Drug Safety-related Labeling Changes (SrLC)

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ERELZI (BLA-761042)

(ETANERCEPT-SZZS)

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

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11/10/2022 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Neurologic Reactions

(Additions and/or revisions underlined)

Treatment with TNF-blocking agents, including etanercept products, has been associated with rare (< 0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barre syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with etanercept products therapy. Prescribers should exercise caution in considering the use of ERELZI in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders [see Postmarketing Experience (6.3)].

5.9 Autoimmunity

(Additions and/or revisions underlined)

Treatment with ERELZI may result in the formation of autoantibodies [see Adverse Reactions (6.1)] and, rarely (< 0.1%), in the development of a lupus-like syndrome or autoimmune hepatitis [see Adverse Reactions (6.2 Immunogenicity)], which may resolve following withdrawal of ERELZI. If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with ERELZI, treatment should be discontinued and the patient should be carefully evaluated.

5.11 Use in Granulomatosis with Polyangiitis Patients

(Additions and/or revisions underlined)

The use of ERELZI in patients with granulomatosis with polyangiitis receiving immunosuppressive agents is not recommended. In a study of patients with granulomatosis with polyangiitis, the addition of etanercept 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

6.3 Postmarketing Experience

(Additions and/or revisions underlined)

Adverse reactions have been reported during post approval use of etanercept products in adults and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to etanercept exposure.

Adverse reactions are listed by body system below:

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

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Administration of ERELZI

If a patient or caregiver is to administer ERELZI, the patient or caregiver should be instructed in injection techniques and how to measure and administer the correct dose [see the ERELZI (etanercept-szzs) “Instructions for Use” insert]. For weight-based dosing, instruct caregivers and patients on the proper techniques for preparing, storing, measuring, and administering ERELZI reconstituted lyophilized powder in a multiple-dose vial.

The first injection should be performed under the supervision of a qualified healthcare professional. The patient’s or caregiver’s ability to inject subcutaneously should be assessed. Patients and caregivers should be instructed in the technique, as well as proper syringe and needle disposal, and be cautioned against reuse of needles and syringes.

When using the Sensoready Pen to administer ERELZI, the patient or caregiver should be informed that the window turns green when the injection is complete. After removing the Sensoready Pen, if the window has not turned green, 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.

A puncture-resistant container for disposal of needles, syringes and Sensoready Pens should be used. If the product is intended for multiple use, additional syringes, needles and alcohol swabs will be required.

06/11/2020 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

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. The 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.

Infections

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 etanercept developed injection site reactions. In controlled trials in patients with PsO, 15% of adult patients and 7% of pediatric patients treated with etanercept developed injection site reactions during the first 3 months of treatment. All injection site reactions were described as mild to moderate (erythema, itching, pain, swelling, bleeding, bruising) and generally did not necessitate drug discontinuation. Injection site reactions generally occurred in the first month and subsequently decreased in frequency. The mean duration of injection site reactions was 3 to 5 days.

6.2 Immunogenicity

(Additions and/or revisions underlined)

Immunogenicity

Patients with RA, PsA, AS or PsO were tested at multiple time points for antibodies to etanercept. Antibodies to the TNF receptor portion or other protein components of etanercept were detected at least once in sera of approximately 6% of adult patients with RA, PsA, AS or PsO. These antibodies were all non-neutralizing. Results from JIA patients were similar to those seen in adult RA patients treated with etanercept.

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. The percentage of patients testing positive increased with an increase in the duration of study; however, the clinical significance of this finding is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed. The immunogenicity data of etanercept beyond 120 weeks of exposure are unknown.

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.

Autoantibodies

Patients with RA had serum samples tested for autoantibodies at multiple time points. In RA Studies I and II, the percentage of patients evaluated for antinuclear antibodies (ANA) who developed new positive ANA (titer greater than or equal to 1:40) was higher in patients treated with etanercept (11%) than in placebo-treated patients (5%)…

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

Etanercept has been studied in 69 children with moderately to severely active polyarticular JIA aged 2 to 17 years.

Etanercept has been studied in 211 pediatric patients with moderate to severe PsO aged 4 to 17 years.

Etanercept has not been studied in children < 2 years of age with JIA and < 4 years of age with PsO. For pediatric specific safety information concerning malignancies and inflammatory bowel disease.

10/18/2019 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

Serious Infections

Among 4410 adult PsO patients treated with etanercept 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 etanercept- or placebo-treated patients during the controlled portions of these trials.

Among 3306 adult rheumatology (RA, PsA, AS) patients treated with etanercept in controlled clinical trials representing approximately 2669 patient-years of therapy, the observed rate of NMSC was 0.41 cases per 100 patient-years vs 0.37 cases per 100 patient-years among 1521 control-treated patients representing 1077 patient-years. Among 1245 adult PsO patients treated with etanercept in controlled clinical trials, representing approximately 283 patient-years of therapy, the observed rate of NMSC was 3.54 cases per 100 patient-years vs 1.28 cases per 100 patient-years among 720 control-treated patients representing 156 patient-years.

6 Adverse Reactions

Clinical Trials Experience

Extensive changes; please refer to label for complete information.

Immunogenicity

Newly added information

Patients with RA, PsA, AS or PsO were tested at multiple time points for antibodies to etanercept. Antibodies to the TNF receptor portion or other protein components of etanercept were detected at least once in sera of approximately 6% of adult patients with RA, PsA, AS or PsO. These antibodies were all non-neutralizing. Results from JIA patients were similar to those seen in adult RA patients treated with etanercept.

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. The percentage of patients testing positive increased with an increase in the duration of study; however, the clinical significance of this finding is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed. The immunogenicity data of etanercept beyond 120 weeks of exposure are unknown.

Postmarketing Experience

Additions and/or revisions underlined:

Adverse reactions are listed by body system below:

Neoplasms benign, malignant, and unspecified:

lupus-like syndrome

7 Drug Interactions

Vaccines

Newly added information

Most PsA patients receiving etanercept were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower and fewer patients had 2-fold rises in titers compared to patients not receiving etanercept. The clinical significance of this is unknown.

8 Use in Specific Populations

Geriatric Use

Newly added information:

In PsO randomized clinical trials, a total of 138 out of 1965 patients treated with etanercept 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.

Pregnancy

Additions and/or revisions underlined:

Risk Summary

Clinical data are available from the Organization of Teratology Information Specialists (OTIS) Pregnancy Registry in women with rheumatic diseases or psoriasis and a Scandinavian study in pregnant women with chronic inflammatory disease.

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.

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

Medication Guide

Additions and/or revisions underlined:

Risk of Cancer

•             There have been cases of unusual cancers, some resulting in death, in children and teenage patients who started using TNF-blocking agents at less than 18 years of age.

What is ERELZI?

ERELZI is a prescription medicine called a Tumor Necrosis Factor (TNF) blocker. ERELZI is used to treat:

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

•             moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in children ages 2 years and older.

•             psoriatic arthritis (PsA). ERELZI can be used alone or with methotrexate.

•             ankylosing spondylitis (AS).

•            chronic moderate to severe plaque psoriasis (PsO) in adults who may benefit from taking injections or pills (systemic therapy) or phototherapy (ultraviolet light).

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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

01/26/2018 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Malignancies

(Additions and/or revisions are underlined)

Lymphomas

…During the controlled portions of etanercept’s trials in adult patients with RA, AS, and another indication, 2 lymphomas were observed among 3306 etanercept-treated patients versus 0 among 1521 control patients (duration of controlled treatment ranged from 3 to 36 months).

Among 6543 adult rheumatology patients with RA, AS, and another indication treated with etanercept 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…

 

Melanoma and Non-Melanoma Skin Cancer (NMSC)

Among 3306 adult rheumatology (RA, AS, and another indication), patients treated with etanercept in controlled clinical trials representing approximately 2669 patient-years of therapy, the observed rate of NMSC was 0.41 cases per 100 patient-years vs 0.37 cases per 100 patient- years among 1521 control-treated patients representing 1077 patient-years.

6 Adverse Reactions

(Additions and/or revisions are underlined)

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

(Additions and/or revisions are underlined)

…

Adverse Reactions in Adult Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and two other indications

The data described below reflect exposure to etanercept in 2219 adult patients with RA followed for up to 80 months, in 182 patients with another indication for up to 24 months, in 138 patients with AS for up to 6 months, and in 1204 adult patients with another indication for up to 18 months).

 

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.

…

Infections

…

In controlled portions of trials, the types and severity of infection were similar between etanercept and the respective control group (placebo or MTX for patients with RA and another indication) in patients with RA, AS, and two other indications…

In controlled portions of trials in RA, AS, and two other indications, the rates of serious infection were similar…

6.2 Immunogenicity

(Additions and/or revisions are 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 etanercept in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Immunogenicity

Patients with RA, AS, and two other indications treated with etanercept were tested at multiple time points for antibodies to etanercept. Antibodies to the TNF receptor portion or other protein components of etanercept were detected at least once in sera of approximately 6% of adult patients with RA, AS or two other indications…

6.3 Postmarketing Experience

(Additions and/or revisions are underlined)

…

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

8 Use in Specific Populations

8.1 Pregnancy

(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) Pregnancy Registry in women with rheumatic diseases or another indication 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 etanercept once weekly.

…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 etanercept is unknown. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to etanercept 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 another indication 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 etanercept 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 etanercept once weekly (on an AUC basis with maternal subcutaneous doses up to 30 mg/kg/day).

8.2 Lactation

(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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ERELZI and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Etanercept has been studied in 69 children with moderately to severely active polyarticular JIA aged 2 to 17 years.

Etanercept has not been studied in children < 2 years of age with JIA. For pediatric specific safety information concerning malignancies and inflammatory bowel disease. The clinical significance of infant exposure to etanercept in utero is unknown…For pediatric specific safety information concerning vaccinations.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

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

…

Administration of ERELZI

…

When using the Sensoready Pen to administer ERELZI, the patient or caregiver should be informed that the window turns green when the injection is complete. After removing the Sensoready Pen, if the window has not turned green, 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.

Medication Guide

(Additions and/or revisions are underlined)

Other important medical information you should tell your healthcare provider before starting ERELZI, includes if you:

• are breastfeeding or plan to breastfeed. ERELZI can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby while taking ERELZI.

How should I store ERELZI?

If needed, you may store the ERELZI prefilled syringe or pen, at room temperature between 68°F to 77°F (20°C to 25°C) for up to 28 days.