against the TNF receptor portion or other protein components of etanercept was detected at least once in the sera of approximately 6% of adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or plaque psoriasis. All of these antibodies were non-neutralizing. No apparent correlation of antibody development to clinical response or adverse events was observed. Results from pediatric patients with juvenile idiopathic arthritis were similar to results seen in adults with rheumatoid arthritis treated with etanercept. The long term immunogenicity of etanercept is not known.
Etanercept may be associated with a risk of lymphoma, leukemia, melanoma, non-melanoma skin cancer, or new primary malignancy and carries a black box warning regarding the increased risk of lymphoma and leukemia in children and adolescent patients. Etanercept receipt may increase the risk of a new primary malignancy such as hepatosplenic T-cell lymphoma (HSTCL), which is an aggressive cancer that is usually fatal. Before prescribing etanercept, especially in adolescents and young adults, carefully weigh the risks and benefits of using etanercept due to the potential increased risk for cancers including HSTCL. The FDA continues to receive reports of HSTCL, primarily in adolescents and young adults being treated for Crohn's disease and ulcerative colitis with etanercept. Most reported cases of HSTCL occurred in patients treated with a combination of medicines known to suppress the immune system. Educate patients and caregivers about the signs and symptoms of malignancies such as HSTCL, so that they are aware of and can seek evaluation and treatment of any signs or symptoms. These may include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss. Monitor for the emergence of malignancies when a patient has been treated with etanercept. Consider periodic skin examinations for all patients at increased risk for skin cancer. People with rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis may be more likely to develop lymphoma than the general population and therefore, it may be difficult to measure the added risk of etanercept. Healthcare professionals and patients are encouraged to report adverse events to the FDA's MedWatch Safety Information and Adverse Event Reporting Program by calling 1-800-332-1088. The effect of TNF inhibition on the development and course of malignancies is not fully understood. The prescribing information for etanercept contains a boxed box warning regarding the risk of secondary malignancy in children and adolescents. Lymphoma and other malignancies, some fatal, have been reported in children, adolescents, and young adults who started a TNF blocker such as etanercept at the age of 18 years or younger; the malignancies occurred after a median of 30 months of therapy (range, 1 to 84 months), and most patients were receiving concomitant immunosuppressants. Approximately half of the cancers were lymphomas and included both Hodgkin's and non-Hodgkin's lymphoma. Other cases represented a variety of different malignancies and included rare cancers usually associated with immunosuppression and cancers that are not usually observed in children and adolescents. In adults, for malignancies other than lymphoma and non-melanoma skin cancer, the malignancy types and rates were similar to what is expected in the general population; postmarketing cases of Merkel cell carcinoma and of melanoma and non-melanoma skin cancers have been received. Further, the data suggest no increase in rates over time. For non-melanoma skin cancer, the observed rate was 0.41 cases per 100 patient-years among adult rheumatology patients who received etanercept and was 3.54 cases per 100 patient-years among adult psoriasis patients who received etanercept. In contrast, among control recipients, the respective rates were 0.37 cases per 100 patient-years and 1.28 cases per 100 patient-years. The observed rate of lymphoma in adult rheumatology patients treated with etanercept was 0.1 cases per 100 patient-years, which was 3-fold higher than the rate of lymphoma expected in the general population. In contrast, the observed rate of lymphoma in adult patients with psoriasis treated with etanercept was 0.05 cases per 100 patient-years, which was comparable to the rate in the general population. Of note, patients with rheumatoid arthritis may be at a higher risk (up to several fold) than the general population for lymphoma development. Further, patients with rheumatoid arthritis who have more severe disease activity may be at higher risk as compared with patients who have less disease activity. In one study, after adjustment for age, gender, and rheumatoid arthritis duration, the risk of lymphoma development in patients after exposure to a TNF blocker (infliximab, etanercept, or adalimumab) was no higher than the risk in patients with the disease who did not receive TNF blocker treatment. Further, lymphomas that occurred in patients treated with a TNF blocker had similar characteristics as compared with lymphomas in patients with rheumatoid arthritis who did not receive these drugs. Patients in this study received a TNF blocker for a maximum of 4 years.
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. Evaluate patients at risk for hepatitis B exacerbation before initiating TNF-blocker therapy with etanercept. 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 recipients are at increased risk for developing serious infections that may result in hospitalization and/or death. 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, or bone marrow suppression. 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 Bacillus 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. 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. In September 2011, the FDA issued an alert warning of the association between etanercept and the development of serious infections. Evaluate 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.
Lymphoma, leukemia, melanoma, non-melanoma skin cancer, and other new primary malignancy have been reported in adults and pediatric patients; fatal cases have been reported in children and adolescents (therapy initiation at 18 years of age or younger). Among children and adolescents, malignancies developed after a median of 30 months of therapy (range of 1 to 84 months) and majority of cases involved concurrent use of immunosuppressants. Lymphomas, including Hodgkin's and non-Hodgkin's lymphoma, accounted for about half of the reported cancers in children and adolescent patients. 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. Consider periodic skin examinations for all patients at increased risk of developing skin cancer.
Etanercept use by patients with granulomatosis with polyangiitis, 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. Postmarketing 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.
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.
Limited data are available regarding the response to vaccination in patients receiving etanercept. Ensure that all patients are brought up to date with immunizations, if possible, prior to beginning etanercept therapy. Avoid concurrent administration of live virus vaccines with etanercept therapy. 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. Consider treatment with Varicella Zoster Immune Globulin in these patients.
Available studies with use of etanercept during pregnancy do not 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. In animal reproduction studies, no fetal harm or malformations were observed with subcutaneous administration of etanercept during the period of organogenesis at doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg etanercept once weekly. Guidelines suggest that the continuation of etanercept may be considered in pregnant patients with rheumatic diseases during early pregnancy. Transfer of biologics like etanercept is thought to be very low during organogenesis, but to increase steadily after week 13 throughout pregnancy. The drug is generally recommended to be discontinued by week 30 to 32 of pregnancy, to help limit transfer. Three case reports from the literature showed that cord blood levels of etanercept at delivery, in newborns born to women administered etanercept during pregnancy, were between 3% and 32% of the maternal serum level. The risk of adverse reactions in neonates and infants 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.
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. Per expert reviews, 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, the indication for use, treat-to-target strategies, and patient specific factors should be assessed before considering an alternative agent.
The safety and efficacy of etanercept have not been established for the treatment of juvenile psoriatic arthritis (JPsA) or polyarticular juvenile idiopathic arthritis (pJIA) in infants and children younger than 2 years of age. In addition, safety and efficacy of etanercept have not been established for the treatment of plaque psoriasis in pediatric patients younger than 4 years of age. There are specific considerations and precautions for the use of etanercept in pediatric patients. Etanercept has a boxed warning regarding lymphoma and other cancers; these cancers, sometimes fatal, have been reported with the use of TNF blockers in children and adolescents (therapy initiation at 18 years of age or younger), and etanercept may affect host defenses against infection. Among children and adolescents, malignancies developed after a median of 30 months of therapy (range of 1 to 84 months) and the majority of cases involved concurrent use of immunosuppressants. Lymphomas, including Hodgkin's and non-Hodgkin's lymphoma, accounted for about half of the reported cancers in children and adolescent patients. No data are available regarding the safety and efficacy of vaccines and toxoids in pediatric patients treated with etanercept. Ensure all pediatric patients are brought up to date with immunizations, if possible, prior to beginning etanercept therapy. Live-virus vaccine administration during etanercept therapy is to be avoided. 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. Consider treatment with Varicella Zoster Immune Globulin in these patients.
Allergic reactions have been reported with etanercept. Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Of note, the needle cap on the Erelzi prefilled syringe and the internal needle cover within the cap of the Erelzi Sensoready Pen contain dry natural rubber (latex) that may cause allergic reactions in persons with latex hypersensitivity.
Before starting etanercept test potential drug recipients for hepatitis C (IgG) and HIV serum status (HIV-1 and HIV-2 antibodies and HIV-1 antigen). Consider ongoing screening (e.g., annually) in people who are at increased risk for HIV or hepatitis C infection. Retest for HIV infection in any person who displays symptoms or other conditions that may suggest HIV seroconversion or infection. In patients found to be infected with HIV, consider involving relevant specialists to ensure HIV viral load is suppressed on antiretroviral therapy. Similarily, retest for viral hepatitis in any person who develops unexplained elevations in hepatic enzymes. It is recommended to consult a hepatologist when using a biological therapy in patients who are infected with hepatitis C, whether newly diagnosed or chronically infected.
Patients who undergo surgery while taking a biologic therapy, such as etanercept, may be at greater risk for postoperative infections. In patients undergoing elective surgery, balance the risk of postoperative infection against the risk of developing a severe or unstable disease by stopping the biologic therapy. When possible, it is advised to stop the biologic therapy 3- to 5-times the half-live or the length of the treatment cycle (whichever is longer) between the last dose and the planned surgery. Restart the biologic therapy postoperatively if there is no evidence of infection and wound healing is satisfactory.
For the treatment of moderately to severely active rheumatoid arthritis:
Subcutaneous dosage:
Adults: 50 mg subcutaneously once weekly. May be used with or without methotrexate. Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, and analgesics may be continued during etanercept treatment.
For the reduction in signs and symptoms of moderately to severely active polyarticular course juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA) in patients who have had an inadequate response to 1 or more disease-modifying antirheumatic drugs:
NOTE: Etanercept has been designated an orphan drug by the FDA for this indication.
Subcutaneous dosage:
Children and Adolescents 2 years and older: 0.8 mg/kg subcutaneously once weekly. Max: 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 has not been studied. Higher doses of etanercept have not been shown to be effective in patients who do not respond to the recommended dose. In clinical studies, most responding patients did so within 3 months of treatment. 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, only 28% (7 of 25 patients) of patients receiving etanercept withdrew due to disease flare. The median time to disease flare was 28 days with placebo compared to more than 116 days with etanercept.
For the treatment of chronic moderate to severe plaque psoriasis in persons who are candidates for systemic therapy or phototherapy:
Subcutaneous dosage:
Adults: 50 mg subcutaneously twice weekly given 3 to 4 days apart for 3 months, then 50 mg subcutaneously once weekly. May increase the dose to 50 mg subcutaneously twice weekly if an inadequate primary response may be due to insufficient drug exposure (e.g., known subtherapeutic drug concentrations, obesity, relapse during treatment); however, consider the increased risk for infection and adverse reactions.
Children and Adolescents 4 to 17 years weighing 63 kg or more: 50 mg subcutaneously once weekly. Guidelines recommend etanercept as an effective therapy for moderate to severe psoriasis.
Children and Adolescents 4 to 17 years weighing less than 63 kg: 0.8 mg/kg/dose subcutaneously once weekly. Guidelines recommend etanercept as an effective therapy for moderate to severe psoriasis.
For the treatment of active juvenile psoriatic arthritis (JPsA) in pediatric patients and psoriatic arthritis (PsA) in adults to reduce signs and symptoms, inhibit progression of structural damage of active arthritis, and improve physical function:
Subcutaneous dosage:
Adults: 50 mg subcutaneously once weekly. Etanercept can be used with or without methotrexate. Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics may be continued during treatment.
Children and Adolescents 2 to 17 years weighing 63 kg or more: 50 mg subcutaneously once weekly.
Children and Adolescents 2 to 17 years weighing less than 63 kg: 0.8 mg/kg/dose subcutaneously once weekly.
For the treatment of the signs and symptoms of spondylitis, such as active ankylosing spondylitis in adults or for the treatment of juvenile spondyloarthropathy* (JSpA) in pediatric patients:
Subcutaneous dosage:
Adults: 50 mg subcutaneously once weekly is recommended. Clinical trials also used a dose of 25 mg subcutaneously twice weekly (every 3 to 4 days). Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, analgesics, or methotrexate may be continued during treatment. In clinical trials, 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.
Children* and Adolescents* 2 years and older: Safety and efficacy have not been definitively established; not FDA-approved. 0.8 mg/kg subcutaneously once weekly (Max: 50 mg/week) is the recommended dosage from clinical trials that suggest etanercept is effective. A 2016 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 American College of Rheumatology (ACR) treatment guidelines due to the lack of sufficient data at time of review. In phase 1 of a randomized, controlled clinical trial in pediatric patients with JSpA 6 years and older (n = 41), all patients were administered etanercept for 24 weeks. 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 (e.g., tender joints, swollen joints, and joints with active arthritis) occured. 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. Treatment responders at week 24 according to the ACR Pedi 30 entered Phase 2, a 24-week randomized, double-blind, placebo-controlled withdrawal study; 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.
For the treatment of Stevens-Johnson syndrome* (SJS) and toxic epidermal necrolysis* (TEN):
Subcutaneous dosage:
Adults: 50 mg subcutaneously as a single dose; may consider a second dose after 2 to 4 days as necessary. Alternatively, 25 to 50 mg subcutaneously twice weekly.
Children and Adolescents 2 to 17 years: 0.8 mg/kg/dose (Max: 50 mg/dose) subcutaneously as a single dose; may consider a second dose after 2 to 4 days as necessary.
For the treatment of IVIG-resistant Kawasaki disease*:
Subcutaneous dosage:
Infants, Children, and Adolescents: 0.8 mg/kg/dose subcutaneously once weekly for 3 doses. Administer the first dose within 24 hours after IVIG.
For the treatment of graft-versus-host disease (GVHD)*:
-for the treatment of acute GVHD*:
Subcutaneous dosage:
Adults: 0.4 mg/kg/dose (Max: 25 mg/dose) subcutaneously twice weekly for 8 weeks. Alternatively, 0.4 mg/kg/dose (Max: 25 mg/dose) subcutaneously twice weekly for 4 weeks, then 0.4 mg/kg/dose (Max: 25 mg/dose) subcutaneously once weekly for 4 weeks. Guidelines suggest etanercept as a second-line treatment option for steroid-refractory acute GVHD.
Children and Adolescents 3 to 17 years: 0.4 mg/kg/dose (Max: 25 mg/dose) subcutaneously twice weekly for 8 weeks. Guidelines suggest etanercept as a second-line treatment option for steroid-refractory acute GVHD.
-for the treatment of chronic GVHD*:
Subcutanous dosage:
Adults: 0.4 mg/kg/dose (Max: 25 mg/dose) subcutaneously twice weekly for 4 to 12 weeks. Alternatively, 0.4 mg/kg/dose (Max: 25 mg/dose) subcutaneously twice weekly for 4 weeks, then 0.4 mg/kg/dose (Max: 25 mg/dose) subcutaneously once weekly for 4 weeks. Etanercept may be useful in select persons with gastrointestinal or cutaneous manifestations of steroid-refractory chronic GVHD.
Children and Adolescents 3 to 17 years: 0.4 mg/kg/dose (Max: 25 mg/dose) subcutaneously twice weekly for 4 to 12 weeks. Alternatively, 0.4 mg/kg/dose (Max: 25 mg/dose) subcutaneously twice weekly for 4 weeks, then 0.4 mg/kg/dose (Max: 25 mg/dose) subcutaneously once weekly for 4 weeks. Etanercept may be useful in select persons with gastrointestinal or cutaneous manifestations of steroid-refractory chronic GVHD.
Maximum Dosage Limits:
-Adults
50 mg/week subcutaneously. Induction therapy for plaque psoriasis should not exceed 100 mg/week with no more than 50 mg/dose subcutaneously.
-Geriatric
50 mg/week subcutaneously. Induction therapy for plaque psoriasis should not exceed 100 mg/week with no more than 50 mg/dose subcutaneously.
-Adolescents
0.8 mg/kg/week subcutaneously (Max: 50 mg/week).
-Children
2 to 12 years: 0.8 mg/kg/week subcutaneously (Max: 50 mg/week).
younger than 2 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abatacept: (Major) Concomitant use of abatacept with other biologic agents, such as tumor necrosis factor (TNF) inhibitors, is not recommended because of the possibility of additive immunosuppression and increased risk of infection. In controlled clinical trials, patients receiving concomitant abatacept and TNF inhibitor therapy experienced more infections (63%) and serious infections (4.4%) as compared with patients treated with only TNF inhibitors (43% and 0.8%, respectively). These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of abatacept with a TNF inhibitor. Monitor patients for signs of infection during the transition from TNF antagonist therapy to abatacept therapy.
Adalimumab: (Contraindicated) 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: (Major) Avoid the concomitant use of anakinra with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection with no additional clinical benefit. Data suggest a higher rate of serious infections when anakinra and a TNF inhibitor is used in combination with anakinra compared with either drug given alone. Neutropenia (1,000/mcL or less) was observed in 2% of patients receiving the combination. The use of anakinra with a TNF inhibitor in combination did not yield any additional clinical benefit as compared to the use of the TNF inhibitor alone.
Anifrolumab: (Major) Coadministration is not recommended. Anifrolumab has not been studied in combination with other biologic therapies including tumor necrosis factor modifiers (TNF blockers). Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) 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 system.
Baricitinib: (Major) Concomitant use of baricitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Belimumab: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including tumor necrosis factor modifiers (TNF blockers). Therefore, belimumab use is not recommended in combination with TNF blockers. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
Canakinumab: (Major) Avoid concomitant administration of canakinumab with tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection. 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 canakinumab and TNF inhibitors is not recommended.
Certolizumab pegol: (Contraindicated) 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.
Chikungunya Vaccine, Live: (Contraindicated) 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 system.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Golimumab: (Contraindicated) 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: (Contraindicated) 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.
Intranasal Influenza Vaccine: (Contraindicated) 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 system.
Live Vaccines: (Contraindicated) 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 system.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) 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 system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) 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 system.
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: (Contraindicated) 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.
Rotavirus Vaccine: (Contraindicated) 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 system.
Sarilumab: (Major) Avoid the concomitant use of sarilumab with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) 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 system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) 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 system.
Sulfasalazine: (Moderate) The combined use of etanercept and sulfasalazine may cause neutropenia. Carefully monitor patients who receive etanercept and sulfasalazine concurrently.
Tocilizumab: (Major) Avoid the concomitant use of tocilizumab with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Tofacitinib: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
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.
Typhoid Vaccine: (Contraindicated) 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 system.
Upadacitinib: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) 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 system.
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.
Yellow Fever Vaccine, Live: (Contraindicated) 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 system.
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).
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.
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 25 mg subcutaneous dose, 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 P450 (CYP450) enzymes and drug transporters: None known
-Route-Specific Pharmacokinetics
Subcutaneous Route
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 4-fold increase in the systemic exposure (range, 1- to 17-fold) was noted. In another study involving RA patients, the mean Cmax, Cmin, and partial AUC at steady-state were similar in patients treated with 50 mg subcutaneously once weekly and those treated with 25 mg subcutaneously twice weekly. 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. In adults with plaque psoriasis (PsO), the mean steady-state concentrations were 1.5 +/- 0.7 mcg/mL after etanercept 50 mg once weekly. The mean steady-state concentrations for 50 mg once weekly in adults with psoriatic arthritis (PsA) were 2.1 +/- 1.2 mcg/mL and 2.1 +/- 1.4 mcg/mL at weeks 24 and 48, respectively.
-Special Populations
Hepatic Impairment
No formal pharmacokinetic studies of etanercept have been done in patients with hepatic impairment to determine the effects on etanercept disposition.
Renal Impairment
No formal pharmacokinetic studies have been done in patients with renal impairment to determine the effects on etanercept disposition.
Pediatrics
Etanercept clearance in children 4 to 8 years may be slightly reduced. Administration of 0.4 mg/kg subcutaneously twice weekly (max of 50 mg/week) for up to 18 weeks to pediatric patients 4 to 17 years of age with polyarticular juvenile idiopathic arthritis (pJIA) led to a mean concentration of 2.1 mcg/mL (range, 0.7 to 4.3 mcg/mL). Based upon population pharmacokinetic analyses, the predicted pharmacokinetic differences between 0.4 mg/kg twice weekly and 0.8 mg/weekly are expected to be of the same magnitude as the differences observed between twice weekly and weekly regimens in adults with RA. In pediatric PsO patients (4 to 17 years) administered 0.8 mg/kg of etanercept once weekly (up to 50 mg/week) for up to 48 weeks, the mean serum steady-state trough concentrations ranged from 1.6 +/- 0.8 to 2.1 +/- 1.3 mcg/mL at weeks 12, 24, and 48. Overall, the observed drug concentrations in patients with pJIA and pediatric PsO were within the range of those observed for adults with RA, PsA, and PsO. The pharmacokinetic exposure is expected to be comparable between pediatric patients with juvenile psoriatic arthritis (JPsA) and adults with PsA.
Geriatric
In clinical studies, pharmacokinetic parameters of etanercept did not vary with age in adult patients.
Gender Differences
In clinical studies, pharmacokinetic parameters of etanercept did not differ between female and male patients.