0311-'00
`issue Date 11/1998
`
`ENBREL“
`(etanercept)
`
`
`
`
`
`
`
`DESCRIPTION
`
`ENBREL (etanercept) is a dimeric fusion protein consisting of the extracellular ligand—binding portion of the human
`75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human lgG1. The Fc component of
`etanercept contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgG1. Etanercept is
`produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It
`consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons.
`ENBREL is supplied as a sterile, white, preservative—free, lyophilized powder for parenteral administration after
`reconstitution with 1 mL of the supplied Sterile Bacteriostatic Water for lniection, USP (containing 0.9% benzyl alcohol).
`Following reconstitution, the solution of ENBHEL is clear and colorless, with a pH of 7.4 : 0.3. Each single-use vial of
`ENBREL contains 25 mg efanercept, 40 mg mannitol. 10 mg sucrose, and 1.2 mg tromethamine.
`CLINICAL PHARMACOLOGY
`General
`
`receptors.
`Etanercept binds specifically to tumor necrosis factor (TNF) and blocks its interaction with cell surface
`TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. it plays an
`important role in the inflammatory processes of rheumatoid arthritis (RA) and the resulting joint pathology.‘ tlevareo *
`levels of TNF are found in the synovial fluid of RA patients?
`K
`Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a.7__5 kilodalton protein (p75), exist naturally
`as monomeric molecules on cell surfaces and in soluble forms? Biological activity of TNF is dependent upon binding to
`either cell surface TNFR.
`
`-V
`
`Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind to two TNF molecules. It inhibits the
`activity of TNF in vitro and has been shown to affect several animal models of inflammation, including munne collagen-
`induced arthritis.” Etanercept inhibits binding of both TNFor and TNFB (lymphotoxin alpha [LTor]) to cell surface
`TNFRs, rendering TNF biologically inactive? Cells expressing transmembrane TNF that bind ENBREL are not lysed in
`vitro in the presence or absence of complement?
`
`Etanercept can also modulate biological responses that are induced or regulated by TNF, including expression of
`adhesion molecules responsible for leukocyte migration (i.e., E—se|ectin and to a lesser extent intercellular adhesion
`molecule-1 [ICAM-1]), serum levels of cytokines (e.g., ILA6), and serum levels of matrix metalloproteinase-3 (MMP-3
`or stromelysin).5
`Pharmacokinetics
`
`After administration of 25 mg of ENBREL by a single subcutaneous (SC) injection to three patients with RA, a median
`half—life of 115 hours (range 98 to 300 hours) was observed with a clearance of 89 mL/hr (52 mL/hr/m2). A maximum
`serum concentration (Cmax) of 1.2 mcg/mL (range 0.6 to 1.5 mcg/mL) and time to Cmax of 72 hours (range 48 to 96
`hours) was observed in these patients. After continued dosing of RA patients (N = 25) with ENBREL for 6 months with
`25 mg twice weekly, the median observed level was 3.0 mcg/mL (range 1.7 to 5.6 mcg/mL). Based on the available data,
`individual patients may undergo a two— to five—lold increase in serum levels with repeated dosing. Serum concentrations
`in patients with RA have not been measured for periods of dosing that exceed 6 months.
`Pharmacokinetic parameters were not different between men and women and did not vary with age in adult or pediatric
`patients. No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment
`or interactions with methotrexate.
`_
`
`Pediatric patients with JHA (ages 4 to 17 years) were administered 0.4 mg/kg of ENBREL for up to 18 weeks. The
`average serum concentration after repeated dosing was 2.1 mcg/mL, with a range of 0.7 to 4.3 mcg/mL. Clearance of
`ENBREL was 45.9 mt./hr/m2.
`
`CLINICAL STUDIES
`
`The safety and efficacy of ENBREL were assessed intwo randomized, double—blind, placebo-controlled studies.
`Study l evaluated 234 patients with active RA who were 2 18 years old, had failed therapy with at least one but no more
`than four disease—modifying antirheumatic drugs (DMARDs; e.g., hydroxychloroquine, oral or iniectable gold,
`methotrexate, azathioprine, D-penicillamine, sulfasalazine), and had 3 12 tender loints. > 10 swollen ioints. and either
`
`APOTEX EX1047
`
`Page 1
`
`APOTEX EX1047
`
`Page 1
`
`

`
`
`
`ENBREL” (etanercept)
`
`ESR 2 28 mm/hour, CRP > 2.0 mg/dL, or morning stiffness for 2 45 minutes. Doses of 10 mg or 25 mg ENBREL or
`placebo were administered SC twice a week for 6 consecutive months. Study ll evaluated 89 patients with similar
`inclusion criteria to Study l except that subjects in Study II had additionally received mettiotrexate for at least 6 months
`with a stable dose (12.5 to 25 mg/wk) for at least 4 weeks and they had at least 6 tender or painful joints. Subjects in
`study It received a dose of 25 mg ENBREL or placebo SC twice a week for 6 months in addition to their stable
`methotrexate dose.
`
`3 0500.7, ENBREL vs ciacebo
`
`stud, ||
`P|acebolMTX ENBREL/MTX'
`N = 30
`N = 59
`
`Study i
`Placebo
`ENBREL‘
`N = so
`N = 73
`0/ 0, mm
`23%
`62,,“
`11%
`59%.,
`
`8%
`5%
`
`41%:
`40%s
`
`& 25 my ENBREL SC mm? mm
`
`Time course of Act! 20 Responses
`
`-----o----- Placebo, Study l (placebo alone)
`----4----- Placebo, Study ll (placebo + MTX)
`——-u——— 25mg ENBREL, Study I (ENBREL Jlone)
`-—I—-— 25mg ENBREL, study It (ENBREL + MTX)
`
`
`
`
`
` Percent
`Responding Month of Study
`
`Components of ACE Response in Study I
`Placebo
`N = 80
`
`ENBREL‘
`N = 78
`
`
`
`
`3Months'
`
`10.0’
`
`12.6’
`3.0‘
`30‘
`24,
`.
`
`
`
`
`
`
`Number of tender joints“
`
`Number of swollen joints‘
`Physician global assessment‘
`Patient global assessment“
`P _
`4
`ain
`
`34.0
`
`24.0
`70
`7.0
`69
`.
`
`29.5
`
`22.0
`6.5
`7.0
`66
`.
`
`31.2
`
`23.5
`70
`7.0
`69
`.
`
`
`
`
`
`
`
`
`
`
`
`32.0
`3.9
`
`28.0
`3.5
`
`15.5‘
`0.9’
`
`31.0
`ESR (mm/hour)
`2.8
`CRP (mg/dL)
`’ Results at 6 months showed similar improvement.
`a. 25 mg ENBREL SC twice weelrly
`tr. Scale 0-71.
`c. Scale 0-65.
`d Visual analog scale," 0 = best, 10 = worst
`e. Health assessment questionnaire,‘ 0 = best, 3 : worst,’ includes eight categories.’ dressing and
`grooming, arising, eating, walking, hygiene, reach, grip, and activities.
`l p < 0.07, ENBREL vs placebo, based on mean percent change from baseline.
`
`
`
`
`
`
`
`
`
`
`
`
`Page 2
`
`The results of the controlled trials were expressed in percentage improvement in RA using American College of
`Rheumatology (ACR) response criteria. The primary endpoint of Study l was achievement of an ACR 20 response at
`month 3. Subjectswho tai led to respond based on prespecified criteria for lack of efficacy before month 3 were allowed to
`drop out early and were considered treatment failures. For Study ii, the primary endpoint was achievement of an ACR 20
`response at month 6. By definition, an
`AC8 20 response is achieved it a patient
`experiences a 20% improvement in their
`tend” ‘NT °.°””' a”d 5w°."e“ jomt C°“”‘
`plus 2 20 /o improvement in at least three
`of the following five criteria: (1) patient
`pain assessment, (2) patient global
`assessment, (3) physician global
`assessment, (4) patient self—assessed
`disability. and (5) acute-phase reactant
`(ESR or CRP).6 ACR 50 and 70 responses
`are defined using the same criteria with a
`50% improvement or a 70°/
`im rovement
`0
`9
`respectively.
`Responses were higher in patients
`treated with ENBREL at 3 and 6 months in
`both trials. The results of the two trials are
`summarized in the table titled ACR
`Responses.
`In both studies, approximately l5’./s ct
`subjects who received ENBREL achieved
`an ACR 70 response at month 3 and
`month 6 compared to fewer than 5% of
`subjects in the placebo arms.
`The time course for ACR 20 response
`rates for patients receiving placebo or
`25 mg ENBREL in the two trials is
`summarized in the graph titled Time
`Course of ACR 20 Responses.
`Among patients receiving ENBREL, the
`c ‘nical responses generally appeared
`wthin 1 to 2 weeks after initiation of
`tterapy and nearly always occurred by 3
`rronths. A dose response was seen in
`Study l; results with 10 mg were
`irtermediate between placebo and 25 mg.
`ENBREL was significantly better than
`pacebo in all components of the ACR
`criteria as well as other measures of RA
`dsease activity not included in the ACH
`sponse criteria, such as morning
`tiffness. A Health Assessment
`Qjesnonnaire (HA0) 7 which included
`dsabimy Vnamy mama] health genera‘
`'
`'
`.
`.
`'
`.
`health status, and arthritis—associated
`h
`1 h t
`I
`.
`V
`
`Parameter (median)
`
`Baseline
`
`3Months
`
`Baseline
`
`
`
`
`
`
`
`~
`
`
`
`
`
`s
`
`g
`y
`trial. All subdomains of the HAO were
`improved in patients treated with ENBREL
`compared to controls at 3 and 6 months.
`The table titled Components of ACR
`Response in Study l shows the results of
`the components of the ACR response
`criteria for Study l. Findings were similar
`in Study ll.
`
`Page 2
`
`

`
`
`
`ENBREL" (etanercept)
`
`An additional randomized, controlled, double-blind trial evaluated 180 patients with similar criteria to Study I.“ Doses
`of 0.25 mg/mg," 2 mg/m2 and i6 mg/mz ENBFtEL‘were administered 80 twice a week for 3 consecutive months. A dose-
`dependent increase in the proportion of subjects achieving an ACR 20 response was seen, with 75% of subjects
`responding in the highest dose group (16 mg/m2 ENBREL).
`After discontinuation of ENBREL, symptoms of arthritis generally returned within a month. Reintroduction of treatment
`with ENBREL after discontinuations of up to 18 months resulted in the same magnitudes of response as patients who
`received ENBREL without interruption of therapy based on results of open-label studies. Continued durable’ responses
`have been seen for up to 18 months in open-label extension treatment trials when’ patients received ENBREL without
`interruption.
`lmmunogenicity
`Patients were tested at multiple timepoints for antibodies to ENBREL. Antibodies to ENBREL, all non-neutralizing, were
`detected at least once in sera of 16% of rheumatoid arthritis patients. No apparent correlation of antibody development to
`clinical response or adverse events was observed. The long—lerm immunogenicity of ENBREL is unknown.
`
`INDICATIONS AND USAGE
`ENBREL is indicated for reduction in signs and symptoms of moderately to severely active rheumatoid arthritis in
`patients who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMAROS).
`ENBREL can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.
`
`CONTRAINDICATIONS
`ENBREL should not be administered to patients with sepsis or with known hypersensitivity to ENBREL or any of its
`components.
`
`
`
`WARNINGS
`Administration of ENBREL should be discontinued if a patient develops a serious infection (see ADVERSE
`REACTIONS, Infections).
`
`
`
`PRECAUTIONS
`General
`
`Allergic reactions associated with administration of ENBREL during clinical trials have been reported rarely (< 0.5%).
`Anaphylaxis has not been observed. if an anaphylactic reaction or other serious allergic reaction occurs. administration of
`ENBREL should be discontinued immediately and appropriate therapy initiated.
`'“
`Information to Patients
`
`if a patient is to seli—administer ENBREL, they should be instructed in injection techniques to ensure the safe self-
`administration of ENBREL. (See How to Use ENBREL, Instructions for Preparing and Givi_n_g an injection.) The
`first injection should be performed under the supervision of a qualified health care professional. The ability of that patient
`to self—inject subcutaneously should be assessed. A puncture—resistant container for disposal of needles and syringes
`should be used. Patients should be instructed in the technique and told the importance of proper syringe and needle
`disposal, and be cautioned against reuse of these items
`immunosuppression
`The possibility exists for anti-TNF therapies, including ENBREL, to affect host defenses against infections and
`malignancies since TNF mediates inflammation and modulates cellular immune responses. in a study of 49 patients with
`RA treated with ENBREL, there was no evidence of depression of delayed-type hypersensitivity, depression of
`immunoglobulin levels, or change in enumeration of effector cell populations. The impact of treatment with ENBREL on
`the development and course of malignancies and infections is not fully understood (see ADVERSE REACTIONS,
`Infections and Malignancies). The safety and efficacy of ENBREL in patients with immunosuppression or chronic
`infections have not been evaluated.
`Vaccinations
`
`No data are available on the effects of vaccination in patients receiving ENBREL. Live vaccines should not be given
`concurrently with ENBREL. No data are available on the secondary transmission of infection by live vaccines in patients
`receiving ENBREL (see PRECAUTIONS, immunosuppression).
`Autoantihody Formation
`Treatment with ENBREL may result in the formation of autoimmune antibodies (see ADVERSE REACTIONS.
`Autoantibodies).
`Drug Interactions
`Specific drug interaction studies have not been conducted with ENBREL.
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`Long—term animal studies have not been conducted to evaluate the carcinogenic potential of ENBREL or its effect on
`fertility. Mutagenesis studies were conducted in vitro and in vivo, and no evidence of mulagenic activity was observed.
`Pregnancy (Category B)
`Developmental toxicity studies have been performed in rats and rabbits at doses ranging from 60- to 100-fold higher
`than the human dose and have revealed no evidence of harm to the fetus due to ENBREL. There are, however, no studies
`in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should
`be used during pregnancy only it clearly needed.
`Nursing Mothers
`It is not known whether ENBREL is excreted in human milk or absorbed systemically after ingestion. Because many
`
`Page 3
`
`Page 3
`
`

`
`
`
`ENBREL“ (etanercept)
`
`
`
`drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in
`nursing infants from ENBREL. a decision should be made whether to discontinue nursing or to discontinue the drug.
`Geriatric Use
`A total of 123 RA patients ages 65 years or older have been studied in clinical trials. No overall differences in safety or
`effectiveness were observed between these patients and younger patients. Greater sensitivity of some older individuals
`cannot be ruled out.
`.
`Pediatric Use
`in the open-label part of a two-part trial, 69 patients with polyarticular course ,iRA ages 4 to 17 years, who were
`refractory to or intolerant of methotrexate and had moderately to severely active~JRA, were administered 0.4 mg/kg
`(maximum 25 mg dose) of ENBREL SC twice weekly for 3 months. Of 54 patients for whom 3-month treatment data were
`available, 76% demonstrated a clinical response measured by the JRA Definition of improvement. The JRA Definition of
`improvement is defined as 2 30% improvement in at least three oi six and 2 30% worsening in no more than one of six
`JRA core set criteria, which include physician and patient global assessments, active ioint count, limitation of motion,
`functional assessment, and ESR?
`Of 69 JRA patients for whom safety data were available, the safety profile was similar to that seen in adult RA patients
`treated with ENBREL. However, the percent of JRA patients reporting abdominal pain (17%) and vomiting (14.5%) was
`higher than in adult RA. While receiving ENBREL, two JRA patients developed varicella infection associated with signs and
`symptoms of aseptic meningitis; the infection resolved without sequelae. It is recommended that patients with a significant
`exposure to varicella virus temporarily discontinue ENBREL therapy and treatment with varicella Zoster immune Globulin
`be considered.
`it is recommended that JRA
`Responses to immunizations have not been studied in children receiving ENBREL.
`patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines
`prior to initiating ENBREL therapy.
`The safety of ENBREL has not been studied in children < 4 years of age.
`
`ADVERSE REACTIONS
`ENBREL has been studied in 1039 patients with RA. In controlled studies, 349 patients received ENBREL and 152
`patients received placebo. The proportion of patients who discontinued treatment due to adverse events was the same in
`both the ENBREL and placebo treatment groups (4%)
`injection site reactions
`in controlled trials, 37% of patients treated with ENBREL developed injection site reactions. All injection we reactions
`were described as mild to moderate (erythema and/or itching, pain, or swelling) 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. Seven percent of patients experienced redness at a
`previous injection site when subsequent injections were given.
`.-
`infections
`‘
`Upper respiratory iniections (“colds") and sinusitis were the most frequently reported infections in patients receiving
`ENBREL or placebo. in placebo-controlled trials, the incidence of upper respiratory tract infections was 16% in the
`placebo treatment group and 29% in the group treated with ENBREL. 068 events per patient year in the placebo group
`and 082 events per patient year in the group treated with ENBREL when the longer observation of patients on ENBREL
`was accounted for.
`in placebo-controlled trials evaluating ENBREL, no increase in the incidence of serious infections was observed (1.3%
`placebo, 0.9% ENBREL).
`in open-label and placebo-controlled trials, 22 serious infections were observed in a total of
`745 subiects exposed to ENBREL, including: pyelonephritis, bronchitis, septic arthritis, abdominal abscess, cellulitis,
`osteomyelitis, wound infection, pneumonia, foot abscess, leg ulcer, diarrhea, sinusitis, and sepsis. Data from a sepsis
`clinical trial not specifically in patients with RA suggest that ENBREL treatment may increase mortality in patients with
`established sepsis.”
`Malignancies
`Seven new malignancies of various types were observed in 745 RA patients treated in clinical trials with ENBREL for
`up to 18 months. The observed rates and incidences were similar to those expected for the population studied.
`Autoantihodies
`Patients had serum samples tested for autoantibodies at multiple timepoints. Of the patients evaluated for antinuclear
`antibodies (ANA), the percentage of patients who developed new positive ANA (21:40) was higher in patients treated
`with ENBREL (ii%) than in placebo—treated patients (5%). The percentage of patients who developed new positive
`anti-double—stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with ENBREL
`compared to 4% of placebo—treated patients) and by crithidia lucilae assay (3% of patients treated with ENBREL
`compared to none of placebo—treated patients). The proportion of patients treated with ENBREL who developed
`anticardiolipin antibodies was similarly increased compared to placebo—treated patients. No patients developed clinical
`signs suggestive of a lupus-like syndrome or other new autoimmune diseases. The impact of long—term treatment with
`ENBREL on the development of autoimmune diseases is unknown.
`Other Adverse Reactions
`.
`Events reported in at least 3% of all patients with higher incidence in patients treated with ENBREL compared to
`controls in placebo-controlled RA trials (including the combination methotrexate trial) and events per patient year are
`summarized in the next table.
`Among patients with rheumatoid arthritis treated in controlled trials, serious adverse events occurred at a frequency of
`
`Page 4
`
`Page 4
`
`

`
`
`
`ENBIIEL” (etanercept)
`
`
`
`Percent of RA Patients Reporting Adverse Events
`
`and Events per Patient Year in Placebo-Controlled Clinical Trials‘
`Events per patient year
`Percent of patients
`Placebo
`ENBREL
`Placebo
`ENBREL
`
`Event
`(n =152)
`(n = 349)
`(40 pt years)
`(117 of years)
`
`
`
`4% in 349 patients treated with
`ENBREL compared to 5% of 152
`placebo—treated patients. Among
`rheumatoid arthritis patients in
`COmml|gd and op3n.jabej mats of
`
`ENBRELI malignancies (599
`ADVERSE REACTIONS,
`Malignancies) and infections
`(see ADVERSE REACTIONS,
`Intentions) Wm me most
`,
`common serious adverse events
`observed. Other infrequent serious
`adverse events observed included:
`heart failure, myocardial infarction,
`myocardial ischemia, cerebral
`iscliemia. hypertension
`hypotension, cholecystitis,
`iiancrealilis. gastrointestinal
`hemorrhage. bursitis, depression,
`and dyspnea.
`
`f
`D I
`I d d
`036 0
`8 maximum 0 era 8
`ENBREL has not been established in
`
`10
`32
`
`37
`as
`
`,.
`
`' 4
`
`0.62,
`ice‘
`
`7.73
`1.32
`
`injection site reaction
`Infection
`_N°“'l_ii’P§f IBSPWOIY
`15°
`“54
`38
`_, 32
`.
`'”'e°"°”
`.
`.
`,
`0.82
`0.68
`29
`16
`Upper respiratory iniection
`068
`0.62
`17
`13
`Headache
`0.45
`0.35
`12
`8
`Rhmms
`O21
`O25
`7
`5
`Dmess
`024
`0.17
`7
`5
`pharyngitis
`0,8
`0.1,
`5
`3
`Cough
`0,5
`010
`5
`3
`Asmema
`0.17
`0.12
`5
`3
`Pall), abdomen
`(121
`012
`5
`3
`R35),
`0.17
`0.05
`5
`I
`Respiratory disorder
`0.12
`ms
`4
`1
`DYSDeDSla
`
`sinusitis 0.12 2 3 0.07
`
`
`
`' includes data from the 6—nranIh study in which patients received concurrent rnethotrexate therapy
`
`''lrrc/odes data tramtwo atthethreecontrolledtrials
`
`
`
`
`
`
`humans Toxicology studies have been performed in monkeys at doses up to 30 times the human dose with no evidence of
`dose—limiting toxicities. No dose-limiting toxicities have been observed during clinical trials of ENBREL. Single IV doses
`up to 60 mg/m2 have been administered to healthy volunteers in an endotoxemia study without evidence of dose~limiting
`toxicities. The highest dose level evaluated in RA patients has been a single IV loading dose of 32 mg/m2 followed by SC
`doses of 16 mg/m2 (~25 mg) administered twice weekly. In one RA trial, one patient mistakeiily self—administereo 62 mg
`». ..
`ENBREL SC twice weekly for 3 weeks without experiencing adverse effects.
`
`DOSAGE AND ADMINISTRATION
`
`The recommended dose of ENBREL for adult patients with rheumatoid arthritis is 25 mg given twice weekly as a
`subcutaneous injection (see Clinical Studies). Melhotrexate, glucocorticoids, salicylates, nonsteroidal anti-
`intlammatory drugs (NSAlDs), or analgesics may be continued during treatment with ENBREL. Higher doses of ENBREL
`have not been studied. See PRECAUTIONS, Pediatric Use for experience in pediatric populations.
`Preparation of ENBREL
`
`ENBREL is intended for use under the guidance and supervision of a physician. Patients may se|t—inject only if their
`physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in injection
`technique.
`-
`
`Note: The needle cover of the diluent syringe contains dry natural rubber (latex), which should not be
`handled by persons sensitive to this substance.
`
`ENBREL should be reconstituted aseptically with 1 mL of the supplied Sterile Bacteriostatlc Water for Injection, USP
`(0.9% benzyl alcohol). During reconstitution of ENBREL, the diluent should be m injected into the vial. Some
`foaming will occur. To avoid excessive foaming, do not shake or vigorously agitate. The contents should be swirled gently
`during dissolution. Generally, dissolution of ENBREL takes less than 5 minutes. The reconstituted solution should be
`clear and colorless.
`
`Visually inspect the solution for particulate matter and discoloration prior to administration. The solution should not be
`used if discolored or cloudy, or if particulate matter remains. Withdraw the solution into the syringe, removing as much
`liquid as possible from the vial Some foam or bubbles may remain in the vial. The final volume in the syringe will be
`approximatelyl mL.
`.
`
`No other medications should be added to solutions containing ENBREL, and ENBREL should not be reconstituted with
`other diluents. Do not filter reconstituted solution during preparation or administration.
`Sites for self-injection include thigh, abdomen, or upper arm. Injection sites should be rotated. New injections should
`be given at least one inch from an old site and never into areas where the skin is tender, bruised, red, or hard. (See How
`to Use ENBFIEL, Instructions for Preparing and Giving an Injection instruction sheet.)
`Storage and Stability
`1
`Do not use a dose tray beyond the date stamped on the canon or vial label. The dose tray containing ENBREL (sterile
`powder) must be refrigerated at 2-8°C l36~46°F). DO NOT FREEZE.
`Reconstituted solutions of ENBREL should be administered as soon as possible after reconstitution. If not administered
`immediately aiief ’9C°”3“‘“"°”i ENBREL may be stored in the vial at 2-8°C (36-46°F) for up to 6 hours.
`HOW SUPPLIED
`
`ENBREL is supplied in a carton containing four dose trays (NDC 58406-425-34). Each dose tray contains one 25 mg
`single—use vial of etanercept, one SYllilG€
`(1 mL Sterile Bacteriostatlc Water for Injection, USP, containing 0.9% benzyl
`alcohol), one plunger, and two alcohol swabs.
`
`Page 5
`
`Page 5
`
`

`
`
`
`ENBREL” (etanercept)
`
`REFERENCES
`1.
`2.
`
`3.
`
`Feldman M, Brennan FM, Maini RN. The role of cytokines in rheumatoid arthritis. Ann Rev lmmunol 1996;14:397.
`Saxne T, Palladino Jr MA, Heinegard D, et al. Detection of tumor necrosis factor alpha but not tumor necrosis factor
`beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum 1988;31:1041.
`A
`Smith CA, Farrah T, Goodwin RG. The TNF receptor superfamily of cellular and viral proteins: activation,
`costimulation, and death. Cell 1994;75:959.
`,.
`Wooley PH, DutcherJ, Widmer MB, et al. Influence of a recombinant human,—soluble tumor necrosis factor receptor FC
`fusion protein on type ll collagen-induced arthritis in mice. J lrnmunol'1993;151:6602.
`Data on file, lmmunex Corporation.
`Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in
`rheumatoid arthritis. Arthritis Rheum 1995;6:727.
`-
`'
`
`Ramey DR, Fries JF, Singh G. The Health Assessment Questionnaire 1995 — Status and Review. in: Spilker 8, ed.
`“Quality of Life and Pharmacoeconomics in Clinical Trials." 2nd ed. Philadelphia, PA. Llppincott—Raven;1996.
`Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor
`necrosis factor receptor (p75)—Fc fusion protein. N Engl J Med 1997;337(3):141.
`Giannini EH, Ruperto N, Ravelli A, et al. Preliminary definition of improvement in juvenile arthritis. Arthr Rheum
`1997;40(7):1202.
`
`8.
`
`9.
`
`10. Fisher CJ Jr, Agosti JM, Opal SM, et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion
`protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996;334(26):1697.
`
`Rx only
`0311-00 .
`
`Issue Date11/1998
`
`
`
`Manufactured by:
`lmmunex Corporation
`Seattle, Washington 98101
`U.S. License Number 1132
`
`Marketed by lmmunex Corporation and Wyeth-Ayerst Laboratories
`
`J WYETH-AYERST
`’
`LABORATORIES
`®
`||'l1l'T'lL.JrIE)(®
`
`© 1998 lmmunex Corporation
`lmmunex U.S. Patent Numbers:
`5,605,690; 5,712,155; 5,395,750
`
`..’
`
`my
`%& This paper can be recycled.
`
`'*‘
`
`
`
`Page 6
`
`Page 6