Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

ENBREL (BLA-103795)

(ETANERCEPT)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

Download Data

Expand all

10/18/2023 (SUPPL-5595)

Approved Drug Label (PDF)

Boxed Warning

Additions and revisions underlined:

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.

4 Contraindications

Additions and revisions underlined:

Enbrel is contraindicated in patients with sepsis.

5 Warnings and Precautions

5.12 Not Recommended for Use in Patients with Granulomatosis with Polyangiitis Receiving Immunosuppressants

Subsection title revised

5.13 Increased Mortality in Patients with Moderate to Severe Alcoholic Hepatitis

Subsection title revised

5.4 New Onset or Worsening of Heart Failure

Subsection title revised

5.7 Allergic Reactions

Additions and revisions underlined:

Allergic reactions associated with administration of Enbrel during clinical trials have been reported in < 2% of patients. If an anaphylactic reaction or other serious allergic reaction occurs, discontinue administration of Enbrel and initiate appropriate therapy immediately.

5.8 Immunizations

Additions and revisions underlined:

Avoid concurrent administration of live vaccines with Enbrel. It is recommended that patients, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines prior to initiating Enbrel therapy [see Drug Interactions (7.1) and Use in Specific Populations (8.4)].

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

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)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and revisions underlined:

Enbrel is used to treat:

• moderately to severely active rheumatoid arthritis (RA). Enbrel can be used alone or with a medicine called

  methotrexate.

• moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA) in children 2 years of age or older.

• psoriatic arthritis (PsA) in adults. Enbrel can be used alone or with methotrexate.

• active juvenile psoriatic arthritis (JPsA) in children 2 years of age or older.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Enbrel for a condition for which it was not prescribed. Do not give Enbrel to other people, even if they have the same symptoms that you have.

02/26/2021 (SUPPL-5582)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Use in Granulomatosis with Polyangiitis Patients

(Subsection title revised; Additions and/or revisions underlined)

The use of Enbrel in patients with granulomatosis with polyangiitis receiving immunosuppressive agents is not recommended. In a study of patients with granulomatosis with polyangiitis, the addition of Enbrel to standard therapy (including cyclophosphamide) was associated with a higher incidence of non-cutaneous solid malignancies and was not associated with improved clinical outcomes when compared with standard therapy alone [see Drug Interactions (7.3)].

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

…

Nervous system disorders:     convulsions, multiple sclerosis, demyelination, optic neuritis, transverse myelitis, paresthesias, headache [see Warnings and Precautions (5.2)]

…

10/03/2018 (SUPPL-5569)

Approved Drug Label (PDF)

Other

INSTRUCTIONS FOR USE

(Additions and/or revisions are underlined)

Read these instructions before using an AutoTouch reusable autoinjector with Enbrel MiniTM single-dose prefilled cartridge for use with Enbrel (etanercept).

 …

Sound switch Turning sounds off

AutoTouch makes sounds (?) to help guide your injection. When you receive a new AutoTouch, it will be set with the sounds on (sound switch down).

• To turn off these sounds, slide the sound switch up (red bar is visible).

• Even when the sound is turned off, you will still hear the noise of the motor during the injection and will hear any error alerts to warn you there is a problem. See (Troubleshooting: Error symbols) below if you receive any error alerts

…

To reset AutoTouch:

Hold AutoTouch away from skin and press the status button to wake AutoTouch. The failure symbol should begin blinking and a chime should sound.

While the failure symbol is blinking, press and hold door button until all symbols are temporarily displayed and the status button blinks green. The door button should be held for at least 10 seconds. After a successful reset, if an Enbrel Mini™ single-dose prefilled cartridge is still inside AutoTouch, remove it. Close the AutoTouch door. Then, for the next injection, start by pressing the door button to open Enbrel Mini door.

…

An Enbrel Mini error symbol appears immediately after loading the Enbrel Mini™ single- dose prefilled cartridge.

 …

Enbrel Mini™ single-dose prefilled cartridge will not eject.

Reason #1: If the viewing window has no light, press the status button to wake up AutoTouch. Then press and hold the door button for at least two seconds to eject.

09/14/2017 (SUPPL-5556)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Allergic Reactions

Additions and/or revisions underlined:

… the needle cover of the prefilled syringe the needle cover within the white cap of the SureClick autoinjector, and the needle cover within the purple cap of the Enbrel Mini cartridge.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Throughout this section, doctor replaces health care provider.

Additions and/or revisions underlined:

Other important medical information you should tell your doctor BEFORE starting Enbrel, includes if you:

• are pregnant or plan to become pregnant. It is not known if Enbrel will harm your unborn baby …

  • If you become pregnant while taking Enbrel, you are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. You can enroll by calling 1-800- 77-AMGEN (1-800-772-6436).

• Enbrel can pass into breast milk. You and your doctor should decide if you will take Enbrel or breastfeed. You should not do both.

  • If you choose to breastfeed while taking Enbrel, you are encouraged to enroll in Amgen’s Lactation Surveillance Program. You can enroll by calling 1-800- 77-AMGEN (1-800-772-6436).

What is Enbrel?

Enbrel is used to treat:

• chronic moderate to severe plaque psoriasis in adults ages 18 years and older.

How should I use Enbrel?

Enbrel is available in the forms listed below. Your doctor will prescribe the type that is best for you.

Addition of the following:

• Enbrel Mini single-use cartridge used in the AutoTouch™   reusable autoinjector

Common side effects of Enbrel include:

Addition of the following:

• Headache

General Information about the safe and effective use of Enbrel

Addition of the following:

For more information, call 1-888-4ENBREL (1-888-436-2735).

What are the ingredients in Enbrel?

Single-use Prefilled Syringe, the Single-use Prefilled SureClick Autoinjector, and Enbrel Mini single-use cartridge

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Allergic Reactions

… the needle cover within the white cap of the SureClick autoinjector, and within the purple cap of the Enbrel Mini cartridge.

Administration of Enbrel

When using the AutoTouch reusable autoinjector to administer Enbrel, the patient or caregiver should be informed that the status button turns green upon contact with the skin, flashes green after starting the injection, and turns off at completion of the injection. After removing the AutoTouch reusable autoinjector from the skin, if the status button has turned red, the patient or caregiver should be advised to call 1-888-4Enbrel (1-888-436-2735) immediately. If it looks like the medicine is still injecting or there is still fluid in Enbrel Mini, this means the patient has not received a full dose. The patient or caregiver should be advised to call their health care practitioner immediately.

A puncture-resistant container for disposal of needles, syringes SureClick autoinjectors, and Enbrel Mini cartridges should be used.

07/11/2017 (SUPPL-5551)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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. 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.

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

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.

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.

Three case reports from the literature showed that cord blood levels of etanercept at delivery, in infants born to women administered etanercept during pregnancy, were between 3% and 32% of the maternal serum level.

 

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).

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

Limited data from published literature show that etanercept is present in low levels in human milk and minimally absorbed by a breastfed infant. No data are available on the effects of etanercept on the breastfed child or the effects on milk production…

11/04/2016 (SUPPL-5552)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Neurologic Reactions (replaces Events in subheading title)

 

5.5 Hemotologic Reactions (replaces Events in subheading title)

 

6 Adverse Reactions

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

•  Serious Infections

• Neurologic Reactions

• Malignancies

• Patients with Heart Failure

• Hematologic Reactions

• Hepatitis B Reactivation

• Allergic Reactions Autoimmunity

• Immunosuppression

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in clinical practice.

Adverse Reactions in Pediatric Patients

In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients.

In a 48-week clinical study in 211 children aged 4 to 17 years with pediatric PsO, the adverse reactions reported were similar to those seen in previous studies in adults with PsO. Long-term safety profile for up to 264 additional weeks was assessed in an open-label extension study and no new safety signals were identified.

 In open-label clinical studies of children with JIA, adverse reactions reported in those ages 2 to 4 years were similar to adverse reactions reported in older children.

Infections

Rates of infections in RA and adult PsO patients are provided in Table 3 and Table 4, respectively. Infections consisted primarily of upper respiratory tract infection, sinusitis and influenza.

 In clinical trials in adult PsO patients, serious infections experienced by patients have included, but are not limited to, pneumonia, cellulitis, gastroenteritis, abscess and osteomyelitis.

 The types of infections reported in pediatric patients with PsO and JIA were generally mild and consistent with those commonly seen in the general pediatric population. Two JIA patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae.

Injection Site Reactions

In placebo-controlled trials in rheumatologic indications, approximately 37% of patients treated with Enbrel developed injection site reactions. In controlled trials in patients with PsO, 15% of adult patients and 7% of pediatric patients treated with Enbrel … (additions underlined)

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Enbrel in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Immunogenicity (addition of subheading)

Patients with RA, PsA, AS or PsO were tested at multiple time points …

In adult PsO studies that evaluated the exposure of etanercept for up to 120 weeks, the percentage of patients testing positive at the assessed time points of 24, 48, 72 and 96 weeks ranged from 3.6%-8.7% and were all non- neutralizing.

In pediatric PsO studies, approximately 10% of subjects developed antibodies to etanercept by Week 48 and approximately 16% of subjects developed antibodies to etanercept by Week 264. All of these antibodies were non- neutralizing. However, because of the limitations of the immunogenicity assays, the incidence of binding and neutralizing antibodies may not have been reliably determined. (additions and/or revisions underlined)

6.3 Postmarketing Experience

Rare (less than 0.1%) cases of IBD have been reported in JIA patients receiving Enbrel, which is not effective for the treatment of IBD.

8 Use in Specific Populations

8.4 Pediatric Use

Enbrel has been studied in 69 children with moderately to severely active polyarticular JIA aged 2 to 17 years. Enbrel has been studied in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years.

Enbrel has not been studied in children less than 2 years of age with JIA and less than 4 years of age with PsO. (additions and/or revisions underlined)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(section addition; please refer to label)

Patient Counseling Information

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before the patient starts using Enbrel, and each time the prescription is renewed, as there may be new information they need to know.

Administration of Enbrel

For weight-based dosing, instruct caregivers and patients on the proper techniques for preparing, storing, measuring, and administering Enbrel lyophilized powder for reconstitution.

When using the SureClick autoinjector to administer Enbrel, the patient or caregiver should be informed that the window turns yellow when the injection is complete. After removing the autoinjector, if the window has not turned yellow, or if it looks like the medicine is still injecting, this means the patient has not received a full dose. The patient or caregiver should be advised to call their healthcare provider immediately. (additions underlined)