These highlights do not include all the information needed to use ORENCIA safely and effectively. See full prescribing information for ORENCIA. ORENCIA (abatacept) Lyophilized Powder for Intravenous Infusion Initial U.S. Approval: 2005

ORENCIA isindicated for reducing signs and symptoms, inducing major clinical response,inhibiting the progression of structural damage, and improving physical functionin adult patients with moderately to severely active rheumatoid arthritis.ORENCIA may be used as monotherapy or concomitantly with disease-modifyingantirheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) antagonists.

ORENCIA is indicated for reducing signsand symptoms in pediatric patients 6 years of age and older with moderatelyto severely active polyarticular juvenile idiopathic arthritis. ORENCIA maybe used as monotherapy or concomitantly with methotrexate (MTX).

ORENCIA should not be administered concomitantlywith TNF antagonists. ORENCIA is not recommended for use concomitantly withother biologic rheumatoid arthritis (RA) therapy, such as anakinra.

For adult patients with RA, ORENCIA shouldbe administered as a 30-minute intravenous infusion utilizing the weight range-baseddosing specified in Table 1. Following the initial administration, ORENCIAshould be given at 2 and 4 weeks after the first infusion and every 4 weeksthereafter. ORENCIA may be used as monotherapy or concomitantly with DMARDsother than TNF antagonists.

For pediatric juvenileidiopathic arthritis, a dose calculated based on each patient’s body weightis used [see Dosage and Administration (2.2) ].

The recommended dose of ORENCIA forpatients 6 to 17 years of age with juvenile idiopathic arthritis who weighless than 75 kg is 10 mg/kg calculated based on the patient’s body weightat each administration. Pediatric patients weighing 75 kg or more should beadministered ORENCIA following the adult dosing regimen, not to exceed a maximumdose of 1000 mg. ORENCIA should be administered as a 30-minute intravenousinfusion. Following the initial administration, ORENCIA should be given at2 and 4 weeks after the first infusion and every 4 weeks thereafter. Any unusedportions in the vials must be immediately discarded.

Use aseptic technique.

ORENCIAis provided as a lyophilized powder in preservative-free, single-use vials.Each ORENCIA vial provides 250 mg of abatacept for administration. The ORENCIApowder in each vial must be reconstituted with 10 mL of Sterile Water forInjection, USP, using ONLY the SILICONE-FREE DISPOSABLE SYRINGE PROVIDEDWITH EACH VIAL and an 18- to 21-gauge needle. After reconstitution,the concentration of abatacept in the vial will be 25 mg/mL. If the ORENCIApowder is accidentally reconstituted using a siliconized syringe, the solutionmay develop a few translucent particles. Discard any solutions prepared usingsiliconized syringes.

If the SILICONE-FREE DISPOSABLESYRINGE is dropped or becomes contaminated, use a new SILICONE-FREEDISPOSABLE SYRINGE from inventory. For information on obtaining additional SILICONE-FREEDISPOSABLE SYRINGES, contact Bristol-Myers Squibb 1-800-ORENCIA.

Duringreconstitution, to minimize foam formation in solutions of ORENCIA, the vialshould be rotated with gentle swirling until the contents are completely dissolved.Avoid prolonged or vigorous agitation. DO NOT SHAKE. Upon complete dissolutionof the lyophilized powder, the vial should be vented with a needle to dissipateany foam that may be present. The solution should be clear and colorless topale yellow. Do not use if opaque particles, discoloration, or other foreignparticles are present.

250 mg single-use vial

None.

In controlled clinical trials in patientswith adult RA, patients receiving concomitant ORENCIA and TNF antagonist therapyexperienced more infections (63%) and serious infections (4.4%) compared topatients treated with only TNF antagonists (43% and 0.8%, respectively) [see Adverse Reactions (6.1) ]. These trials failedto demonstrate an important enhancement of efficacy with concomitant administrationof ORENCIA with TNF antagonist; therefore, concurrent therapy with ORENCIAand a TNF antagonist is not recommended. While transitioning from TNF antagonisttherapy to ORENCIA therapy, patients should be monitored for signs of infection.

Of 2688 patients with adult RA treatedwith ORENCIA in clinical trials, there were two cases of anaphylaxis or anaphylactoidreactions. Other events potentially associated with drug hypersensitivity,such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9%of ORENCIA-treated patients. Of the 190 patients with juvenile idiopathicarthritis treated with ORENCIA in clinical trials, there was one case of ahypersensitivity reaction (0.5%). Appropriate medical support measures forthe treatment of hypersensitivity reactions should be available for immediateuse in the event of a reaction [see Adverse Reactions(6.1, 6.2) ].

Physicians should exercise caution whenconsidering the use of ORENCIA in patients with a history of recurrent infections,underlying conditions which may predispose them to infections, or chronic,latent, or localized infections. Patients who develop a new infection whileundergoing treatment with ORENCIA should be monitored closely. Administrationof ORENCIA should be discontinued if a patient develops a serious infection[see Adverse Reactions (6.1) ].A higher rate of serious infections has been observed in adult RA patientstreated with concurrent TNF antagonists and ORENCIA [see Warningsand Precautions (5.1) ].

Prior to initiatingimmunomodulatory therapies, including ORENCIA, patients should be screenedfor latent tuberculosis infection with a tuberculin skin test. ORENCIA hasnot been studied in patients with a positive tuberculosis screen, and thesafety of ORENCIA in individuals with latent tuberculosis infection is unknown.Patients testing positive in tuberculosis screening should be treated by standardmedical practice prior to therapy with ORENCIA.

Antirheumatictherapies have been associated with hepatitis B reactivation. Therefore, screeningfor viral hepatitis should be performed in accordance with published guidelinesbefore starting therapy with ORENCIA. In clinical studies with ORENCIA, patientswho screened positive for hepatitis were excluded from study.

Live vaccines should not be given concurrentlywith ORENCIA or within 3 months of its discontinuation. No data are availableon the secondary transmission of infection from persons receiving live vaccinesto patients receiving ORENCIA. The efficacy of vaccination in patients receivingORENCIA is not known. Based on its mechanism of action, ORENCIA may bluntthe effectiveness of some immunizations.

It is recommendedthat patients with juvenile idiopathic arthritis be brought up to date withall immunizations in agreement with current immunization guidelines priorto initiating ORENCIA therapy.

Adult COPD patients treated with ORENCIAdeveloped adverse events more frequently than those treated with placebo,including COPD exacerbations, cough, rhonchi, and dyspnea. Use of ORENCIAin patients with RA and COPD should be undertaken with caution and such patientsshould be monitored for worsening of their respiratory status [see Adverse Reactions (6.1) ].

The possibility exists for drugs inhibitingT cell activation, including ORENCIA, to affect host defenses against infectionsand malignancies since T cells mediate cellular immune responses. The impactof treatment with ORENCIA on the development and course of malignancies isnot fully understood [see Adverse Reactions(6.1) ]. In clinical trials in patients with adult RA, a higherrate of infections was seen in ORENCIA-treated patients compared to placebo[see Adverse Reactions (6.1) ].

Because clinical trials are conductedunder widely varying and controlled conditions, adverse reaction rates observedin clinical trials of a drug cannot be directly compared to rates in the clinicaltrials of another drug and may not predict the rates observed in a broaderpatient population in clinical practice.

The data describedherein reflect exposure to ORENCIA in patients with active RA in placebo-controlledstudies (1955 patients with ORENCIA, 989 with placebo). The studies had eithera double-blind, placebo-controlled period of 6 months (258 patients with ORENCIA,133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo).A subset of these patients received concomitant biologic DMARD therapy, suchas a TNF blocking agent (204 patients with ORENCIA, 134 with placebo).

Themajority of patients in RA clinical studies received one or more of the followingconcomitant medications with ORENCIA: MTX, nonsteroidal anti-inflammatorydrugs (NSAIDs), corticosteroids, TNF blocking agents, azathioprine, chloroquine,gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra.

Themost serious adverse reactions were serious infections and malignancies.

Themost commonly reported adverse events (occurring in ≥10% of patients treatedwith ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis,and nausea.

The adverse events most frequently resultingin clinical intervention (interruption or discontinuation of ORENCIA) weredue to infection. The most frequently reported infections resulting in doseinterruption were upper respiratory tract infection (1.0%), bronchitis (0.7%),and herpes zoster (0.7%). The most frequent infections resulting in discontinuationwere pneumonia (0.2%), localized infection (0.2%), and bronchitis (0.1%).

In the placebo-controlled trials, infectionswere reported in 54% of ORENCIA-treated patients and 48% of placebo-treatedpatients. The most commonly reported infections (reported in 5-13% of patients)were upper respiratory tract infection, nasopharyngitis, sinusitis, urinarytract infection, influenza, and bronchitis. Other infections reported in fewerthan 5% of patients at a higher frequency (>0.5%) with ORENCIA compared toplacebo, were rhinitis, herpes simplex, and pneumonia [see Warningsand Precautions (5.3) ].

Serious infectionswere reported in 3.0% of patients treated with ORENCIA and 1.9% of patientstreated with placebo. The most common (0.2-0.5%) serious infections reportedwith ORENCIA were pneumonia, cellulitis, urinary tract infection, bronchitis,diverticulitis, and acute pyelonephritis [see Warningsand Precautions (5.3) ].

In the placebo-controlled portions ofthe clinical trials (1955 patients treated with ORENCIA for a median of 12months), the overall frequencies of malignancies were similar in the ORENCIA-and placebo-treated patients (1.3% and 1.1%, respectively). However, morecases of lung cancer were observed in ORENCIA-treated patients (4, 0.2%) thanplacebo-treated patients (0). In the cumulative ORENCIA clinical trials (placebo-controlledand uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 casesper 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years)were observed in 2688 patients (3827 patient-years). The rate observed forlymphoma is approximately 3.5-fold higher than expected in an age- and gender-matchedgeneral population based on the Surveillance, Epidemiology, and End ResultsDatabase. Patients with RA, particularly thosewith highly active disease, are at a higher risk for the development of lymphoma.Other malignancies included skin, breast, bile duct, bladder, cervical, endometrial,lymphoma, melanoma, myelodysplastic syndrome, ovarian, prostate, renal, thyroid,and uterine cancers [see Warnings and Precautions(5.6) ]. The potential role of ORENCIA in the development ofmalignancies in humans is unknown.

Acute infusion-related events (adversereactions occurring within 1 hour of the start of the infusion) in StudiesIII, IV, and V [see Clinical Studies (14.1) ]were more common in the ORENCIA-treated patients than the placebo patients(9% for ORENCIA, 6% for placebo). The most frequently reported events (1-2%)were dizziness, headache, and hypertension.

Acuteinfusion-related events that were reported in >0.1% and ≤1% of patients treatedwith ORENCIA included cardiopulmonary symptoms, such as hypotension, increasedblood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria,cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactionswere mild to moderate. Fewer than 1% of ORENCIA-treated patients discontinueddue to an acute infusion-related event. In controlled trials, 6 ORENCIA-treatedpatients compared to 2 placebo-treated patients discontinued study treatmentdue to acute infusion-related events.

Of 2688 patientstreated with ORENCIA in clinical trials, there were two cases of anaphylaxisor anaphylactoid reactions. Other events potentially associated with drughypersensitivity, such as hypotension, urticaria, and dyspnea, each occurredin less than 0.9% of ORENCIA-treated patients and generally occurred within24 hours of ORENCIA infusion. Appropriate medical support measures for thetreatment of hypersensitivity reactions should be available for immediateuse in the event of a reaction [see Warnings andPrecautions (5.2) ].

In Study V [see ClinicalStudies (14.1) ], there were 37 patients with chronic obstructivepulmonary disease (COPD) who were treated with ORENCIA and 17 COPD patientswho were treated with placebo. The COPD patients treated with ORENCIA developedadverse events more frequently than those treated with placebo (97% vs 88%,respectively). Respiratory disorders occurred more frequently in ORENCIA-treatedpatients compared to placebo-treated patients (43% vs 24%, respectively) includingCOPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-treatedpatients developed a serious adverse event compared to placebo-treated patients(27% vs 6%), including COPD exacerbation (3 of 37 patients [8%]) and pneumonia(1 of 37 patients [3%]) [see Warnings and Precautions(5.5) ].

Adverse events occurring in 3% or moreof patients and at least 1% more frequently in ORENCIA-treated patients duringplacebo-controlled RA studies are summarized in Table 2.

Antibodies directed against the entireabatacept molecule or to the CTLA-4 portion of abatacept were assessed byELISA assays in RA patients for up to 2 years following repeated treatmentwith ORENCIA. Thirty-four of 1993 (1.7%) patients developed binding antibodiesto the entire abatacept molecule or to the CTLA-4 portion of abatacept. Becausetrough levels of abatacept can interfere with assay results, a subset analysiswas performed. In this analysis it was observed that 9 of 154 (5.8%) patientsthat had discontinued treatment with ORENCIA for over 56 days developed antibodies.

Sampleswith confirmed binding activity to CTLA-4 were assessed for the presence ofneutralizing antibodies in a cell-based luciferase reporter assay. Six of9 (67%) eva luable patients were shown to possess neutralizing antibodies.

Nocorrelation of antibody development to clinical response or adverse eventswas observed.

The data reflect the percentage of patientswhose test results were positive for antibodies to abatacept in specific assays.The observed incidence of antibody (including neutralizing antibody) positivityin an assay is highly dependent on several factors, including assay sensitivityand specificity, assay methodology, sample handling, timing of sample collection,concomitant medication, and underlying disease. For these reasons, comparisonof the incidence of antibodies to abatacept with the incidence of antibodiesto other products may be misleading.

Study VI was an active-controlled clinicaltrial in MTX-naive patients [see Clinical Studies(14.1) ]. The safety experience in these patients was consistentwith Studies I-V.

In general, the adverse events in pediatricpatients were similar in frequency and type to those seen in adult patients[see Warnings and Precautions (5) , Adverse Reactions (6) ].

ORENCIAhas been studied in 190 pediatric patients, 6 to 17 years of age, with polyarticularjuvenile idiopathic arthritis. Overall frequency of adverse events in the4-month, lead-in, open-label period of the study was 70%; infections occurredat a frequency of 36% [see Clinical Studies (14.2) ].The most common infections were upper respiratory tract infection and nasopharyngitis.The infections resolved without sequelae, and the types of infections wereconsistent with those commonly seen in outpatient pediatric populations. Otherevents that occurred at a preva lence of at least 5% were headache, nausea,diarrhea, cough, pyrexia, and abdominal pain.

A totalof 6 serious adverse events (acute lymphocytic leukemia, ovarian cyst, varicellainfection, disease flare [2], and joint wear) were reported during the initial4 months of treatment with ORENCIA.

Of the 190 patientswith juvenile idiopathic arthritis treated with ORENCIA in clinical trials,there was one case of a hypersensitivity reaction (0.5%). During Periods A,B, and C, acute infusion-related reactions occurred at a frequency of 4%,2%, and 3%, respectively, and were consistent with the types of events reportedin adults.

Upon continued treatment in the open-labelextension period, the types of adverse events were similar in frequency andtype to those seen in adult patients, except for a single patient diagnosedwith multiple sclerosis while on open-label treatment.

Antibodies directed against the entireabatacept molecule or to the CTLA-4 portion of abatacept were assessed byELISA assays in patients with juvenile idiopathic arthritis following repeatedtreatment with ORENCIA throughout the open-label period. For patients whowere withdrawn from therapy for up to 6 months during the double-blind period,the rate of antibody formation to the CTLA-4 portion of the molecule was 41%(22/54), while for those who remained on therapy the rate was 13% (7/54).

Thepresence of antibodies was generally transient and titers were low. The presenceof antibodies was not associated with adverse events, changes in efficacy,or an effect on serum concentrations of abatacept. For patients who were withdrawnfrom ORENCIA during the double-blind period for up to 6 months, no seriousacute infusion-related events were observed upon re-initiation of ORENCIAtherapy.

Adverse reactions have been reported duringthe post-approval use of ORENCIA. Because these reactions are reported voluntarilyfrom a population of uncertain size, it is not always possible to reliablyestimate their frequency or establish a causal relationship to ORENCIA. Basedon the postmarketing experience with ORENCIA in adult RA patients, the adverseevent profile of ORENCIA does not differ from that listed/discussed abovein Section 6.1 in adults.

Concurrent administration of a TNF antagonistwith ORENCIA has been associated with an increased risk of serious infectionsand no significant additional efficacy over use of the TNF antagonists alone.Concurrent therapy with ORENCIA and TNF antagonists is not recommended [see Warnings and Precautions (5.1) ].

There is insufficient experience to assessthe safety and efficacy of ORENCIA administered concurrently with other biologicRA therapy, such as anakinra, and therefore such use is not recommended.

Parenteral drug products containing maltosecan interfere with the readings of blood glucose monitors that use test stripswith glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The GDH-PQQbased glucose monitoring systems may react with the maltose present in ORENCIA,resulting in falsely elevated blood glucose readings on the day of infusion.When receiving ORENCIA, patients that require blood glucose monitoring shouldbe advised to consider methods that do not react with maltose, such as thosebased on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucoseoxidase, or glucose hexokinase test methods.

There are no adequate and well-controlledstudies of ORENCIA use in pregnant women. Abatacept has been shown to crossthe placenta in animals, and in animal reproduction studies alterations inimmune function occurred. ORENCIA should be used during pregnancy only ifthe potential benefit to the mother justifies the potential risk to the fetus.

Abataceptwas not teratogenic when administered to pregnant mice at doses up to 300mg/kg and in pregnant rats and rabbits at doses up to 200 mg/kg daily representingapproximately 29 times the exposure associated with the maximum recommendedhuman dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentrationcurve).

Abatacept administered to female rats everythree days during early gestation and throughout the lactation period, producedno adverse effects in offspring at doses up to 45 mg/kg, representing 3 timesthe exposure associated with the MRHD of 10 mg/kg based on AUC. However, at200 mg/kg, 11 times the MRHD exposure, alterations in immune function wereobserved consisting of a 9-fold increase in T-cell dependent antibody responsein female pups and thyroid inflammation in one female pup. It is not knownwhether these findings indicate a risk for development of autoimmune diseasesin humans exposed in utero to abatacept. However, exposureto abatacept in the juvenile rat, which may be more representative of thefetal immune system state in the human, resulted in immune system abnormalitiesincluding inflammation of the thyroid and pancreas [see NonclinicalToxicology (13.2) ].

PregnancyRegistry: To monitor maternal-fetal outcomes of pregnant women exposedto ORENCIA, a pregnancy registry has been established. Healthcare professionalsare encouraged to register patients and pregnant women are encouraged to enrollthemselves by calling 1-877-311-8972.

It is not known whether ORENCIA is excretedinto human milk or absorbed systemically after ingestion by a nursing infant.However, abatacept was excreted in rat milk. Because many drugs are excretedin human milk, and because of the potential for serious adverse reactionsin nursing infants from ORENCIA, a decision should be made whether to discontinuenursing or to discontinue the drug, taking into account the importance ofthe drug to the mother.

ORENCIA is indicated for reducing signsand symptoms in pediatric patients with moderately to severely active polyarticularjuvenile idiopathic arthritis ages 6 years and older. ORENCIA may be usedas monotherapy or concomitantly with MTX.

Studies injuvenile rats exposed to ORENCIA prior to immune system maturity have shownimmune system abnormalities including an increase in the incidence of infectionsleading to death as well as inflammation of the thyroid and pancreas [see Nonclinical Toxicology (13.2) ]. Studies inadult mice and monkeys have not demonstrated similar findings. As the immunesystem of the rat is undeveloped in the first few weeks after birth, the relevanceof these results to humans greater than 6 years of age (where the immune systemis largely developed) is unknown.

The safety and effectivenessof ORENCIA in pediatric patients below 6 years of age have not been established.Therefore, ORENCIA is not recommended for use in patients below the age of6 years.

Safety and efficacy of ORENCIA in pediatricpatients for uses other than juvenile idiopathic arthritis have not been established.

A total of 323 patients 65 years of ageand older, including 53 patients 75 years and older, received ORENCIA in clinicalstudies. No overall differences in safety or effectiveness were observed betweenthese patients and younger patients, but these numbers are too low to ruleout differences. The frequency of serious infection and malignancy among ORENCIA-treatedpatients over age 65 was higher than for those under age 65. Because thereis a higher incidence of infections and malignancies in the elderly populationin general, caution should be used when treating the elderly.

ORENCIA is administered as an intravenousinfusion under medically controlled conditions. Doses up to 50 mg/kg havebeen administered without apparent toxic effect. In case of overdosage, itis recommended that the patient be monitored for any signs or symptoms ofadverse reactions and appropriate symptomatic treatment instituted.

ORENCIA (abatacept) is a soluble fusionprotein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associatedantigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains)portion of human immunoglobulin G1 (IgG1). Abatacept is produced by recombinantDNA technology in a mammalian cell expression system. The apparent molecularweight of abatacept is 92 kilodaltons.

ORENCIA is suppliedas a sterile, white, preservative-free, lyophilized powder for parenteraladministration. Following reconstitution with 10 mL of Sterile Water for Injection,USP, the solution of ORENCIA is clear, colorless to pale yellow, with a pHrange of 7.2 to 7.8. Each single-use vial of ORENCIA provides 250 mg abatacept,500 mg maltose, 17.2 mg monobasic sodium phosphate, and 14.6 mg sodium chloridefor administration.

Abatacept, a selective costimulation modulator,inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, therebyblocking interaction with CD28. This interaction provides a costimulatorysignal necessary for full activation of T lymphocytes. Activated T lymphocytesare implicated in the pathogenesis of RA and are found in the synovium ofpatients with RA.

In vitro, abataceptdecreases T cell proliferation and inhibits the production of the cytokinesTNF alpha (TNFα), interferon-γ, and interleukin-2. In a rat collagen-inducedarthritis model, abatacept suppresses inflammation, decreases anti-collagenantibody production, and reduces antigen specific production of interferon-γ.The relationship of these biological response markers to the mechanisms bywhich ORENCIA exerts its effects in RA is unknown.

In clinical trials with ORENCIA at dosesapproximating 10 mg/kg, decreases were observed in serum levels of solubleinterleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), rheumatoid factor (RF),C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3), and TNFα. Therelationship of these biological response markers to the mechanisms by whichORENCIA exerts its effects in RA is unknown.

The pharmacokinetics of abataceptwere studied in healthy adult subjects after a single 10 mg/kg intravenousinfusion and in RA patients after multiple 10 mg/kg intravenous infusions(see Table 3).

The pharmacokinetics of abatacept in RA patients and healthysubjects appeared to be comparable. In RA patients, after multiple intravenousinfusions, the pharmacokinetics of abatacept showed proportional increasesof C and AUC over the dose range of 2 mg/kg to 10mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady-state byday 60 with a mean (range) trough concentration of 24 (1 to 66) mcg/mL. Nosystemic accumulation of abatacept occurred upon continued repeated treatmentwith 10 mg/kg at monthly intervals in RA patients.

Populationpharmacokinetic analyses in RA patients revealed that there was a trend towardhigher clearance of abatacept with increasing body weight. Age and gender(when corrected for body weight) did not affect clearance. Concomitant MTX,NSAIDs, corticosteroids, and TNF blocking agents did not influence abataceptclearance.

No formal studies were conducted to examinethe effects of either renal or hepatic impairment on the pharmacokineticsof abatacept.

In patients 6 to 17 years of age, themean (range) steady-state serum peak and trough concentrations of abataceptwere 217 (57 to 700) and 11.9 (0.15 to 44.6) mcg/mL. Population pharmacokineticanalyses of the serum concentration data showed that clearance of abataceptincreased with baseline body weight. The estimated mean (range) clearanceof abatacept in the juvenile idiopathic arthritis patients was 0.4 (0.20 to1.12) mL/h/kg. After accounting for the effect of body weight, the clearanceof abatacept was not related to age and gender. Concomitant methotrexate,corticosteroids, and NSAIDs were also shown not to influence abatacept clearance.

In a mouse carcinogenicity study, weeklysubcutaneous injections of 20, 65, or 200 mg/kg of abatacept administeredfor up to 84 weeks in males and 88 weeks in females were associated with increasesin the incidence of malignant lymphomas (all doses) and mammary gland tumors(intermediate- and high-dose in females). The mice from this study were infectedwith murine leukemia virus and mouse mammary tumor virus. These viruses areassociated with an increased incidence of lymphomas and mammary gland tumors,respectively, in immunosuppressed mice. The doses used in these studies producedexposures 0.8, 2.0, and 3.0 times higher, respectively, than the exposureassociated with the maximum recommended human dose (MRHD) of 10 mg/kg basedon AUC (area under the time-concentration curve). The relevance of these findingsto the clinical use of ORENCIA is unknown.

In a one-yeartoxicity study in cynomolgus monkeys, abatacept was administered intravenouslyonce weekly at doses up to 50 mg/kg (producing 9 times the MRHD exposure basedon AUC). Abatacept was not associated with any significant drug-related toxicity.Reversible pharmacological effects consisted of minimal transient decreasesin serum IgG and minimal to severe lymphoid depletion of germinal centersin the spleen and/or lymph nodes. No evidence of lymphomas or preneoplasticmorphologic changes was observed, despite the presence of a virus (lymphocryptovirus)known to cause these lesions in immunosuppressed monkeys within the time frameof this study. The relevance of these findings to the clinical use of ORENCIAis unknown.

No mutagenic potential of abatacept wasobserved in the in vitro bacterial reverse mutation (Ames)or Chinese hamster ovary/hypoxanthine guanine phosphoribosyl-transferase (CHO/HGPRT)forward point mutation assays with or without metabolic activation, and nochromosomal aberrations were observed in human lymphocytes treated with abataceptwith or without metabolic activation.

Abatacept hadno adverse effects on male or female fertility in rats at doses up to 200mg/kg every three days (11 times the MRHD exposure based on AUC).

A juvenile animal study was conductedin rats dosed with abatacept from 4 to 94 days of age in which an increasein the incidence of infections leading to death occurred at all doses comparedwith controls. Altered T-cell subsets including increased T-helper cells andreduced T-regulatory cells were observed. In addition, inhibition of T-cell-dependentantibody responses (TDAR) was observed. Upon following these animals intoadulthood, lymphocytic inflammation of the thyroid and pancreatic islets wasobserved.

In studies of adult mice and monkeys, inhibitionof TDAR was apparent. However, infection and mortality, altered T-helper cells,and inflammation of thyroid and pancreas were not observed.

The efficacy and safety of ORENCIA wereassessed in six randomized, double-blind, controlled studies (five placebo-controlledand one active-controlled) in patients ≥18 years of age with active RA diagnosedaccording to American College of Rheumatology (ACR) criteria. Studies I, II,III, IV, and VI required patients to have at least 12 tender and 10 swollenjoints at randomization. Study V did not require any specific number of tenderor swollen joints. ORENCIA or placebo treatment was given intravenously atweeks 0, 2, and 4 and then every 4 weeks thereafter.

StudyI eva luated ORENCIA as monotherapy in 122 patients with active RA who hadfailed at least one non-biologic DMARD or etanercept. In Study II and StudyIII, the efficacy and safety of ORENCIA were assessed in patients with aninadequate response to MTX and who were continued on their stable dose ofMTX. In Study IV, the efficacy and safety of ORENCIA were assessed in patientswith an inadequate response to a TNF blocking agent, with the TNF blockingagent discontinued prior to randomization; other DMARDs were permitted. StudyV primarily assessed safety in patients with active RA requiring additionalintervention in spite of current therapy with DMARDs; all DMARDs used at enrollmentwere continued. Patients in Study V were not excluded for comorbid medicalconditions. In Study VI, the efficacy and safety of ORENCIA wereassessed in MTX-naive patients with RA of less than 2 years disease duration.In Study VI, patients previously naive to MTX were randomized to receive ORENCIAplus MTX or MTX plus placebo.

Study I patients wererandomized to receive one of three doses of ORENCIA (0.5, 2, or 10 mg/kg)or placebo ending at week 8. Study II patients were randomized to receiveORENCIA 2 or 10 mg/kg or placebo for 12 months. Study III, IV, V, and VI patientswere randomized to receive a dose of ORENCIA based on weight range or placebofor 12 months (Studies III, V, and VI) or 6 months (Study IV). The dose ofORENCIA was 500 mg for patients weighing less than 60 kg, 750 mg for patientsweighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100kg.

The percent of ORENCIA-treated patientsachieving ACR 20, 50, and 70 responses and major clinical response in StudiesI, III, IV, and VI are shown in Table 4. ORENCIA-treated patients had higherACR 20, 50, and 70 response rates at 6 months compared to placebo-treatedpatients. Month 6 ACR response rates in Study II for the 10 mg/kg group weresimilar to the ORENCIA group in Study III.

In StudiesIII and IV, improvement in the ACR 20 response rate versus placebo was observedwithin 15 days in some patients and within 29 days versus MTX in Study VI.In Studies II, III, and VI, ACR response rates were maintained to 12 monthsin ORENCIA-treated patients. ACR responses were maintained up to three yearsin the open-label extension of Study II.

In Study VI,a greater proportion of patients treated with ORENCIA plus MTX achieved alow level of disease activity as measured by a DAS28-CRP less than 2.6 at12 months compared to those treated with MTX plus placebo (Table 4). Of patientstreated with ORENCIA plus MTX who achieved DAS28-CRP less than 2.6, 54% hadno active joints, 17% had one active joint, 7% had two active joints, and22% had three or more active joints, where an active joint was a joint thatwas rated as tender or swollen or both.

The results of the components of the ACR response criteriafor Studies III and IV are shown in Table 5. In ORENCIA-treated patients,greater improvement was seen in all ACR response criteria components through6 and 12 months than in placebo-treated patients.

The percent of patients achieving the ACR 50 response forStudy III by visit is shown in Figure 1. The time coursefor the ORENCIA group in Study VI was similar to that in Study III.

Figure1: Percent of Patients Achieving ACR 50 Response by Visit* (Study III)

ORENCIA-treated patients experienced greater improvementthan placebo-treated patients in morning stiffness.