Review ENBREL’s safety data in treating patients with moderate to severe plaque psoriasis (PsO)
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
| 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 |
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
| 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 |
| 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 |
| 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) |
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.
Combined safety from 4 double-blind, placebo-controlled trials and 3 open-label trials
*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
| 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
*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.
Other serious adverse events from the 7 studies:
CI, confidence interval; SEER, surveillance, epidemiology, and end results; SIR, standardized incidence ratio.
Real-world safety of ENBREL analyzed in a 5-year observational registry
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
*Gaps defined as an interruption in treatment.
| 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 |
*Primary endpoint
†Secondary endpoint
Select adverse events of medical interest across 6,167 patient-years of exposure23*
*Secondary endpoint
Evaluated patients with plaque PsO between 4 and 17 years of age over 48 weeks
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
| 4-17 years old9,31 |
Moderate to severe plaque PsO defined as:
|
| Disease duration ≥6 months31 |
| Had a history of receiving phototherapy or systemic therapy, or were inadequately controlled on topical therapy |
Age, mean
|
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 ENBREL9,31,32
*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 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
*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.
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.
| 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) | Year 6 (n=63) (events/pt-yr) | |
|---|---|---|---|---|---|---|
| Malignancy | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| Lymphoma | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| Opportunistic infection | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| Serious infection | 0.000 | 0.000 | 0.000 | 0.011 | 0.013 | 0.000 |
| Other serious adverse events | 0.006 | 0.014 | 0.008 | 0.021 | 0.000 | 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) | Year 6 (n=63) (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 | 0.011 | 0.013 | 0.000 |
| Other serious adverse events | 0.021 | 0.000 | 0.000 |
*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.
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.
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.
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 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
Patients treated with ENBREL are at increased risk for developing serious infections that may lead to
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