Plaque Psoriasis (PsO) Safety | Enbrel® (etanercept)

Global Psoriasis Pivotal Trial and US Psoriasis Pivotal Trial

Study Design for Global Psoriasis Pivotal Trial

The Global Psoriasis Pivotal Trial was a 48-week, multicenter, double-blind, randomized, phase 3 trial of 611 adult patients with active but clinically stable PsO involving at least 10% of body surface area (BSA) and a minimum Psoriasis Area and Severity Index (PASI) score of 10. 583 patients received at least one dose of study drug and these were the 583 patients included in the primary analysis. Patients were randomized to receive ENBREL 50 mg (n=194), ENBREL 25 mg (n=196), or placebo (n=193) twice weekly (BIW) over 12 weeks. After Week 12, all patients (N=583) received open-label ENBREL 25 mg BIW over 36 weeks. Patients were limited to low- to moderate-strength topical corticosteroids in the axillary, groin, and scalp regions. A post hoc analysis was conducted for an open-label extension (OLE), including 473 patients from the Global Psoriasis Pivotal Trial after completing a minimum of 36 weeks of open-label treatment. Patients in the OLE received ENBREL 50 mg weekly (QW).¹

Primary endpoint: PASI 75 at Week 12²
Select secondary endpoints: PASI 50, PASI 90, percent improvement from baseline PASI, static Physician's Global Assessment (sPGA) of clear or almost clear, and the patient’s global assessment of psoriasis at Weeks 12, 24, and 48^1,2
OLE primary endpoints: The incidence of adverse events, infectious episodes, serious adverse events, serious infectious episodes, injection site reactions, changes from baseline in laboratory values, and presence/absence of an antibody response³
OLE select secondary endpoint: Percent PASI improvement relative to baseline in the parent study³

Global Psoriasis Pivotal Trial^1-3
(N=583)

Global Psoriasis Pivotal Trial on Enbrel® (etanercept)

Selected Baseline Demographics^2,4

Age (median)	45 years
Male	66%
Caucasian	91%
Weight (mean)	194 lb
Body mass index (mean)	30
BSA involvement (mean)	28%
PsO duration (mean)	20 years
PASI (mean)	19

Study Design for US Psoriasis Pivotal Trial

US Psoriasis Pivotal Trial was a two-part, multicenter, phase 3 study consisting of a 24-week double-blind period followed by a 60-week withdrawal and retreatment period. A total of 652 patients with active but clinically stable plaque psoriasis involving at least 10% of BSA and a minimum PASI score of 10. Patients were randomized to receive ENBREL 50 mg BIW (n=164), ENBREL 25 mg BIW (n=162), ENBREL 25 mg weekly (QW, n=160), or placebo (n=166) for 12 weeks. After Week 12, patients in the placebo group began blinded treatment with ENBREL 25 mg BIW.^5,6

At Week 24, patients with 50% PASI improvement from baseline discontinued ENBREL treatment until disease relapse (loss of the 50% PASI improvement that was obtained by Week 24). Upon relapse, patients resumed blinded ENBREL therapy at the same dose they had received from Weeks 13 to 24.⁶

A post hoc analysis was conducted for an OLE, including 439 patients from the US Psoriasis Pivotal Trial after completing a minimum of 60 weeks in the primary study. Patients in the OLE received 50 mg QW for the first 12 weeks followed by a dose escalation to 50 mg BIW for patients with an inadequate clinical response.^1,3

Patients were limited to low- to moderate-strength topical corticosteroids in the axillary, groin, and scalp regions⁵
Primary endpoint: PASI 75 at Week 12⁵
Select secondary endpoints: PASI 50, PASI 90, percent improvement from baseline PASI, sPGA of clear or almost clear, and the patient’s global assessment of psoriasis at Weeks 12, 24, 48, and 72¹
OLE primary endpoints: The incidence of adverse events, infectious episodes, serious adverse events, serious infectious episodes, injection site reactions, changes from baseline in laboratory values, and presence/absence of an antibody response⁶
OLE select secondary endpoint: Percent PASI improvement relative to baseline in the parent study⁶

US Psoriasis Pivotal Trial^1,3,5
(N=652)

US Psoriasis Pivotal Trial on Enbrel® (etanercept)

Selected Baseline Demographics^6,7

Age (mean)	45 years
Male	67%
Caucasian	87%
Weight (mean)	208 lb (86-437 lb)
Body mass index (mean)	31
BSA involvement (mean)	29%
PsO duration (mean)	19 years
PASI (mean)	18

Serious Adverse Event Rates

Serious adverse event rates were similar to control

Exposure-Adjusted Rates⁸

Global Psoriasis Pivotal Trial			US Psoriasis Pivotal Trial
	Placebo (n=193) (events/pt-yr)	ENBREL (n=390) (events/pt-yr)	Placebo (n=166) (events/pt-yr)	ENBREL (n=486) (events/pt-yr)
Malignancy	0.000	0.012	0.029	0.019
Lymphoma	0.000	0.000	0.000	0.000
Serious infection	0.024	0.012	0.057	0.029
Opportunistic infection	0.000	0.000	0.000	0.000

Global Psoriasis Pivotal Trial
	Placebo (n=193) (events/pt-yr)	ENBREL (n=390) (events/pt-yr)
Malignancy	0.000	0.012
Lymphoma	0.000	0.000
Serious infection	0.024	0.012
Opportunistic infection	0.000	0.000

US Psoriasis Pivotal Trial
	Placebo (n=166) (events/pt-yr)	ENBREL (n=486) (events/pt-yr)
Malignancy	0.029	0.019
Lymphoma	0.000	0.000
Serious infection	0.057	0.029
Opportunistic infection	0.000	0.000

Observed Rates^8,9

Global Psoriasis Pivotal Trial			US Psoriasis Pivotal Trial
	Placebo (n=193) (events)	ENBREL (n=390) (events)	Placebo (n=166) (events)	ENBREL (n=486) (events)
Malignancy	0 (no cases)	1 (0.3%)	1 (0.6%)	2 (0.4%)
Lymphoma	0 (no cases)	0 (no cases)	0 (no cases)	0 (no cases)
Serious infection	1 (0.5%)	1 (0.3%)	2 (1.2%)	3 (0.6%)
Opportunistic infection	0 (no cases)	0 (no cases)	0 (no cases)	0 (no cases)

Global Psoriasis Pivotal Trial
	Placebo (n=193) (events)	ENBREL (n=390) (events)
Malignancy	0 (no cases)	1 (0.3%)
Lymphoma	0 (no cases)	0 (no cases)
Serious infection	1 (0.5%)	1 (0.3%)
Opportunistic infection	0 (no cases)	0 (no cases)

US Psoriasis Pivotal Trial
	Placebo (n=166) (events)	ENBREL (n=486) (events)
Malignancy	1 (0.6%)	2 (0.4%)
Lymphoma	0 (no cases)	0 (no cases)
Serious infection	2 (1.2%)	3 (0.6%)
Opportunistic infection	0 (no cases)	0 (no cases)

Important Information About Risks

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including ENBREL⁹
Lymphoma: In clinical trials of all TNF inhibitors, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients; the role of TNF inhibitors in the development of malignancies is unknown^9-11
NMSC: Nonmelanoma skin cancer has been reported in patients treated with TNF antagonists including ENBREL. Among adult psoriasis patients treated with ENBREL (n=1,245) in controlled clinical trials, the observed rate of NMSC was 0.04 events/pt-yr vs 0.01 events/pt-yr among control-treated patients (n=720)⁹
Other malignancies: Other malignancies have been reported during postmarketing for ENBREL and other TNF blockers, including cases of acute and chronic leukemia⁹
Serious infection: Infections, including serious infections, some fatal, have been observed in patients treated with ENBREL. Discontinue ENBREL if a patient develops a serious infection or sepsis. Patients are at increased risk for developing serious infections when taking ENBREL that may lead to hospitalization or death. Most patients who developed these serious infections were taking concomitant immunosuppressants⁹
Opportunistic infection: In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis, have been reported⁹
Tuberculosis (TB): Cases of reactivation of TB or new TB infections have been observed in patients receiving ENBREL. Patients should be evaluated for TB risk factors and be tested for latent TB infection prior to initiating ENBREL and during treatment⁹

BIW, biweekly (twice a week); BSA, body surface area; OLE, open-label extension; PASI, Psoriasis Area and Severity Index; QW, once a week; RA, rheumatoid arthritis; sPGA, static Physician’s Global Assessment; TNF, tumor necrosis factor.

Integrated Safety Analysis

Combined safety from 4 double-blind, placebo-controlled trials and 3 open-label trials

Analysis Overview

An integrated safety analysis from 7 PsO trials evaluated the safety of ENBREL in over 4,400 patients. Data were combined from 4 double-blind, placebo-controlled trials and 3 open-label trials. Patients included in this analysis were ≥18 years of age with moderate to severe plaque psoriasis and had ≥10% BSA involvement at baseline¹²
1,965 patients were included in the short-term, placebo-controlled, double-blinded analysis (12 weeks) for a total of 283 patient-years of ENBREL exposure among 1,245 patients^9,12*
4,410 patients were included in the long-term analysis (up to 144 weeks) for a total of 4,775 patient-years of ENBREL exposure^12†‡
Objective: To determine the safety risk of short- and long-term ENBREL exposure in patients with plaque psoriasis¹²
Safety endpoint: Exposure-adjusted incidence rates^§ and standardized incidence ratio** were calculated for malignancies, infectious adverse events, noninfectious adverse events, and clinically significant events¹²
Safety endpoint: Other adverse events of medical interest included lymphoma, tuberculosis, opportunistic infections, demyelination, and congestive heart failure¹²

*Of the 1,965 patients in the short-term analysis, 160 received ENBREL 25 mg QW, 415 received ENBREL 25 mg BIW, 670 received ENBREL 50 mg BIW, and 720 received placebo.¹²

^†Of the 4,410 patients in the long-term analysis, 501 received ENBREL 25 mg QW or BIW, 3,311 received ENBREL 50 mg BIW with step-down dosing or treatment interruption, and 598 received continuous ENBREL 50 mg BIW therapy.¹²

^‡Includes data from controlled and uncontrolled trials during the short-term analysis.¹²

^§Exposure-adjusted incidence rate = (total adverse events reported)/(total patient exposure) x 100.¹²

**The standardized incidence ratio (SIR) is an estimate of the occurrence of the specified condition in the ENBREL population relative to what might be expected in a larger comparison population designated as normal or average, such as the general population.¹³

Serious Adverse Event Rates Through 3 Years of Treatment

Serious Adverse Event Rates Through 3 Years of Treatment
From 7 PsO Trials That Included 4,410 Patients^12,14-17*

	Year 1 (n=4,410) (events/pt-yr)	Year 2 (n=1,457) (events/pt-yr)	Year 3 (n=1,174) (events/pt-yr)
Malignancy^†	0.007	0.006	0.004
Lymphoma	0.001	0.000	0.000
Serious infection^‡	0.012	0.015	0.006
Opportunistic infection^§**	0.000	0.001	0.000

*Exposure-adjusted rates were based on events per patient-year. Study drug exposure was calculated as the duration from the ﬁrst dose of study drug to the last dose of study drug.¹²

^†Data are from clinical trials and include all SEER-deﬁned cancers (excluding nonmelanoma skin cancers, in situ carcinomas except bladder, and recurrent cancers). SEER (Surveillance, Epidemiology, and End Results) is a database compiled by the National Cancer Institute to collect information on cancer incidence, prevalence, and survival from speciﬁc geographic areas representing 28% of the US population and compile reports on all of these plus cancer mortality for the entire country.^12,18

^‡Serious infections are infectious events that are classiﬁed as serious when any of the following outcomes were associated with the event: hospitalization or intravenous antibiotic therapy use.¹⁹

^§An opportunistic infection is an infection typically seen only in a host whose resistance is lowered.²⁰

**In ENBREL clinical trials, the following types of opportunistic infections were observed: aspergillus (invasive forms only), Candida species (excluding oral or vaginal candidiasis; also includes Torulopsis glabrata), herpes zoster (only systemic or disseminated), Listeria monocytogenes, Mycobacterium tuberculosis, nontuberculosis Mycobacterium, and 1 unknown opportunistic infection. Serious and sometimes fatal infections due to opportunistic pathogens have been reported in patients receiving TNF-blocking agents, including ENBREL.^9,21

These serious adverse event rates were consistent in over 1,100 patients through 3 years of exposure⁹

Malignancy Rates
Malignancy rates across these 7 PsO trials were comparable to the general population (SIR: 1.15; 95% CI: 0.78, 1.64)¹²*

These data come from 7 controlled and uncontrolled psoriasis studies. Safety data include patients who received continuous ENBREL 50 mg BIW therapy. Malignancy rates above do not include nonmelanoma skin cancers and in situ cancers other than bladder cancer. Cases of nonmelanoma skin cancer have been reported in clinical trials and postmarketing experience. Opportunistic infection rates do not include tuberculosis^9,12

These post hoc analysis results are exploratory and no statistical conclusions can be drawn

The most commonly reported adverse events in clinical trials were injection site reaction and infection⁹

Events/patient-year: A rate of 0.007 events/patient-year is equivalent to observing 0.7 malignancies among 100 patients taking study drug continuously for 1 year¹²

*Exposure-adjusted rates were based on events per patient-year. Study drug exposure was calculated as the duration from the first dose of study drug to the last dose of study drug.
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Other Serious Adverse Events
Other serious adverse events from the 7 studies:

2 cases of demyelination were observed (0.0004 events/pt-yr)⁸

7 cases of congestive heart failure were observed (0.001 events/pt-yr)⁸

11 cases of myocardial infarction were observed (0.002 events/pt-yr)12¹²
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Important Information About Risks

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including ENBREL⁹
Lymphoma: In clinical trials of all TNF inhibitors, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients; the role of TNF inhibitors in the development of malignancies is unknown^9-11
NMSC: Nonmelanoma skin cancer has been reported in patients treated with TNF antagonists including ENBREL. Among adult psoriasis patients treated with ENBREL (n=1,245) in controlled clinical trials, the observed rate of NMSC was 0.04 events/pt-yr vs 0.01 events/pt-yr among control-treated patients (n=720)⁹
Other malignancies: Other malignancies have been reported during postmarketing for ENBREL and other TNF blockers, including cases of acute and chronic leukemia⁹
Serious infection: Infections, including serious infections, some fatal, have been observed in patients treated with ENBREL. Discontinue ENBREL if a patient develops a serious infection or sepsis. Patients are at increased risk for developing serious infections when taking ENBREL that may lead to hospitalization or death. Most patients who developed these serious infections were taking concomitant immunosuppressants⁹
Opportunistic infection: In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis, have been reported⁹
Tuberculosis (TB): Cases of reactivation of TB or new TB infections have been observed in patients receiving ENBREL. Patients should be evaluated for TB risk factors and be tested for latent TB infection prior to initiating ENBREL and during treatment⁹

CI, confidence interval; SEER, surveillance, epidemiology, and end results; SIR, standardized incidence ratio.

ENBREL 5-Year Observational Registry (OBSERVE-5)

Real-world safety of ENBREL analyzed in a 5-year observational registry

Study Design

Real-world safety of ENBREL was analyzed in a 5-year observational registry (OBSERVE-5). OBSERVE-5 was a prospective, multicenter, observational surveillance registry evaluating data on long-term safety of ENBREL use in moderate to severe plaque psoriasis.²²

Additional Study Details and Study Schema
OBSERVE-5 was a prospective, multicenter, observational surveillance registry evaluating data on long-term safety of ENBREL use in moderate to severe plaque psoriasis²²

This study was conducted at 375 sites (37 in Canada, 338 in US)²²

Patients received ENBREL at a dose and regimen determined by the investigator in accordance with the ENBREL Prescribing Information (ENBREL 50 mg BIW/QW for US patients).⁹ The registry included patients from Canada, and these patients received a maintenance dosing regimen that was aligned to the Canadian product monograph (ENBREL 50 mg BIW) and may differ from US Prescribing Information maintenance dosing^22,23

Patients were able to:²²

Discontinue ENBREL therapy

Switch to another antipsoriatic therapy

Use other antipsoriatic treatments in combination with ENBREL

Discontinue any or all antipsoriatic treatments

Patients were tracked through 5 years at 6-month intervals²²

Primary endpoint: The occurrence of serious adverse events and serious infectious events²²

Inclusion criteria:²⁴

Patients with moderate to severe plaque psoriasis for whom ENBREL is indicated according to the Prescribing Information

Decision of the treating physician to initiate, reinitiate, or continue ENBREL according to usual care

Obtained appropriate written informed consent prior to any study-specific procedure

2,511 moderate to severe plaque psoriasis patients were administered ENBREL at baseline across 375 study centers in the United States and Canada²²

1,455 (58%) continued in the study until the end of follow-up

164 patients received ENBREL continuously without interruption

182 patients received ENBREL throughout the study with 1- to 30-day gaps*

63 patients received ENBREL throughout the study with 31- to 60-day gaps*

Of patients who experienced gaps in ENBREL treatment, most had only 1 or 2 gaps*

A limitation of this study was a lack of an internal comparator²²

The size and duration of the study may not have been sufficient to detect extremely rare adverse events that may be related to treatment²²

Interpretation of standardized incidence ratios should consider differences in data collection methods, sampling designs, and study populations in a prospective registry vs an administrative claims database compiled for billing purposes²²

Interpretation of safety and effectiveness-related outcomes should take into account the 42% dropout rate, which may lead to an underestimation of safety events and an overestimation of effectiveness if discontinuation was related to these outcomes²²

≥80% of enrolled patients continued their treatment with ENBREL at each time point²²
OBSERVE-5 Study Design^22,23
*Gaps defined as an interruption in treatment.

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Serious Adverse Event Rates Through 5 Years

Cumulative Serious Adverse Event Rates in OBSERVE-5 (n=2,510)^22,23

	Year 1 (1,988 pt-yrs exposure) (events/pt-yr)	Year 2 (1,379 pt-yrs exposure) (events/pt-yr)	Year 3 (1,076 pt-yrs exposure) (events/pt-yr)	Year 4 (884 pt-yrs exposure) (events/pt-yr)	Year 5 (705 pt-yrs exposure) (events/pt-yr)
Other serious adverse events*	0.0581	0.1070	0.1386	0.1771	0.2029
Malignancy^†	0.0033	0.0090	0.0156	0.0230	0.0304
Lymphoma^†	0.0007	0.0007	0.0016	0.0016	0.0016
Serious infection*	0.0184	0.0301	0.0408	0.0467	0.0581
Opportunistic infection^†	0	0	0	0	0

Real-world ENBREL data reported serious adverse event rates through 5 years
similar to adverse event rates from the US Psoriasis Pivotal Trial^25-28

*Primary endpoint

^†Secondary endpoint

Events/patient-year: A serious adverse event rate of 0.0581 events/patient-year is equivalent to observing 5.81 serious adverse events among 100 patients taking study drug continuously for 1 year

Other Adverse Events
Select adverse events of medical interest across 6,167 patient-years of exposure²³*

No cases of opportunistic infections

No cases of histoplasmosis

No cases of coccidioidomycosis

2 cases of tuberculosis

2 cases of lymphoma

*Secondary endpoint
Close

Important Information About Risks

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including ENBREL⁹
Lymphoma: In clinical trials of all TNF inhibitors, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients; the role of TNF inhibitors in the development of malignancies is unknown^9-11
NMSC: Nonmelanoma skin cancer has been reported in patients treated with TNF antagonists including ENBREL. Among adult psoriasis patients treated with ENBREL (n=1,245) in controlled clinical trials, the observed rate of NMSC was 0.04 events/pt-yr vs 0.01 events/pt-yr among control-treated patients (n=720)⁹
Other malignancies: Other malignancies have been reported during postmarketing for ENBREL and other TNF blockers, including cases of acute and chronic leukemia⁹
Serious infection: Infections, including serious infections, some fatal, have been observed in patients treated with ENBREL. Discontinue ENBREL if a patient develops a serious infection or sepsis. Patients are at increased risk for developing serious infections when taking ENBREL that may lead to hospitalization or death. Most patients who developed these serious infections were taking concomitant immunosuppressants⁹
Opportunistic infection: In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis, have been reported⁹
Tuberculosis (TB): Cases of reactivation of TB or new TB infections have been observed in patients receiving ENBREL. Patients should be evaluated for TB risk factors and be tested for latent TB infection prior to initiating ENBREL and during treatment⁹

Pediatric Psoriasis Pivotal Study

Evaluated patients with plaque PsO between 4 and 17 years of age over 48 weeks

Study Design

The Pediatric Pivotal Study was a 48-week, randomized, double-blind, placebo controlled US and Canadian study (parent study) in 211 patients with moderate to severe plaque PsO between 4 and 17 years of age. Patients were randomized in double-blind treatment to receive ENBREL QW (dosing of 0.8 mg/kg up to a maximum dose of 50 mg, n=106) or placebo (n=105) over 12 weeks. After Week 12, all patients (N=208) received open-label ENBREL QW for 24 weeks. After Week 36, patients were re-randomized in double-blind treatment to receive ENBREL QW (n=69) or placebo (n=69) for 12 weeks. The primary study was followed up by a 264-week (5-year; N=182) OLE. All patients in the OLE received ENBREL QW.²⁹

Additional Study Design Details

No loading dose or dose adjustments were made except for those based on weight³⁰
Primary endpoint: PASI 75 at Week 12³¹
Select secondary endpoints: PASI 50, PASI 90, sPGA of clear or almost clear³¹
OLE primary endpoints: Subject incidence of adverse events, including infectious episodes, serious adverse events, and serious infectious episodes³²
OLE secondary endpoints: PASI 50/75/90 and sPGA of clear or almost clear³²
42% of all patients (n=89/211) had a baseline weight of >62.5 kg (>138 lb)³⁰
Of the 89 patients, 47 received the maximum dose of ENBREL 50 mg QW and 42 received placebo QW during the 12-week, randomized, double-blind treatment phase³⁰

Inclusion Criteria^9,31

4-17 years old^9,31

Moderate to severe plaque PsO defined as:

PASI ≥12
Involvement of ≥10% of BSA
sPGA ≥3

Disease duration ≥6 months³¹

Had a history of receiving phototherapy or systemic therapy, or were inadequately controlled on topical therapy

Selected Baseline Demographics^9.33

Age, mean 4-11 years 12-17 years	13 years 36% 64%
Weight, mean (range)	136.3 lb (37.9-371.0 lb)
Height, mean (range)	61.2 in (40.9-75.0 in)
BSA involvement, mean (range)	25% (10.0-95.0)
Previously treated with systemic therapy or phototherapy	57%
Male	51%
Caucasian*	75%
Duration of PsO, mean	6.0 years
PASI, mean (range)	18.5 (12.0-56.7)
PASI, median	16.4

*25% were Black or African American, Hispanic or Latino, Asian, Native Hawaiian or Other Pacific Islander, or Other.³³

The Pediatric Pivotal Study evaluated the safety and efficacy of ENBREL^9,31,32

Pediatric Pivotal Study on the efficacy and safety of Enbrel® (etanercept)

*If PASI score worsened >50% at or after Week 4, patients could receive open-label ENBREL.

^†Patients who did not reach PASI 50 at Week 24 or PASI 75 at Week 36 could discontinue or add low to moderate topical corticosteroids.

^‡Patients who lost PASI 75 resumed open-label ENBREL treatment.

^§At Week 312, n=69.

Adverse Event Rates

No serious adverse event was reported during the 12-week double-blind period³³*
1 subject withdrew from the study during the 12-week double-blind period due to an adverse event³³

Adverse Events in 12-Week
Double-Blind Period
(≥5% and Greater Than Placebo)^31†

Adverse events	Placebo (n=105)	ENBREL (n=106)
Upper respiratory tract infection	11.4%	15.1%
Headache	12.4%	13.2%
Influenza	1.9%	7.5%
Gastroenteritis	0.0%	5.7%

^†An adverse event is any untoward medical event associated with the use of a drug, whether or not it is considered drug-related.

Adverse reaction profile was generally similar to adult PsO

In the 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 PsO⁹
In controlled trials, 7% of pediatric patients treated with ENBREL developed injection site reactions during the first 3 months of treatment⁹

*An adverse reaction is an adverse event for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.

Important Safety Considerations

In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients. The types of infections reported in pediatric patients were generally mild and consistent with those commonly seen in the general pediatric population.

Long-Term Safety

Long-term safety was consistent through 6 years of combined parent and open-label extension studies²⁹
Long-term safety profile for up to 264 additional weeks was assessed in an open-label extension study and no new safety signals were identified⁹

Serious Adverse Event Rates Over 6 Years of Treatment³⁴

	Year 1 (n=181) (events/pt-yr)	Year 2 (n=161) (events/pt-yr)	Year 3 (n=129) (events/pt-yr)	Year 4 (n=111) (events/pt-yr)	Year 5 (n=83) (events/pt-yr)
Malignancy	0.000	0.000	0.000	0.000	0.000
Lymphoma	0.000	0.000	0.000	0.000	0.000
Opportunistic infection	0.000	0.000	0.000	0.000	0.000
Serious infection	0.000	0.000	0.000	0.011	0.013
Other serious adverse events	0.006	0.014	0.008	0.021	0.000

	Year 1 (n=181) (events/pt-yr)	Year 2 (n=161) (events/pt-yr)	Year 3 (n=129) (events/pt-yr)
Malignancy	0.000	0.000	0.000
Lymphoma	0.000	0.000	0.000
Opportunistic infection	0.000	0.000	0.000
Serious infection	0.000	0.000	0.000
Other serious adverse events	0.006	0.014	0.008

	Year 4 (n=111) (events/pt-yr)	Year 5 (n=83) (events/pt-yr)
Malignancy	0.000	0.000
Lymphoma	0.000	0.000
Opportunistic infection	0.000	0.000
Serious infection	0.011	0.013
Other serious adverse events	0.021	0.000

No cases of malignancy, lymphoma, or opportunistic infection were reported among patients treated with ENBREL in the study³⁴*
2 cases of serious infection among 181 pediatric patients treated with ENBREL³¹*

Cellulitis (treatment-related)
Infectious mononucleosis

Other serious adverse events included the following: abortion induced, anxiety, intestinal obstruction, osteonecrosis, and thyroid cyst²¹

*A serious adverse event is one that suggests a significant hazard or side effect, including but not limited to any event that is fatal, life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, is a persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

Important Information About Risks

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including ENBREL⁹
Lymphoma: In clinical trials of all TNF inhibitors, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients; the role of TNF inhibitors in the development of malignancies is unknown^9-11
NMSC: Nonmelanoma skin cancer has been reported in patients treated with TNF antagonists including ENBREL. Among adult psoriasis patients treated with ENBREL (n=1,245) in controlled clinical trials, the observed rate of NMSC was 0.04 events/pt-yr vs 0.01 events/pt-yr among control-treated patients (n=720)⁹
Other malignancies: Other malignancies have been reported during postmarketing for ENBREL and other TNF blockers, including cases of acute and chronic leukemia⁹
Serious infection: Infections, including serious infections, some fatal, have been observed in patients treated with ENBREL. Discontinue ENBREL if a patient develops a serious infection or sepsis. Patients are at increased risk for developing serious infections when taking ENBREL that may lead to hospitalization or death. Most patients who developed these serious infections were taking concomitant immunosuppressants⁹
Opportunistic infection: In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis, have been reported⁹
Tuberculosis (TB): Cases of reactivation of TB or new TB infections have been observed in patients receiving ENBREL. Patients should be evaluated for TB risk factors and be tested for latent TB infection prior to initiating ENBREL and during treatment⁹

Prescription Enbrel^® (etanercept) is administered by injection.

IMPORTANT SAFETY INFORMATION AND INDICATIONS

SERIOUS INFECTIONS

Patients treated with ENBREL are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids or were predisposed to infection because of their underlying disease. ENBREL should not be initiated in the presence of sepsis, active infections, or allergy to ENBREL or its components. ENBREL should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: 1) Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before ENBREL use and periodically during therapy. Initiate treatment for latent infection prior to ENBREL use, 2) 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 antifungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness, and 3) 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 1) with chronic or recurrent infection, 2) who have been exposed to TB, 3) who have resided or traveled in areas of endemic TB or endemic mycoses, or 4) with underlying conditions that may predispose them to infections such as advanced or poorly controlled diabetes. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with ENBREL, including the possible development of TB in patients who tested negative for latent TB prior to initiating therapy.

MALIGNANCIES

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including ENBREL.

In adult clinical trials of all TNF blockers, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients. The role of TNF blocker therapy in the development of malignancies is unknown.

Cases of acute and chronic leukemia have been reported in association with postmarketing TNF blocker use in RA and other indications. The risk of leukemia may be higher in patients with RA (approximately 2-fold) than the general population.

Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF blockers, including ENBREL. Periodic skin examinations should be considered for all patients at increased risk for skin cancer.

Pediatric Patients

In patients who initiated therapy at ≤18 years of age, approximately half of the reported malignancies were lymphomas (Hodgkin's and non-Hodgkin's lymphoma). Other cases included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants.

NEUROLOGIC REACTIONS

Treatment with TNF-blocking agents, including ENBREL, 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-Barré syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with ENBREL therapy. Prescribers should exercise caution in considering the use of ENBREL in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.

NEW ONSET OR WORSENING OF HEART FAILURE

Cases of worsening congestive heart failure (CHF) and, rarely, new-onset cases have been reported in patients taking ENBREL. Caution should be used when using ENBREL in patients with CHF. These patients should be carefully monitored.

HEMATOLOGIC REACTIONS

Rare cases of pancytopenia, including aplastic anemia, some fatal, have been reported. The causal relationship to ENBREL therapy remains unclear. Exercise caution when considering ENBREL in patients who have a previous history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs or symptoms of blood dyscrasias or infection. Consider discontinuing ENBREL if significant hematologic abnormalities are confirmed.

HEPATITIS B REACTIVATION

Reactivation of hepatitis B has been reported in patients who were previously infected with hepatitis B virus (HBV) and received concomitant TNF-blocking agents, including ENBREL. Most reports occurred in patients also taking immunosuppressive agents, which may contribute to hepatitis B reactivation. Exercise caution when considering ENBREL in these patients.

ALLERGIC REACTIONS

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.

IMMUNIZATIONS

Avoid concurrent administration of live vaccines with ENBREL. Patients, if possible, should be brought up to date with all immunizations prior to initiating ENBREL. In patients with exposure to varicella virus, temporarily discontinue ENBREL and consider prophylactic treatment with Varicella Zoster Immune Globulin.

AUTOIMMUNITY

Autoantibodies may develop with ENBREL, and rarely lupus-like syndrome or autoimmune hepatitis may occur. These may resolve upon withdrawal of ENBREL. Stop ENBREL if findings suggestive of lupus-like syndrome or autoimmune hepatitis develop and evaluate the patient.

NOT RECOMMENDED FOR GRANULOMATOSIS WITH POLYANGIITIS PATIENTS ON IMMUNOSUPPRESSANTS

The use of ENBREL in patients with granulomatosis with polyangiitis receiving immunosuppressive agents (eg, cyclophosphamide) is not recommended.

INCREASED MORTALITY IN PATIENTS WITH MODERATE TO SEVERE ALCOHOLIC HEPATITIS

Based on a study of patients treated for alcoholic hepatitis, exercise caution when using ENBREL in patients with moderate to severe alcoholic hepatitis.

ADVERSE REACTIONS

The most commonly reported adverse reactions in RA clinical trials were injection site reaction and infection. In clinical trials of all other adult indications, adverse reactions were similar to those reported in RA clinical trials.

DRUG INTERACTIONS

The use of ENBREL in patients receiving concurrent cyclophosphamide therapy is not recommended. The risk of serious infection may increase with concomitant use of abatacept therapy. Concurrent therapy with ENBREL and anakinra is not recommended. Hypoglycemia has been reported following initiation of ENBREL therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

Please see Prescribing Information and Medication Guide.

INDICATIONS

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. ENBREL can be initiated in combination with methotrexate (MTX) or used alone.

ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.

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. ENBREL can be used with or without MTX.

ENBREL is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

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.

ENBREL is indicated for the treatment of active juvenile psoriatic arthritis in pediatric patients 2 years of age and older.

Prescription Enbrel^® (etanercept) is administered by injection.

IMPORTANT SAFETY INFORMATION AND INDICATIONS

SERIOUS INFECTIONS

Patients treated with ENBREL are at increased risk for developing serious infections that may lead to

References:

Data on file, Amgen; CSR 1642. October 8, 2003.
Papp KA, Tyring S, Lahfa M, et al; for the Etanercept Psoriasis Study Group. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005;152:1304-1312.
Data on file, Amgen; CSR 115. November 28, 2005.
Data on file, Amgen; CSR 1642. May 29, 2003.
Leonardi CL, Powers JL, Matheson RT, et al; for the Etanercept Psoriasis Study Group. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349:2014-2022.
Gordon KB, Gottlieb AB, Leonardi CL, et al. Clinical response in psoriasis patients discontinued from and then reinitiated on etanercept therapy. J Dermatolog Treat. 2006;17:9-17.
Data on file, Amgen; CSR 1639. June 11, 2003.
Data on file, Amgen; Safety Data Verification Memo. October 11, 2013.
Enbrel^® (etanercept) Prescribing Information. Thousand Oaks, CA: Immunex Corporation.
HUMIRA (adalimumab) Prescribing Information. North Chicago, IL: AbbVie Inc.; 2021.
REMICADE (inﬂiximab) Prescribing Information. Horsham, PA: Janssen Biotech, Inc.; 2021.
Pariser DM, Leonardi CL, Gordon K, et al. Integrated safety analysis: short- and long-term safety profiles of etanercept in patients with psoriasis. J Am Acad Dermatol. 2012;67(2):245-256.
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Data on file, Amgen; Exposure-adjusted Rate of OI. October 5, 2010.
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Moreland LW, Weinblatt ME, Keystone EC, et al. Etanercept treatment in adults with established rheumatoid arthritis: 7 years of clinical experience. J Rheumatol. 2006;33(5): 854-861.
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Data on file, Amgen; Safety Information Amendment. August 1, 2006.
Kimball AB, Rothman KJ, Kricorian G, et al. OBSERVE-5: observational postmarketing safety surveillance registry of etanercept for the treatment of psoriasis final 5-year results. J Am Acad Dermatol. 2015;72(1):115-122.
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Data on file. Amgen CSR 20040210. November 13, 2013.
Jain S, Self WH, Wunderink RG; CDC EPIC Study Team. Community-acquired pneumonia requiring hospitalization. N Engl J Med. 2015;373(5):415-427.
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Raff AB, Kroshinsky D. Cellulitis: a review. JAMA. 2016;316(3):325-337.
Yawn BP, Gilden D. The global epidemiology of herpes zoster. Neurology. 2013;81(10):928-930.
Paller AS, Siegfried EC, Pariser DM, et al. Long-term safety and efficacy of etanercept in children and adolescents with plaque psoriasis. J Am Acad Dermatol. 2016;74(2): 280-287.e1-3.
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Moderate to SeverePlaque Psoriasis

Safety Data

Global Psoriasis Pivotal Trial and US Psoriasis Pivotal Trial

Global Psoriasis Pivotal Trial1-3 (N=583)

Selected Baseline Demographics2,4

US Psoriasis Pivotal Trial1,3,5 (N=652)

Selected Baseline Demographics6,7

Exposure-Adjusted Rates8

Observed Rates8,9

Important Information About Risks

Integrated Safety Analysis

Analysis Overview

Serious Adverse Event Rates Through 3 Years of Treatment From 7 PsO Trials That Included 4,410 Patients12,14-17*

Important Information About Risks

ENBREL 5-Year Observational Registry (OBSERVE-5)

Study Design

OBSERVE-5 Study Design22,23

Cumulative Serious Adverse Event Rates in OBSERVE-5 (n=2,510)22,23

Real-world ENBREL data reported serious adverse event rates through 5 years similar to adverse event rates from the US Psoriasis Pivotal Trial25-28

Important Information About Risks

Pediatric Psoriasis Pivotal Study

Study Design

Inclusion Criteria9,31

Selected Baseline Demographics9.33

Adverse Events in 12-Week Double-Blind Period (≥5% and Greater Than Placebo)31†

Important Safety Considerations

Serious Adverse Event Rates Over 6 Years of Treatment34

Important Information About Risks

Global Psoriasis Pivotal Trial^1-3
(N=583)

Selected Baseline Demographics^2,4

US Psoriasis Pivotal Trial^1,3,5
(N=652)

Selected Baseline Demographics^6,7

Exposure-Adjusted Rates⁸

Observed Rates^8,9

Serious Adverse Event Rates Through 3 Years of Treatment
From 7 PsO Trials That Included 4,410 Patients^12,14-17*

OBSERVE-5 Study Design^22,23

Cumulative Serious Adverse Event Rates in OBSERVE-5 (n=2,510)^22,23

Real-world ENBREL data reported serious adverse event rates through 5 years
similar to adverse event rates from the US Psoriasis Pivotal Trial^25-28

Inclusion Criteria^9,31

Selected Baseline Demographics^9.33

Adverse Events in 12-Week
Double-Blind Period
(≥5% and Greater Than Placebo)^31†

Serious Adverse Event Rates Over 6 Years of Treatment³⁴