Drug Safety-related Labeling Changes (SrLC) Database
ANDA | Abbreviated New Drug Application |
BLA | Biologics License Application |
CDER | Center for Drug Evaluation and Research |
MG | Medication Guide |
NDA | New Drug Application |
PCI | Patient Counseling Information |
PI | Patient Information |
PLR | Physician Labeling Rule |
PLLR | Pregnancy and Lactation Labeling Rule |
Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
BW | Box Warning |
WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
ENBREL (BLA-103795)
(ETANERCEPT)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
09/12/2024 (SUPPL-5600)
6 Adverse Reactions
6.3 Postmarketing ExperienceAdditions and/or revisions underlined:
…
Renal and urinary disorders:glomerulonephritis
…
07/22/2024 (SUPPL-5599)
8 Use in Specific Populations
8.1 PregnancyAdditions and revisions underlined:
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).
. . .
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.
. . .
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.
Additions and revisions underlined:
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.
10/18/2023 (SUPPL-5595)
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 ImmunosuppressantsSubsection title revised
Subsection title revised
Subsection title revised
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.
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 UseAdditions 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 GuideAdditions 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)
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)
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)
5 Warnings and Precautions
5.7 Allergic ReactionsAdditions 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
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)
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).
(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)
5 Warnings and Precautions
5.2 Neurologic 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
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)
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)
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 UseEnbrel 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)
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)