CLASSES
Antipsoriatic Monoclonal Antibodies and Others
Other Specific Antirheumatics
Tumor Necrosis Factor (TNF)-Alpha Inhibitors
BOXED WARNING
Bone marrow suppression, corticosteroid therapy, diabetes mellitus, fungal infection, geriatric, hematological disease, immunosuppression, infection, mycobacterial infection, sepsis, tuberculosis, viral infection
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.
Leukemia, lymphoma, melanoma, new primary malignancy, skin cancer
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.
DESCRIPTION
TNF-blocker fusion protein; used subcutaneously
Used for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), and plaque psoriasis
Boxed warnings for increased risk of serious infection and potential for malignancy
COMMON BRAND NAMES
Enbrel
HOW SUPPLIED
Enbrel Subcutaneous Inj Pwd F/Sol: 25mg
Enbrel Subcutaneous Inj Sol: 0.5mL, 1mL, 25mg, 50mg
DOSAGE & INDICATIONS
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 who are candidates for systemic therapy or phototherapy.
Subcutaneous dosage
Adults
Initially, 50 mg subcutaneously twice weekly (given 3 to 4 days apart) for 3 months. The maintenance dose is 50 mg subcutaneously once weekly. Clinical trials also used a maintenance dose of 25 mg subcutaneously given twice weekly. In addition to the 50 mg twice weekly recommended starting dose, starting doses of 25 mg or 50 mg per week were shown to be efficacious; however, the proportion of responders was related to the initial dosage. The British Association of Dermatologist guidelines suggest a maintenance dose of 50 mg subcutaneously twice weekly when an inadequate primary response may be due to insufficient drug exposure (e.g., known subtherapeutic drug concentrations, obese patients, relapse during treatment); however, the guidelines warn that consideration should be given to an increased risk for infection and adverse reactions.
Children and Adolescents 4 to 17 years
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.
For the treatment of signs and symptoms of active psoriatic arthritis, to improve physical function, and to prevent the progression of structural damage.
Subcutaneous dosage
Adults
50 mg subcutaneously once weekly. Max: 50 mg/week. Etanercept can be used with or without methotrexate. Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics may be continued during treatment.
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.
†Indicates off-label use
MAXIMUM DOSAGE
Adults
50 mg/week subcutaneously. Induction therapy for psoriatic arthritis should not exceed 100 mg/week with no more than 50 mg/dose subcutaneously.
Geriatric
50 mg/week subcutaneously. Induction therapy for psoriatic arthritis 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.
DOSING CONSIDERATIONS
Hepatic Impairment
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Renal Impairment
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
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.[28060] [61287] [64274]
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.[28060]
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.[28060]
Use of the Enbrel SureClick Autoinjector
The needle cap on the SureClick autoinjector contains dry natural rubber (latex) and should not be handled by persons sensitive to this product.
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.[28060]
Use of the Enbrel prefilled syringe
The needle cap on the prefilled syringe contains dry natural rubber (latex) and should not be handled by persons sensitive to this product.
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.[28060]
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.[28060]
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.
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.[61287]
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.
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.[61287]
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.[64274]
STORAGE
Enbrel:
- Discard product if it contains particulate matter, is cloudy, or discolored
- Discard unused portion. Do not store for later use.
- Do not freeze
- Do Not Shake
- Product stored at controlled room temperature should not be returned to a refrigerator
- Protect from extreme heat
- Protect from light
- Store in original carton in refrigerator (35 to 46 degrees F) until time of use
- Store individual single-dose prefilled syringes, autoinjectors, single-dose vials, or cartridges at room temperature 68 to 77 degrees F (20 to 25 degrees C) for a maximum single period of 30 days
CONTRAINDICATIONS / PRECAUTIONS
Hepatitis, hepatitis B exacerbation
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.
Bone marrow suppression, corticosteroid therapy, diabetes mellitus, fungal infection, geriatric, hematological disease, immunosuppression, infection, mycobacterial infection, sepsis, tuberculosis, viral infection
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.
Leukemia, lymphoma, melanoma, new primary malignancy, skin cancer
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.
Granulomatosis with polyangiitis
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.
Heart failure
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.
Multiple sclerosis, neurological disease, seizure disorder, seizures
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.
Autoimmune disease
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.
Vaccination, varicella
Limited data are available regarding the response to vaccination in patients receiving etanercept. Adult patients may receive vaccinations concurrently with etanercept therapy, with the exception of live virus vaccines. There are no data available regarding the safety and efficacy of live or killed vaccines and toxoids in pediatric patients treated with etanercept. The manufacturer recommends that all pediatric patients be brought up to date with immunizations, if possible, prior to beginning etanercept therapy. Immunosuppressed patients should not be exposed to others who have recently received the oral poliovirus vaccine. Attenuated virus vaccines may also be associated with increased adverse reactions in immunosuppressed patients. There are no data available on secondary transmission of infection by live vaccines in patients receiving etanercept. It is recommended that patients significantly exposed to varicella virus temporarily discontinue etanercept therapy. Treatment with Varicella Zoster Immune Globulin should be considered in these patients. While receiving etanercept, 2 pediatric patients developed varicella infection associated with aseptic meningitis; the infection resolved in these patients without sequelae.
Infants, neonates, pregnancy
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.
Breast-feeding
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.
Children
The safety and efficacy of etanercept have not been established for the treatment of juvenile idiopathic arthritis (JIA) in infants and children less 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 less 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 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. All pediatric patients should be brought up to date with immunizations, if possible, prior to beginning etanercept therapy. Live-virus vaccine administration during etanercept therapy is to be avoided. Immunosuppressed patients should not be exposed to others who have recently received the oral poliovirus vaccine. Attenuated virus vaccines may also be associated with increased adverse reactions in immunosuppressed patients. There are no data available on secondary transmission of infection by live vaccines in patients receiving etanercept. It is recommended that patients significantly exposed to varicella virus temporarily discontinue etanercept therapy. Treatment with Varicella Zoster Immune Globulin should be considered in these patients. While receiving etanercept, 2 pediatric patients developed varicella infection associated with aseptic meningitis; the infection resolved in these patients without sequelae.
Latex hypersensitivity
Allergic reactions have been reported with etanercept. The needle caps on the Enbrel SureClick autoinjector, prefilled Enbrel syringe, Enbrel Mini cartridge, prefilled Erelzi syringe, and Erelzi Sensoready Pen contain dry natural rubber (latex) that may cause allergic reactions in persons with latex hypersensitivity.
Hepatitis C infection, HIV serum status
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.
Surgery
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.
ADVERSE REACTIONS
Severe
aplastic anemia / Delayed / 0-0.1
pancytopenia / Delayed / 0-0.1
heart failure / Delayed / 0-0.1
optic neuritis / Delayed / 0-0.1
seizures / Delayed / 0-0.1
Guillain-Barre syndrome / Delayed / 0-0.1
myelitis / Delayed / 0-0.1
lupus-like symptoms / Delayed / 0-0.1
aseptic meningitis / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
vasculitis / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
uveitis / Delayed / Incidence not known
hepatitis B exacerbation / Delayed / Incidence not known
skin cancer / Delayed / Incidence not known
Merkel cell carcinoma / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
lymphoma / Delayed / Incidence not known
leukemia / Delayed / Incidence not known
Moderate
antibody formation / Delayed / 6.0-15.0
neutropenia / Delayed / 2.0-2.0
inflammatory bowel disease / Delayed / 0-0.1
hepatitis / Delayed / 0-0.1
candidiasis / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
lymphadenopathy / Delayed / Incidence not known
anemia / Delayed / Incidence not known
chest pain (unspecified) / Early / Incidence not known
interstitial lung disease / Delayed / Incidence not known
psoriasis / Delayed / Incidence not known
psoriaform rash / Delayed / Incidence not known
ocular inflammation / Early / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
Mild
infection / Delayed / 27.0-81.0
influenza / Delayed / 17.0-65.0
sinusitis / Delayed / 17.0-65.0
pharyngitis / Delayed / 17.0-65.0
injection site reaction / Rapid / 7.0-43.0
diarrhea / Early / 3.0-16.0
rash / Early / 1.0-13.0
pruritus / Rapid / 1.0-5.0
fever / Early / 2.0-3.0
urticaria / Rapid / 1.0-2.0
paresthesias / Delayed / 0-0.1
ecchymosis / Delayed / Incidence not known
headache / Early / Incidence not known
DRUG INTERACTIONS
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
PREGNANCY AND LACTATION
Pregnancy
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.
MECHANISM OF ACTION
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.
PHARMACOKINETICS
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
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 four-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 adult with plaque psoriasis, the mean steady-state concentrations were 1.5 +/- 0.7 mcg/mL following etanercept 50 mg once weekly.