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Clinical Experience
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Collective clinical experience1:

ENBREL experience encompasses:

  • 16 years of collective clinical experience
  • 1.6 million patient-years of experience worldwide across all indications*

*Based on estimated number of patient-years from 1998 through August 2008. Estimated number of patient-years is calculated by region based on the number of ENBREL units distributed and an estimated average dose.

Collective clinical experience: 16 years
1.6 million patient-years of experience worldwide across all indications

Serious adverse events and serious infection rates
comparable to placebo and control across psoriatic
diseases† and rheumatoid arthritis1,2

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  • No overall differences in safety or effectiveness observed between patients 65 years or older and younger patients in RA and psoriasis clinical trials2
    — Because there is a higher incidence of infections in the elderly population
         in general, caution should be used in treating the elderly
†
Psoriatic diseases are comprised of plaque psoriasis and psoriatic arthritis.

‡
Psoriasis clinical trials include one phase 2 and the global and US phase 3 trials; psoriatic arthritis trial is the phase 3 pivotal trial; RA long-term clinical trials include the early RA trial and the long-standing RA trial.

Opportunistic infection rates in randomized controlled trials (RCTs) comparable to control across adult indications1

—

Serious and sometimes fatal infections due to opportunistic pathogens have been reported in patients receiving TNF-blocking agents, including ENBREL

Opportunistic infection rates in both RCTs and open-label extensions (OLEs)§ (events/100 pt-years)1

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  • An opportunistic infection is an infection typically seen only in a host whose resistance is lowered3
  • These rates do not include tuberculosis1
  • In patients receiving TNF-blocking agents, opportunistic infections, including tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis have been reported2
  • In 38 ENBREL clinical trials and 4 cohort studies in all approved indications representing 27,169 patient-years of exposure (17,696 patients) from the United States and Canada, no histoplasmosis infections were reported among patients treated with ENBREL. Nonetheless, postmarketing cases of serious and sometimes fatal fungal infections, including histoplasmosis, have been reported with TNF blockers, including ENBREL. Empiric anti-fungal therapy should be considered for patients at risk for invasive fungal infections who develop severe systemic illness2
§
Included in this analysis were all patients (psoriasis, psoriatic arthritis, RA, and AS) who had received at least one dose of etanercept in double-blind and open-label trials. For the double-blind portion of the RCTs, all events that occurred with onset dates between the first dose and the last dose were included. In the OLEs, all events with onset dates between the first dose and within 30 days after the last dose were included (within 15 days for ex-US studies). Data as of May 2006.1

||
Includes patients who received at least 50 mg QW of ENBREL.

Malignancy rates consistently low
and comparable to the general population1,2

  • 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 and psoriasis patients: the role of TNF inhibitors in the development of malignancies is unknown2,4,5

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  • Rates do not include nonmelanoma skin cancers
    — Of the 1,261 psoriasis patients who received ENBREL during clinical trials,
         22 patients were diagnosed with 23 malignancies.
         Of those, 12 patients were diagnosed with 13 nonmelanoma skin cancers2
    — Among the placebo-treated patients in psoriasis clinical trials, one
         patient was diagnosed with two nonmelanoma skin cancers2
  • In a randomized, placebo-controlled study of 180 patients with Wegener's granulomatosis where ENBREL was added to standard treatment (including cyclophosphamide, MTX, and corticosteroids), patients receiving ENBREL experienced more noncutaneous solid malignancies than patients receiving placebo2
    — The use of ENBREL in patients with Wegener's granulomatosis receiving
         immunosuppressive agents is not recommended.
         The use of ENBREL in patients receiving concurrent cyclophosphamide
         therapy is not recommended2
  • In the ENBREL Psoriatic Arthritis randomized controlled trial, the rates of malignancy were similar to those seen with placebo1
  • FDA is investigating the possible association between TNF blockers and development of lymphoma and other cancers in children and young adults. Currently, FDA believes the potential benefits of the use of TNF blockers outweigh the potential risks in children and young adults having one of the diseases for which the TNF blockers are indicated. Until the evaluation is completed, HCPs, parents, and caregivers should be aware of the possible risk of lymphoma and other cancers in children and young adults.
Data are from clinical trials and includes all SEER-defined cancers (excluding nonmelanoma skin cancers, in situ carcinomas except bladder, and recurrent cancers), and comparisons are based on age- and sex-matched cohorts.

#
Study drug exposure was calculated as the duration from the first dose of study drug to the last dose of study drug.

**
Observed on study or within 30 days after the last etanercept dose. The population for each year reflects all adult patients at the time of analysis who received at least one dose of study drug. Because completion of year milestones by patients is on a rolling basis, the yearly patient number may not reflect the entire cohort.

Tuberculosis reactivation risk suggested to be lower
than TNF-blocking monoclonal antibodies1,2,††

— Based on data from clinical trials and preclinical studies

  • Patients should be evaluated for tuberculosis risk factors and be tested for latent tuberculosis infection prior to initiating ENBREL and during treatment2
  • Postmarketing cases of tuberculosis reactivation have been reported for TNF blockers including ENBREL.

Tuberculosis in randomized controlled trials and open-label extensions


  • As of May 2006, among 20,070 global study patients across indications (28,308 patient-years of treatment), 3 total cases of tuberculosis were reported, all of which were in RA (approximately 0.01%)1,2
    — Of these global study patients, 15,438 were in the US and Canada (23,524 patient-years of treatment), among whom 1 case of tuberculosis was reported (approximately 0.007%)1,2

  • As of August 2007,‡‡ among 25,306 global study patients across indications (34,034 patient-years of treatment), there were 5 total cases of tuberculosis identified (4 cases in RA and 1 case in AS)1

Infections, including serious infections, some fatal, have been observed in patients treated with ENBREL. Tuberculosis has been observed in patients receiving tumor necrosis factor (TNF)-blocking agents, including ENBREL.2

— Discontinue ENBREL if a patient develops a serious infection or sepsis2
— Patients are at increased risk for developing serious infection when taking ENBREL. Most patients who developed these serious infections were taking concomitant immunosuppressants2
‡‡
The data cut was as of August 2007, except for one registry in which the data cut was October 2007.1

††
Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) has been observed in patients receiving TNF-blocking agents, including ENBREL. Tuberculosis may be due to reactivation of latent tuberculosis infection or to new infection. Data from clinical trials and preclinical studies suggest that the risk of reactivation of latent tuberculosis infection is lower with ENBREL than with TNF-blocking monoclonal antibodies. Nonetheless, postmarketing cases of tuberculosis reactivation have been reported for TNF blockers, including ENBREL.
Other Safety Considerations when administering ENBREL:
  • Physicians should exercise caution when using ENBREL in patients who have heart failure, and monitor patients carefully
  • Formation of autoantibodies, and rarely the development of lupus-like syndrome or autoimmune hepatitis, have been reported
    • These may resolve following withdrawal of ENBREL
    • These patients should be evaluated
  • Pregnancy Category B
    • No studies have been conducted in pregnant women2
    • ENBREL should be used during pregnancy only if clearly needed2
  • Concurrent treatment with anakinra and/or cyclophosphamide is not recommended
  • The most common side effects seen in patients were injection site reactions, infections, and headache

References:

1. Data on file, Amgen.
2. Enbrel® (etanercept) Prescribing Information, Immunex Corporation, Thousand Oaks, Calif.
3. Stedman's Medical Dictionary. 28th ed. Baltimore, Md: Lippincott Williams & Wilkins; 2006.
4. Remicade® (infliximab) Prescribing Information, Centocor, Inc., Malvern, Pa.
5. Humira® (adalimumab) Prescribing Information, Abbott Laboratories, Abbott Park, Ill.
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Medication Guide for ENBREL
Please read the Medication Guide for ENBREL.
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IMPORTANT SAFETY INFORMATION

RISK OF 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, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before ENBREL use and periodically during therapy. Treatment for latent infection should be initiated 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. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness, and 3) Bacterial, viral and other infections due to opportunistic pathogens, such as listeriosis.

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 tuberculosis, 3) who have resided or traveled in areas of endemic tuberculosis or endemic mycoses or 4) with underlying conditions that may predispose them to infections such as advanced or poorly controlled diabetes. Patients should be closely monitored 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 prior to initiating therapy.

Neurologic Events
TNF inhibitors, including ENBREL, have been associated with rare cases of new onset or exacerbation of CNS demyelinating disorders (some presenting with mental status changes and some associated with permanent disability). Transverse myelitis, optic neuritis, multiple sclerosis, and cases of new onset or exacerbation of seizure disorders have been observed in association with ENBREL therapy. A causal relationship to ENBREL therapy remains unclear. Exercise caution when considering ENBREL for patients with these disorders.

Hematologic Events
Rare cases of pancytopenia, including aplastic anemia, some fatal, have been reported. A causal relationship to ENBREL therapy remains unclear. Exercise caution 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.

Malignancies
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 and psoriasis patients. The role of TNF inhibitors in the development of malignancies is unknown.

Hepatitis B Reactivation
TNF inhibitors, including ENBREL, have been associated with reactivation of hepatitis B virus (HBV) in chronic carriers of this virus. The majority of these reports occurred in patients on concomitant immunosuppressive agents, which may also contribute to HBV reactivation. Prescribers should exercise caution in prescribing TNF blockers for patients identified as carriers of HBV.

Moderate to Severe Alcoholic Hepatitis
Based on a study of patients treated for alcoholic hepatitis, physicians should use caution when using ENBREL in patients with moderate to severe alcoholic hepatitis.

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

In a JIA study, infection, headache, abdominal pain, vomiting, and nausea occurred more frequently than in adult RA patients in placebo-controlled trials. The types of infections reported in JIA patients were generally mild and consistent with those commonly seen in outpatient pediatric populations.

Please see accompanying Prescribing Information and Medication Guide.

INDICATIONS
Moderate to Severe Rheumatoid Arthritis (RA)
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.

  • In medical studies, ENBREL was shown to be effective in about 2 out of 3 adults with RA who used it, and has been shown to begin working in as few as 2 weeks, with most patients receiving benefit within 3 months. In an RA medical study, 55% of patients had no progression of joint damage.

Moderate to Severe Polyarticular Juvenile Idiopathic Arthritis (JIA)
ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ages 2 and older.

  • In a medical study, ENBREL was shown to be effective in about 3 out of 4 children with JIA who used it. For these JIA patients, ENBREL has been shown to begin working in approximately 2 to 4 weeks.

Psoriatic Arthritis
ENBREL is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis. ENBREL can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

  • In a medical study, ENBREL was shown to be effective in about 50% of psoriatic arthritis patients who used it. Clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy.

Ankylosing Spondylitis (AS)
ENBREL is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

  • In a medical study, ENBREL was shown to be effective in about 3 out of 5 adults with AS who used it. Clinical responses were seen at 2 weeks in 46% of patients, with 59% of patients receiving benefit within 8 weeks.

Moderate to Severe Plaque Psoriasis
ENBREL is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

  • In medical studies, nearly half of patients saw a significant improvement in their plaque psoriasis within 3 months of using ENBREL. Overall, 3 out of 4 patients saw improvement. ENBREL can work fast; many patients saw improvement within 2 months. ENBREL has been shown to be effective through 12 months of therapy.
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