Boxed Warning
WARNINGS:
SERIOUS INFECTIONS AND MALIGNANCIES
See full prescribing information for complete boxed warning.
SERIOUS INFECTIONS
•Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens.
•Enbrel should be discontinued if a patient develops a serious infection or sepsis during treatment.
•Perform test for latent TB; if positive, start treatment for TB prior to starting Enbrel.
•Monitor all patients for active TB during treatment, even if initial latent TB test is negative. (5.1)
MALIGNANCIES
•Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which Enbrel is a member. (5.3)
Indications And Usage
Enbrel is a tumor necrosis factor (TNF) blocker indicated for the treatment of:
•Rheumatoid Arthritis (RA) (1.1)
•Polyarticular Juvenile Idiopathic Arthritis (JIA) in patients aged 2 years or older (1.2)
•Psoriatic Arthritis (PsA) (1.3)
•Ankylosing Spondylitis (AS) (1.4)
•Plaque Psoriasis (PsO) (1.5)
Dosage And Administration
Enbrel is administered by subcutaneous injection.
•Adult RA and PsA (2.1)
50 mg once weekly with or without methotrexate (MTX)
•AS (2.1)
50 mg once weekly
•Adult PsO (2.2)
50 mg twice weekly for 3 months, followed by 50 mg once weekly
•JIA (2.3)
0.8 mg/kg weekly, with a maximum of 50 mg per week
Dosage And Administration 2
•50 mg Single-use Prefilled Syringe (3)
0.98 mL of a 50 mg/mL solution of etanercept
•50 mg Single-use Prefilled SureClick ® Autoinjector (3)
0.98 mL of a 50 mg/mL solution of etanercept
•25 mg Single-use Prefilled Syringe (3)
0.51 mL of a 50 mg/mL solution of etanercept
•25 mg Multiple-use Vial (3)
25 mg of etanercept
Contraindications
•Sepsis (4)
Warnings And Precautions
•Do not start Enbrel during an active infection. If an infection develops, monitor carefully and stop Enbrel if infection becomes serious. (5.1)
•Demyelinating disease, exacerbation or new onset, may occur. (5.2)
•Cases of lymphoma have been observed in patients receiving TNF-blocking agents. (5.3)
•Congestive heart failure, worsening or new onset, may occur. (5.4)
•Advise patients to seek immediate medical attention if symptoms of pancytopenia or aplastic anemia develop, and consider stopping Enbrel. (5.5)
•Monitor hepatitis B virus carriers for reactivation during and several months after therapy. If reactivation occurs, consider stopping Enbrel and beginning anti viral therapy. (5.6)
•Anaphylaxis or serious allergic reactions may occur. (5.7)
•Stop Enbrel if lupus-like syndrome or autoimmune hepatitis develops. (5.9)
Adverse Reactions
Most common adverse reactions (incidence > 5%): infections and injection site reactions. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6437) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
Drug Interactions
•Live vaccines – should not be given with Enbrel (5.8, 7.1)
•Anakinra – increased risk of serious infection (5.12, 7.2 )
•Abatacept – increased risk of serious adverse events, including infections (5.12, 7.2)
•Cyclophosphamide – use with Enbrel is not recommended (7.3)
Use In Specific Populations
•Pregnancy registry available (8.1)
WARNINGS:SERIOUS INFECTIONS AND MALIGNANCIES
SERIOUS INFECTIONS
Patients treated with Enbrel are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) and Adverse Reactions (6)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
Enbrel should be discontinued if a patient develops a serious infection or sepsis.
Reported infections include:
•Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before Enbrel use and during therapy. Treatment for latent infection should be initiated prior to Enbrel use.
•Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
•Bacterial, viral, and other infections due to opportunistic pathogens.
The risks and benefits of treatment with Enbrel should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Enbrel, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including Enbrel.
1 INDICATIONS AND USAGE
1.1 Rheumatoid Arthritis
Enbrel is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis (RA). Enbrel can be initiated in combination with methotrexate (MTX) or used alone.
1.2 Polyarticular Juvenile Idiopathic Arthritis
Enbrel is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients ages 2 and older.
1.3 Psoriatic Arthritis
Enbrel is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis (PsA). Enbrel can be used in combination with methotrexate (MTX) in patients who do not respond adequately to MTX alone.
1.4 Ankylosing Spondylitis
Enbrel is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS).
1.5 Plaque Psoriasis
Enbrel is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.
2 DOSAGE AND ADMINISTRATION
Table 1. Dosing and Administration for Adult Patients Patient Population Recommended Dosage Strength and Frequency
Adult RA, AS, and PsA Patients 50 mg weekly
Adult PsO Patients Starting Dose: 50 mg twice weekly for 3 months
Maintenance Dose: 50 mg once weekly
See the Enbrel (etanercept) “Patient Instructions for Use” insert for detailed information on injection site selection and dose administration.
2.1 Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients
MTX, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be continued during treatment with Enbrel.
Based on a study of 50 mg Enbrel twice weekly in patients with RA that suggested higher incidence of adverse reactions but similar ACR response rates, doses higher than 50 mg per week are not recommended.
2.2 Adult Plaque Psoriasis Patients
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. The proportion of responders were related to Enbrel dosage [see Clinical Studies (14.5)].
2.3 JIA Patients
Table 2. Dosing and Administration for Juvenile Idiopathic Arthritis Pediatric Patients Weight Recommended Dose
63 kg (138 pounds) or more 50 mg weekly
Less than 63 kg (138 pounds) 0.8 mg/kg weekly
In JIA patients, glucocorticoids, NSAIDs, or analgesics may be continued during treatment with Enbrel. Higher doses of Enbrel have not been studied in pediatric patients.
2.4 Preparation of Enbrel
Enbrel is intended for use under the guidance and supervision of a physician. Patients may self-inject when deemed appropriate and if they receive medical follow-up, as necessary. Patients should not self-administer until they receive proper training in how to prepare and administer the correct dose.
The Enbrel (etanercept) “Patient Instructions for Use” insert for each presentation contains more detailed instructions on the preparation of Enbrel.
Preparation of Enbrel Using the Single-use Prefilled Syringe or Single-use Prefilled SureClick Autoinjector
Before injection, Enbrel may be allowed to reach room temperature (approximately 15 to 30 minutes). DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present.
When using the Enbrel single-use prefilled syringe, check to see if the amount of liquid in the prefilled syringe falls between the two purple fill level indicator lines on the syringe. If the syringe does not have the right amount of liquid, DO NOT USE THAT SYRINGE.
Preparation of Enbrel Using the Multiple-use Vial
Enbrel should be reconstituted aseptically with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol), giving a solution of 1.0 mL containing 25 mg of Enbrel.
A vial adapter is supplied for use when reconstituting the lyophilized powder. However, the vial adapter should not be used if multiple doses are going to be withdrawn from the vial. If the vial will be used for multiple doses, a 25-gauge needle should be used for reconstituting and withdrawing Enbrel, and the supplied “Mixing Date:” sticker should be attached to the vial and the date of reconstitution entered. Reconstituted solution must be used within 14 days. Discard reconstituted solution after 14 days because product stability and sterility cannot be assured after 14 days.
If using the vial adapter, twist the vial adapter onto the diluent syringe. Then, place the vial adapter over the Enbrel vial and insert the vial adapter into the vial stopper. Push down on the plunger to inject the diluent into the Enbrel vial. If using a 25-gauge needle to reconstitute and withdraw Enbrel, the diluent should be injected very slowly into the Enbrel vial. It is normal for some foaming to occur. Keeping the diluent syringe in place, gently swirl the contents of the Enbrel vial during dissolution. To avoid excessive foaming, do not shake or vigorously agitate.
Generally, dissolution of Enbrel takes less than 10 minutes. Do not use the solution if discolored or cloudy, or if particulate matter remains.
Withdraw the correct dose of reconstituted solution into the syringe. Some foam or bubbles may remain in the vial. Remove the syringe from the vial adapter or remove the 25-gauge needle from the syringe. Attach a 27-gauge needle to inject Enbrel.
The contents of one vial of Enbrel solution should not be mixed with, or transferred into, the contents of another vial of Enbrel. No other medications should be added to solutions containing Enbrel and do not reconstitute Enbrel with other diluents. Do not filter reconstituted solution during preparation or administration.
3 DOSAGE FORMS AND STRENGTHS
50 mg Single-use Prefilled Syringe
0.98 mL of a 50 mg/mL solution of etanercept
50 mg Single-use Prefilled SureClick Autoinjector
0.98 mL of a 50 mg/mL solution of etanercept
25 mg Single use Prefilled Syringe
0.51 mL of a 50 mg/mL solution of etanercept
25 mg Multiple-use Vial
25 mg of etanercept
4 CONTRAINDICATIONS
Enbrel should not be administered to patients with sepsis.
5 WARNINGS AND PRECAUTIONS
5.1 Infections
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving TNF-blocking agents. Among opportunistic infections, tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most commonly reported. Patients have frequently presented with disseminated rather than localized disease, and are often taking concomitant immunosuppressants such as methotrexate or corticosteroids with Enbrel.
Treatment with Enbrel should not be initiated in patients with an active infection, including clinically important localized infections. The risks and benefits of treatment should be considered prior to initiating therapy in patients:
•With chronic or recurrent infection;
•Who have been exposed to tuberculosis;
•Who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
•With underlying conditions that may predispose them to infection, such as advanced or poorly controlled diabetes [see Adverse Reactions (6.1)].
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Enbrel.
Enbrel should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with Enbrel should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.
Tuberculosis
Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving Enbrel, including patients who have previously received treatment for latent or active tuberculosis. Data from clinical trials and preclinical studies suggest that the risk of reactivation of latent tuberculosis infection is lower with Enbrel than with TNF-blocking monoclonal antibodies. Nonetheless, postmarketing cases of tuberculosis reactivation have been reported for TNF blockers, including Enbrel. Tuberculosis has developed in patients who tested negative for latent tuberculosis prior to initiation of therapy. Patients should be eva luated for tuberculosis risk factors and tested for latent infection prior to initiating Enbrel and periodically during therapy. Tests for latent tuberculosis infection may be falsely negative while on therapy with Enbrel.
Treatment of latent tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating Enbrel, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).
Anti-tuberculosis therapy should also be considered prior to initiation of Enbrel in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Tuberculosis should be strongly considered in patients who develop a new infection during Enbrel treatment, especially in patients who have previously or recently traveled to countries with a high preva lence of tuberculosis, or who have had close contact with a person with active tuberculosis.
Invasive Fungal Infections
Cases of serious and sometimes fatal fungal infections, including histoplasmosis, have been reported with TNF blockers, including Enbrel. For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. In 38 Enbrel clinical trials and 4 cohort studies in all approved indications representing 27,169 patient-years of exposure (17,696 patients) from the United States and Canada, no histoplasmosis infections were reported among patients treated with Enbrel.
5.2 Neurologic Events
Treatment with TNF-blocking agents, including Enbrel, has been associated with rare (< 0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barré syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with Enbrel therapy. Prescribers should exercise caution in considering the use of Enbrel in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders [see Adverse Reactions (6.2)].
5.3 Malignancies
Lymphomas
In the controlled portions of clinical trials of TNF blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared to control patients. During the controlled portions of Enbrel trials in adult patients with RA, AS, and PsA, 2 lymphomas were observed among 3306 Enbrel-treated patients versus 0 among 1521 control patients (duration of controlled treatment ranged from 3 to 36 months).
Among 6543 adult rheumatology (RA, PsA, AS) patients treated with Enbrel in controlled and uncontrolled portions of clinical trials, representing approximate
