Dosage & Administration
Enbrel is administered by subcutaneous injection.
| Patient Population | Recommended Dose and Frequency | ||||||
|---|---|---|---|---|---|---|---|
Adult RA and PsA (Enbrel is administered by subcutaneous injection (Table 1).
See the Enbrel (etanercept) "Instructions for Use" insert for detailed information on injection site selection and dose administration [see Dosage and Administration (2.3)and Patient Counseling Information (17)] .Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients Methotrexate, 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 American College of Rheumatology (ACR) response rates, doses higher than 50 mg per week are not recommended. 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 was related to Enbrel dosage [see Clinical Studies (14.5)] . | 50 mg once weekly with or without methotrexate (MTX) | ||||||
AS (Enbrel is administered by subcutaneous injection (Table 1).
See the Enbrel (etanercept) "Instructions for Use" insert for detailed information on injection site selection and dose administration [see Dosage and Administration (2.3)and Patient Counseling Information (17)] .Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients Methotrexate, 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 American College of Rheumatology (ACR) response rates, doses higher than 50 mg per week are not recommended. 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 was related to Enbrel dosage [see Clinical Studies (14.5)] . | 50 mg once weekly | ||||||
Adult PsO (Enbrel is administered by subcutaneous injection (Table 1).
See the Enbrel (etanercept) "Instructions for Use" insert for detailed information on injection site selection and dose administration [see Dosage and Administration (2.3)and Patient Counseling Information (17)] .Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients Methotrexate, 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 American College of Rheumatology (ACR) response rates, doses higher than 50 mg per week are not recommended. 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 was related to Enbrel dosage [see Clinical Studies (14.5)] . | 50 mg twice weekly for 3 months, followed by 50 mg once weekly | ||||||
pJIA, Pediatric PsO and JPsA (The recommended weight-based dosage for pediatric patients is administered by subcutaneous injection (Table 2).
To achieve pediatric doses other than 25 mg or 50 mg, use Enbrel solution in a single-dose vial or reconstituted lyophilized powder in a multiple-dose vial. Dosages of Enbrel higher than those described in Table 2 have not been studied in pediatric patients. In pJIA patients, glucocorticoids, NSAIDs, or analgesics may be continued during treatment with Enbrel. | 0.8 mg/kg weekly, with a maximum of 50 mg per week |
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Enbrel Prescribing Information
WARNING: SERIOUS INFECTIONS and MALIGNANCIES
- 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. ()
5.1 Serious InfectionsPatients treated with Enbrel are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease.
Treatment with Enbrel should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. 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;
- With a history of an opportunistic infection;
- 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.
TuberculosisCases 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 evaluated 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 Bacillus 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 prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
Invasive Fungal InfectionsCases 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 anti-fungal 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 anti-fungal 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 anti-fungal 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.
- Enbrel should be discontinued if a patient develops a serious infection or sepsis during treatment. ()
5.1 Serious InfectionsPatients treated with Enbrel are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease.
Treatment with Enbrel should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. 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;
- With a history of an opportunistic infection;
- 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.
TuberculosisCases 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 evaluated 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 Bacillus 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 prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
Invasive Fungal InfectionsCases 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 anti-fungal 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 anti-fungal 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 anti-fungal 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.
- Perform test for latent TB; if positive, start treatment for TB prior to starting Enbrel. ()
5.1 Serious InfectionsPatients treated with Enbrel are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease.
Treatment with Enbrel should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. 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;
- With a history of an opportunistic infection;
- 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.
TuberculosisCases 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 evaluated 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 Bacillus 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 prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
Invasive Fungal InfectionsCases 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 anti-fungal 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 anti-fungal 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 anti-fungal 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.
- Monitor all patients for active TB during treatment, even if initial latent TB test is negative. ()
5.1 Serious InfectionsPatients treated with Enbrel are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease.
Treatment with Enbrel should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. 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;
- With a history of an opportunistic infection;
- 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.
TuberculosisCases 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 evaluated 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 Bacillus 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 prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
Invasive Fungal InfectionsCases 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 anti-fungal 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 anti-fungal 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 anti-fungal 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.
- Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF-blockers, including Enbrel. ()
5.3 MalignanciesLymphomasIn 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 approximately 12,845 patient-years of therapy, the observed rate of lymphoma was 0.10 cases per 100 patient-years. This was 3-fold higher than the rate of lymphoma expected in the general U.S. population based on the Surveillance, Epidemiology, and End Results (SEER) Database. An increased rate of lymphoma up to several-fold has been reported in the RA patient population, and may be further increased in patients with more severe disease activity.
Among 4410 adult PsO patients treated with Enbrel in clinical trials up to 36 months, representing approximately 4278 patient-years of therapy, the observed rate of lymphoma was 0.05 cases per 100 patient-years, which is comparable to the rate in the general population. No cases were observed in Enbrel- or placebo-treated patients during the controlled portions of these trials.
LeukemiaCases of acute and chronic leukemia have been reported in association with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF-blocker therapy, patients with rheumatoid arthritis may be at higher risk (approximately 2-fold) than the general population for the development of leukemia.
During the controlled portions of Enbrel trials, 2 cases of leukemia were observed among 5445 (0.06 cases per 100 patient-years) Enbrel-treated patients versus 0 among 2890 (0%) control patients (duration of controlled treatment ranged from 3 to 48 months).
Among 15,401 patients treated with Enbrel in controlled and open portions of clinical trials representing approximately 23,325 patient-years of therapy, the observed rate of leukemia was 0.03 cases per 100 patient-years.
Other MalignanciesInformation is available from 10,953 adult patients with 17,123 patient-years and 696 pediatric patients with 1282 patient-years of experience across 45 Enbrel clinical studies.
For malignancies other than lymphoma and non-melanoma skin cancer, there was no difference in exposure-adjusted rates between the Enbrel and control arms in the controlled portions of clinical studies for all indications. Analysis of the malignancy rate in combined controlled and uncontrolled portions of studies has demonstrated that types and rates are similar to what is expected in the general U.S. population based on the SEER database and suggests no increase in rates over time. Whether treatment with Enbrel might influence the development and course of malignancies in adults is unknown.
Melanoma and Non-Melanoma Skin Cancer (NMSC)Melanoma and non-melanoma skin cancer has been reported in patients treated with TNF antagonists including etanercept.
Among 15,401 patients treated with Enbrel in controlled and open portions of clinical trials representing approximately 23,325 patient-years of therapy, the observed rate of melanoma was 0.043 cases per 100 patient-years.
Among 3306 adult rheumatology (RA, PsA, AS) patients treated with Enbrel in controlled clinical trials representing approximately 2669 patient-years of therapy, the observed rate of NMSC was 0.41 cases per 100 patient-years versus 0.37 cases per 100 patient-years among 1521 control-treated patients representing 1077 patient-years. Among 1245 adult PsO patients treated with Enbrel in controlled clinical trials, representing approximately 283 patient-years of therapy, the observed rate of NMSC was 3.54 cases per 100 patient-years versus 1.28 cases per 100 patient-years among 720 control-treated patients representing 156 patient-years.
Postmarketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with Enbrel.
Periodic skin examinations should be considered for all patients at increased risk for skin cancer.
Pediatric PatientsMalignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy at ≤ 18 years of age), including Enbrel. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.
In clinical trials of 1140 pediatric patients representing 1927.2 patient-years of therapy, no malignancies, including lymphoma or NMSC, have been reported.
Postmarketing UseIn global postmarketing adult and pediatric use, lymphoma and other malignancies have been reported.
Indications and Usage, Juvenile Psoriatic Arthritis (Enbrel is indicated for the treatment of active juvenile psoriatic arthritis (JPsA) in pediatric patients 2 years of age and older. | 10/2023 | ||||||
Dosage and Administration, Pediatric Patients (The recommended weight-based dosage for pediatric patients is administered by subcutaneous injection (Table 2).
To achieve pediatric doses other than 25 mg or 50 mg, use Enbrel solution in a single-dose vial or reconstituted lyophilized powder in a multiple-dose vial. Dosages of Enbrel higher than those described in Table 2 have not been studied in pediatric patients. In pJIA patients, glucocorticoids, NSAIDs, or analgesics may be continued during treatment with Enbrel. | 10/2023 |
Enbrel is a tumor necrosis factor (TNF) blocker indicated for the treatment of:
Adult patients with:
- Rheumatoid Arthritis (RA) ()
1.1 Rheumatoid ArthritisEnbrel 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.
- Psoriatic Arthritis (PsA) ()
1.3 Psoriatic ArthritisEnbrel is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in adult patients with psoriatic arthritis (PsA). Enbrel can be used with or without methotrexate.
- Ankylosing Spondylitis (AS) ()
1.4 Ankylosing SpondylitisEnbrel is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS).
- Plaque Psoriasis (PsO) ()
1.5 Plaque PsoriasisEnbrel is indicated for the treatment of patients 4 years or older with chronic moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.
Pediatric patients with:
- Polyarticular Juvenile Idiopathic Arthritis (pJIA), 2 years of age or older ()
1.2 Polyarticular Juvenile Idiopathic ArthritisEnbrel is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older.
- Juvenile Psoriatic Arthritis, 2 years of age or older (JPsA) ()
1.6 Juvenile Psoriatic ArthritisEnbrel is indicated for the treatment of active juvenile psoriatic arthritis (JPsA) in pediatric patients 2 years of age and older. - Plaque Psoriasis, 4 years of age or older ()
1.5 Plaque PsoriasisEnbrel is indicated for the treatment of patients 4 years or older with chronic moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.
Enbrel is administered by subcutaneous injection.
| Patient Population | Recommended Dose and Frequency | ||||||
|---|---|---|---|---|---|---|---|
Adult RA and PsA (Enbrel is administered by subcutaneous injection (Table 1).
See the Enbrel (etanercept) "Instructions for Use" insert for detailed information on injection site selection and dose administration [see Dosage and Administration (2.3)and Patient Counseling Information (17)] .Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients Methotrexate, 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 American College of Rheumatology (ACR) response rates, doses higher than 50 mg per week are not recommended. 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 was related to Enbrel dosage [see Clinical Studies (14.5)] . | 50 mg once weekly with or without methotrexate (MTX) | ||||||
AS (Enbrel is administered by subcutaneous injection (Table 1).
See the Enbrel (etanercept) "Instructions for Use" insert for detailed information on injection site selection and dose administration [see Dosage and Administration (2.3)and Patient Counseling Information (17)] .Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients Methotrexate, 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 American College of Rheumatology (ACR) response rates, doses higher than 50 mg per week are not recommended. 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 was related to Enbrel dosage [see Clinical Studies (14.5)] . | 50 mg once weekly | ||||||
Adult PsO (Enbrel is administered by subcutaneous injection (Table 1).
See the Enbrel (etanercept) "Instructions for Use" insert for detailed information on injection site selection and dose administration [see Dosage and Administration (2.3)and Patient Counseling Information (17)] .Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients Methotrexate, 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 American College of Rheumatology (ACR) response rates, doses higher than 50 mg per week are not recommended. 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 was related to Enbrel dosage [see Clinical Studies (14.5)] . | 50 mg twice weekly for 3 months, followed by 50 mg once weekly | ||||||
pJIA, Pediatric PsO and JPsA (The recommended weight-based dosage for pediatric patients is administered by subcutaneous injection (Table 2).
To achieve pediatric doses other than 25 mg or 50 mg, use Enbrel solution in a single-dose vial or reconstituted lyophilized powder in a multiple-dose vial. Dosages of Enbrel higher than those described in Table 2 have not been studied in pediatric patients. In pJIA patients, glucocorticoids, NSAIDs, or analgesics may be continued during treatment with Enbrel. | 0.8 mg/kg weekly, with a maximum of 50 mg per week |
- Injection: 25 mg/0.5 mL and 50 mg/mL clear, colorless solution in a single-dose prefilled syringe
- Injection: 50 mg/mL clear, colorless solution in a single-dose prefilled SureClick autoinjector
- Injection: 25 mg/0.5 mL clear, colorless solution in a single-dose vial
- For Injection: 25 mg lyophilized powder in a multiple-dose vial for reconstitution
- Injection: 50 mg/mL clear, colorless solution in Enbrel Mini single-dose prefilled cartridge for use with the AutoTouch reusable autoinjector only
Available studies with use of etanercept during pregnancy do not reliably support an association between etanercept and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS) Enbrel Pregnancy Registry in women with rheumatic diseases or psoriasis and a Scandinavian study in pregnant women with chronic inflammatory disease. Both the OTIS Registry and the Scandinavian study showed the proportion of liveborn infants with major birth defects was higher for women exposed to etanercept compared to diseased etanercept unexposed women. However, the lack of pattern of major birth defects is reassuring and differences between exposure groups (e.g., disease severity) may have impacted the occurrence of birth defects
A prospective cohort pregnancy registry conducted by OTIS in the US and Canada between 2000 and 2012 compared the risk of major birth defects in liveborn infants of women with rheumatic diseases or psoriasis exposed to etanercept in the first trimester. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 319) and diseased etanercept unexposed cohorts (N = 144) was 9.4% and 3.5%, respectively. The findings showed no statistically significant increased risk of minor birth defects and no pattern of major or minor birth defects.
A Scandinavian study compared the risk of major birth defects in liveborn infants of women with chronic inflammatory disease (CID) exposed to TNF-inhibitors during early pregnancy. Women were identified from the Danish (2004-2012) and Swedish (2006-2012) population-based health registers. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 344) and CID etanercept unexposed cohorts (N = 21,549) was 7.0% and 4.7%, respectively.
Overall, while both the OTIS Registry and Scandinavian study show a higher proportion of major birth defects in etanercept-exposed patients compared to diseased etanercept unexposed patients, the lack of pattern of birth defects is reassuring and differences between exposure groups (e.g., disease severity) may have impacted the occurrence of birth defects.
Reports from the literature showed that cord blood levels of etanercept at delivery, in infants born to women administered etanercept during pregnancy, varied from undetectable to 32% of the maternal serum level. In a cohort study of 30 pregnant women with RA, 29 were treated with etanercept until 30 weeks of gestation and 1 was treated until 36 weeks of gestation. Etanercept was not detected in the cord blood sample from any infant at delivery. In three published case reports, etanercept was detected in cord blood at levels of 3.3, 3.6, and 7.4% of the maternal concentration, when etanercept was administered at 50 mg every 7-12 days in pregnancy until 4 days prior to delivery, 25 mg twice weekly until 36 weeks of gestation, and 25 mg subcutaneous every week through the third trimester, respectively. There was one post-marketing safety report of a pregnant woman who received etanercept 25 mg once to twice weekly throughout pregnancy, and etanercept was detected in cord blood at 32% of the maternal concentration.
In embryofetal development studies with etanercept administered during the period of organogenesis to pregnant rats from gestation day (GD) 6 through 20 or pregnant rabbits from GD 6 through 18, there was no evidence of fetal malformations or embryotoxicity in rats or rabbits at respective doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day in rats and 40 mg/kg/day in rabbits). In a peri-and post-natal development study with pregnant rats that received etanercept during organogenesis and the later gestational period from GD 6 through 21, development of pups through post-natal day 4 was unaffected at doses that achieved exposures 48 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day).
Reports of etanercept use during the third trimester of pregnancy demonstrated that placental transfer of etanercept was low in infants at birth
A prospective cohort pregnancy registry conducted by OTIS in the US and Canada between 2000 and 2012 compared the risk of major birth defects in liveborn infants of women with rheumatic diseases or psoriasis exposed to etanercept in the first trimester. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 319) and diseased etanercept unexposed cohorts (N = 144) was 9.4% and 3.5%, respectively. The findings showed no statistically significant increased risk of minor birth defects and no pattern of major or minor birth defects.
A Scandinavian study compared the risk of major birth defects in liveborn infants of women with chronic inflammatory disease (CID) exposed to TNF-inhibitors during early pregnancy. Women were identified from the Danish (2004-2012) and Swedish (2006-2012) population-based health registers. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 344) and CID etanercept unexposed cohorts (N = 21,549) was 7.0% and 4.7%, respectively.
Overall, while both the OTIS Registry and Scandinavian study show a higher proportion of major birth defects in etanercept-exposed patients compared to diseased etanercept unexposed patients, the lack of pattern of birth defects is reassuring and differences between exposure groups (e.g., disease severity) may have impacted the occurrence of birth defects.
Reports from the literature showed that cord blood levels of etanercept at delivery, in infants born to women administered etanercept during pregnancy, varied from undetectable to 32% of the maternal serum level. In a cohort study of 30 pregnant women with RA, 29 were treated with etanercept until 30 weeks of gestation and 1 was treated until 36 weeks of gestation. Etanercept was not detected in the cord blood sample from any infant at delivery. In three published case reports, etanercept was detected in cord blood at levels of 3.3, 3.6, and 7.4% of the maternal concentration, when etanercept was administered at 50 mg every 7-12 days in pregnancy until 4 days prior to delivery, 25 mg twice weekly until 36 weeks of gestation, and 25 mg subcutaneous every week through the third trimester, respectively. There was one post-marketing safety report of a pregnant woman who received etanercept 25 mg once to twice weekly throughout pregnancy, and etanercept was detected in cord blood at 32% of the maternal concentration.
In embryofetal development studies with etanercept administered during the period of organogenesis to pregnant rats from gestation day (GD) 6 through 20 or pregnant rabbits from GD 6 through 18, there was no evidence of fetal malformations or embryotoxicity in rats or rabbits at respective doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day in rats and 40 mg/kg/day in rabbits). In a peri-and post-natal development study with pregnant rats that received etanercept during organogenesis and the later gestational period from GD 6 through 21, development of pups through post-natal day 4 was unaffected at doses that achieved exposures 48 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day).
Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis is correlated with maternal disease activity and that active disease increases the risk of adverse pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) and small for gestational age birth.
The risk of fetal/neonatal adverse reactions with
In animal reproduction studies with pregnant rats and rabbits, 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 Enbrel once weekly
A prospective cohort pregnancy registry conducted by OTIS in the US and Canada between 2000 and 2012 compared the risk of major birth defects in liveborn infants of women with rheumatic diseases or psoriasis exposed to etanercept in the first trimester. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 319) and diseased etanercept unexposed cohorts (N = 144) was 9.4% and 3.5%, respectively. The findings showed no statistically significant increased risk of minor birth defects and no pattern of major or minor birth defects.
A Scandinavian study compared the risk of major birth defects in liveborn infants of women with chronic inflammatory disease (CID) exposed to TNF-inhibitors during early pregnancy. Women were identified from the Danish (2004-2012) and Swedish (2006-2012) population-based health registers. The proportion of major birth defects among liveborn infants in the etanercept-exposed (N = 344) and CID etanercept unexposed cohorts (N = 21,549) was 7.0% and 4.7%, respectively.
Overall, while both the OTIS Registry and Scandinavian study show a higher proportion of major birth defects in etanercept-exposed patients compared to diseased etanercept unexposed patients, the lack of pattern of birth defects is reassuring and differences between exposure groups (e.g., disease severity) may have impacted the occurrence of birth defects.
Reports from the literature showed that cord blood levels of etanercept at delivery, in infants born to women administered etanercept during pregnancy, varied from undetectable to 32% of the maternal serum level. In a cohort study of 30 pregnant women with RA, 29 were treated with etanercept until 30 weeks of gestation and 1 was treated until 36 weeks of gestation. Etanercept was not detected in the cord blood sample from any infant at delivery. In three published case reports, etanercept was detected in cord blood at levels of 3.3, 3.6, and 7.4% of the maternal concentration, when etanercept was administered at 50 mg every 7-12 days in pregnancy until 4 days prior to delivery, 25 mg twice weekly until 36 weeks of gestation, and 25 mg subcutaneous every week through the third trimester, respectively. There was one post-marketing safety report of a pregnant woman who received etanercept 25 mg once to twice weekly throughout pregnancy, and etanercept was detected in cord blood at 32% of the maternal concentration.
In embryofetal development studies with etanercept administered during the period of organogenesis to pregnant rats from gestation day (GD) 6 through 20 or pregnant rabbits from GD 6 through 18, there was no evidence of fetal malformations or embryotoxicity in rats or rabbits at respective doses that achieved systemic exposures 48 to 58 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day in rats and 40 mg/kg/day in rabbits). In a peri-and post-natal development study with pregnant rats that received etanercept during organogenesis and the later gestational period from GD 6 through 21, development of pups through post-natal day 4 was unaffected at doses that achieved exposures 48 times the exposure in patients treated with 50 mg Enbrel once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day).
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the United States, about 2-4% of liveborn babies have a major birth defect and about 15-20% of pregnancies end in miscarriage, regardless of drug exposure.