Dosage & Administration
Enbrel is administered by subcutaneous injection.
| Patient Population | Recommended Dose and Frequency |
|---|---|
| Adult RA and PsA | 50 mg once weekly with or without methotrexate (MTX) |
| AS | 50 mg once weekly |
| Adult PsO | 50 mg twice weekly for 3 months, followed by 50 mg once weekly |
| pJIA, Pediatric PsO and JPsA | 0.8 mg/kg weekly, with a maximum of 50 mg per week |
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Enbrel Prescribing Information
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. Test patients for latent tuberculosis before Enbrel use and during therapy. Initiate treatment for latent infection 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. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.
The risks and benefits of treatment with Enbrel should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Monitor patients closely 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.
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.
Polyarticular Juvenile Idiopathic Arthritis
Enbrel 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.
Psoriatic Arthritis
Enbrel 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
Enbrel is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS).
Plaque Psoriasis
Enbrel 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.
Juvenile Psoriatic Arthritis
Enbrel is indicated for the treatment of active juvenile psoriatic arthritis (JPsA) in pediatric patients 2 years of age and older.
Testing and Procedures Prior to Treatment Initiation
Perform the following evaluations and procedures prior to initiating treatment with Enbrel:
- Prior to initiating Enbrel and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5.1)].
- Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with Enbrel [see Warnings and Precautions (5.8)].
Important Administration Instructions
Administration of one 50 mg Enbrel single-dose prefilled syringe, one single-dose prefilled Enbrel SureClick autoinjector, or one Enbrel Mini single-dose prefilled cartridge (for use with the AutoTouch reusable autoinjector only), provides a dose equivalent to two 25 mg Enbrel single-dose prefilled syringes, two 25 mg single-dose vials, or two multiple-dose vials of lyophilized Enbrel, when multiple-dose vials are reconstituted and administered as recommended.
Recommended Dosage in Adult Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriatic Arthritis, and Plaque Psoriasis
Enbrel is administered by subcutaneous injection (Table 1).
| Patient Population | Recommended Dosage |
|---|---|
| Adult RA, AS, and PsA | 50 mg weekly |
| Adult PsO | Starting Dose: 50 mg twice weekly for 3 months Maintenance Dose: 50 mg once weekly |
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)].
Recommended Dosage for Pediatric Patients with Polyarticular Juvenile Idiopathic Arthritis, Plaque Psoriasis, and Juvenile Psoriatic Arthritis
The recommended weight-based dosage for pediatric patients is administered by subcutaneous injection (Table 2).
| Body Weight | Recommended Dosage |
|---|---|
| 63 kg (138 pounds) or more | 50 mg weekly |
| Less than 63 kg (138 pounds) | 0.8 mg/kg weekly |
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.
Preparation Instructions for 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. Administer injections subcutaneously in the thigh, abdomen or outer area of the upper arm.
The Enbrel devices are not made with natural rubber latex.
The Enbrel (etanercept) "Instructions for Use" insert for each presentation contains more detailed instructions on injection site selection and the preparation of Enbrel.
Preparation of Enbrel Single-dose Prefilled Syringe
For a more comfortable injection, leave Enbrel prefilled syringes at room temperature for about 15 to 30 minutes before injecting. DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature.
Inspect 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-dose 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 Single-dose Prefilled SureClick Autoinjector
Leave the autoinjector at room temperature for at least 30 minutes before injecting. DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature.
Inspect 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.
Preparation of Enbrel Single-dose Vial
For a more comfortable injection, leave Enbrel vial(s) at room temperature for at least 30 minutes before injecting. DO NOT remove the vial cap while allowing the vial to reach room temperature.
Inspect 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-dose vial, administer the correct dose of solution using the following recommended materials:
- A 1 mL Luer-Lock syringe.
- A withdrawal needle with Luer-Lock connection, sterile, 22-gauge, length 1 ½ inch.
- An injection needle with Luer-Lock connection, sterile, 27-gauge, length ½ inch.
Two vials may be required to administer the total prescribed dose. Use the same syringe for each vial. The vial does not contain preservatives; therefore, discard unused portions.
Preparation of Enbrel Lyophilized Powder in a Multiple-dose Vial
Enbrel lyophilized powder 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 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 refrigerated at 36°F to 46°F (2°C to 8°C) and used within 14 days. Discard reconstituted solution after 14 days because product stability and sterility cannot be assured after 14 days. DO NOT store reconstituted Enbrel solution at room temperature.
For a more comfortable injection, leave the Enbrel dose tray at room temperature for about 15 to 30 minutes before injecting.
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.
Preparation of Enbrel Mini® single-dose prefilled cartridge using the AutoTouch® reusable autoinjector
Leave Enbrel Mini single-dose prefilled cartridge at room temperature for at least 30 minutes before injecting. DO NOT remove the purple cap while allowing the cartridge 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.
To use AutoTouch reusable autoinjector, open the door by pushing the door button and inserting Enbrel Mini single-dose prefilled cartridge into AutoTouch. When inserted correctly, Enbrel Mini single-dose prefilled cartridge will slide freely and completely into the door. Close the door and AutoTouch reusable autoinjector is ready for injection.
- 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
Pregnancy
Risk Summary
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 (see Data).
Reports of etanercept use during the third trimester of pregnancy demonstrated that placental transfer of etanercept was low in infants at birth (see Data). There are risks to the mother and fetus associated with active rheumatoid arthritis. The theoretical risks of administration of live or live-attenuated vaccines to the infants exposed in utero to Enbrel should be weighed against the benefits of vaccinations (see Clinical Considerations).
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 (see Data).
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.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
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.
Fetal/Neonatal Adverse Reactions
The risk of fetal/neonatal adverse reactions with in utero exposure to Enbrel is unknown. Risks and benefits should be considered prior to administering live or live -attenuated vaccines to infants exposed to Enbrel in utero [see Warnings and Precautions (5.8) and Drug Interactions (7.1)].
Data
Human Data
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.
Animal Data
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).
Lactation
Risk Summary
Data from published literature show that etanercept is present in low levels in human milk but is not detected in the plasma of breastfed infants (see Data). There are no data on the effects of etanercept on milk production. There have been no consistent reports of adverse events in breastfed infants over decades of use. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Enbrel and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.
Data
In three case reports, etanercept was detected in breast milk at levels ranging from <2 to 7.5 ng/mL after lactating women had received doses of etanercept of 25 mg weekly or twice weekly. Although etanercept was detected in breast milk in these cases, etanercept was not detected in the serum of the breastfed infants.
Pediatric Use
Polyarticular Juvenile Idiopathic Arthritis
The safety and effectiveness of Enbrel have been established in pediatric patients 2 years of age and older with pJIA. Enbrel has been studied in 69 children with moderately to severely active polyarticular JIA 2 to 17 years of age.
The safety and effectiveness of Enbrel in pediatric patients less than 2 years of age with pJIA have not been established.
Juvenile Psoriatic Arthritis
The safety and effectiveness of Enbrel have been established in pediatric patients 2 years to 17 years old with JPsA. Use of Enbrel in JPsA is supported by evidence from adequate and well controlled studies of Enbrel in adults with PsA; pharmacokinetic data from adult patients with PsA, RA, and PsO; and pharmacokinetic data from pediatric patients with active JIA and PsO. Safety of Enbrel in JPsA is supported by a clinical study in 69 pediatric patients with moderately to severely active JIA aged 2 to 17 years; a clinical study in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years; and an open-label extension study in 182 pediatric patients with moderate to severe PsO aged 4 to 17 years.
The observed pre-dose (trough) concentrations are generally comparable between adults with RA and PsA and pediatric patients with active JIA, as well as adults with PsO and pediatric patients with PsO. The PK exposure is expected to be comparable between adults with PsA and pediatric patients with JPsA [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2, 14.3, 14.5, 14.6)].
The safety and effectiveness in pediatric patients below the age of 2 years have not been established in JPsA.
Plaque Psoriasis
The safety and effectiveness of Enbrel for plaque psoriasis have been established in pediatric patients 4 years of age and older. Enbrel has been studied in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years.
The safety and effectiveness of Enbrel in pediatric patients below the age of 4 years with PsO have not been established.
Malignancies in Pediatric Patients
Malignancies, 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 [see Warnings and Precautions (5.3)].
Geriatric Use
A total of 480 RA patients ages 65 years or older have been studied in clinical trials. In PsO randomized clinical trials, a total of 138 out of 1965 patients treated with Enbrel or placebo were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but the number of geriatric PsO patients is too small to determine whether they respond differently from younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.
Use in Patients with Diabetes
There have been reports of hypoglycemia following initiation of Enbrel therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.
Enbrel is contraindicated in patients with sepsis.