Orencia

Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Orencia

Adult Rheumatoid Arthritis (RA)

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

Juvenile Idiopathic Arthritis

Orencia is indicated for reducing signs and symptoms in pediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis. Orencia may be used as monotherapy or concomitantly with methotrexate (MTX).

Important Limitations of Use

Orencia should not be administered concomitantly with TNF antagonists. Orencia is not recommended for use concomitantly with other biologic rheumatoid arthritis (RA) therapy, such as anakinra.

Orencia Dosage and Administration

Adult Rheumatoid Arthritis

For adult patients with RA, Orencia may be administered as an intravenous infusion or a subcutaneous injection.

Orencia may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists.

For pediatric juvenile idiopathic arthritis, a dose calculated based on each patient's body weight is used [see Dosage and Administration (2.2)].

Intravenous Dosing Regimen

Orencia intravenous should be administered as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, an intravenous infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter.

Table 1: Dose of Orencia for Intravenous Infusion in Adult RA Patients

Body Weight of Patient	Dose	Number of Vialsa
a  Each vial provides 250 mg of abatacept for administration.
Less than 60 kg	500 mg	2
60 to 100 kg	750 mg	3
More than 100 kg	1000 mg	4

Subcutaneous Dosing Regimen

 Following a single intravenous loading dose (as per body weight categories listed in Table 1), the first 125 mg subcutaneous injection of Orencia should be given within a day, followed by 125 mg subcutaneous injections once weekly.

 Patients who are unable to receive an infusion may initiate weekly injections of subcutaneous Orencia without an intravenous loading dose.

 Patients transitioning from Orencia intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Juvenile Idiopathic Arthritis

The recommended dose of Orencia for patients 6 to 17 years of age with juvenile idiopathic arthritis who weigh less than 75 kg is 10 mg/kg intravenously calculated based on the patient’s body weight at each administration. Pediatric patients weighing 75 kg or more should be administered Orencia following the adult intravenous dosing regimen, not to exceed a maximum dose of 1000 mg. Orencia should be administered as a 30-minute intravenous infusion. Following the initial administration, Orencia should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Any unused portions in the vials must be immediately discarded.

Preparation and Administration Instructions for Intravenous Infusion

Use aseptic technique.

Orencia is provided as a lyophilized powder in preservative-free, single-use vials. Each Orencia vial provides 250 mg of abatacept for administration. The Orencia powder in each vial must be reconstituted with 10 mL of Sterile Water for Injection, USP, using only the silicone-free disposable syringe provided with 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 Orencia powder is accidentally reconstituted using a siliconized syringe, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes.

If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory. For information on obtaining additional silicone-free disposable syringes, contact Bristol-Myers Squibb 1-800-Orencia.

1)

Use 10 mL of Sterile Water for Injection, USP to reconstitute the Orencia powder. To reconstitute the Orencia powder, remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Do not use the vial if the vacuum is not present. Rotate the vial with gentle swirling to minimize foam formation, until the contents are completely dissolved. Do not shake. Avoid prolonged or vigorous agitation.

2)

Upon complete dissolution of the lyophilized powder, the vial should be vented with a needle to dissipate any foam that may be present. After reconstitution, each milliliter will contain 25 mg (250 mg/10 mL). The solution should be clear and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present.

3)

The reconstituted Orencia solution must be further diluted to 100 mL as follows. From a 100 mL infusion bag or bottle, withdraw a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of the reconstituted Orencia solution required for the patient’s dose. Slowly add the reconstituted Orencia solution into the infusion bag or bottle using the same silicone-free disposable syringe provided with each vial. Gently mix. Do not shake the bag or bottle. The final concentration of abatacept in the bag or bottle will depend upon the amount of drug added, but will be no more than 10 mg/mL. Any unused portions in the vials must be immediately discarded.

4)

Prior to administration, the Orencia solution should be inspected visually for particulate matter and discoloration. Discard the solution if any particulate matter or discoloration is observed.

5)

The entire, fully diluted Orencia solution should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 µm to 1.2 µm).

6)

The infusion of the fully diluted Orencia solution must be completed within 24 hours of reconstitution of the Orencia vials. The fully diluted Orencia solution may be stored at room temperature or refrigerated at 2°C to 8°C (36°F to 46°F) before use. Discard the fully diluted solution if not administered within 24 hours.

7)

Orencia should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of Orencia with other agents.

General Considerations for Subcutaneous Administration

 Orencia Injection, 125 mg/syringe is not intended for intravenous infusion.

 Orencia Injection is intended for use under the guidance of a physician or healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject with Orencia if a physician/healthcare practitioner determines that it is appropriate. Patients should be instructed to follow the directions provided in the Instructions for Use for additional details on medication administration.

 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use Orencia prefilled syringes exhibiting particulate matter or discoloration. Orencia should be clear and colorless to pale yellow.

 Patients using Orencia for subcutaneous administration should be instructed to inject the full amount in the syringe (1 mL), which provides 125 mg of Orencia, according to the directions provided in the Instructions for Use.

 Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard.

Dosage Forms and Strengths

• Lyophilized Powder for Intravenous Infusion
  
  250 mg single-use vial


• Solution for Subcutaneous Injection
  
  125 mg/mL single-dose prefilled glass syringe

Contraindications

None.

Warnings and Precautions

Concomitant Use with TNF Antagonists

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

Hypersensitivity

Of 2688 patients with adult RA treated with Orencia intravenously in clinical trials, there were two cases of anaphylaxis or anaphylactoid reactions. 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 idiopathic arthritis treated with Orencia in clinical trials, there was one case of a hypersensitivity reaction (0.5%). Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see Adverse Reactions (6.1, 6.3)].

Infections

 Serious infections, including sepsis and pneumonia, have been reported in patients receiving Orencia. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infection. Physicians should exercise caution when considering 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 while undergoing treatment with Orencia should be monitored closely. Administration of 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 patients treated with concurrent TNF antagonists and Orencia [see Warnings and Precautions (5.1)].

Prior to initiating immunomodulatory therapies, including Orencia, patients should be screened for latent tuberculosis infection with a tuberculin skin test. Orencia has not been studied in patients with a positive tuberculosis screen, and the safety of Orencia in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with Orencia.

Antirheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with Orencia. In clinical studies with Orencia, patients who screened positive for hepatitis were excluded from study.

Immunizations

Live vaccines should not be given concurrently with Orencia or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Orencia. The efficacy of vaccination in patients receiving Orencia is not known. Based on its mechanism of action, Orencia may blunt the effectiveness of some immunizations.

It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Orencia therapy.

Use in Patients with Chronic Obstructive Pulmonary Disease (COPD)

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

Immunosuppression

The possibility exists for drugs inhibiting T cell activation, including Orencia, to affect host defenses against infections and malignancies since T cells mediate cellular immune responses. The impact of treatment with Orencia on the development and course of malignancies is not fully understood [see Adverse Reactions (6.1)]. In clinical trials in patients with adult RA, a higher rate of infections was seen in Orencia-treated patients compared to placebo [see Adverse Reactions (6.1)].

Adverse Reactions

Clinical Studies Experience in Adult RA Patients Treated with Intravenous Orencia

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.

The data described herein reflect exposure to Orencia administered intravenously in patients with active RA in placebo-controlled studies (1955 patients with Orencia, 989 with placebo). The studies had either a 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, such as a TNF blocking agent (204 patients with Orencia, 134 with placebo).

The majority of patients in RA clinical studies received one or more of the following concomitant medications with Orencia: methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF blocking agents, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra.

The most serious adverse reactions were serious infections and malignancies.

The most commonly reported adverse events (occurring in ≥10% of patients treated with Orencia) were headache, upper respiratory tract infection, nasopharyngitis, and nausea.

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

Infections

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

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

Malignancies

In the placebo-controlled portions of the clinical trials (1955 patients treated with Orencia for a median of 12 months), the overall frequencies of malignancies were similar in the Orencia- and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of lung cancer were observed in Orencia-treated patients (4, 0.2%) than placebo-treated patients (0). In the cumulative Orencia clinical trials (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). The rate observed for lymphoma is approximately 3.5-fold higher than expected in an age- and gender-matched general population based on the National Cancer Institute's Surveillance, Epidemiology, and End Results Database. Patients with RA, particularly those with 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 of malignancies in humans is unknown.

Infusion-Related Reactions and Hypersensitivity Reactions

Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, 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.

Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated with Orencia included cardiopulmonary symptoms, such as hypotension, increased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of Orencia-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 Orencia-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events.

Of 2688 patients treated with Orencia in clinical trials, there were two cases of anaphylaxis or anaphylactoid reactions. Other events potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of Orencia-treated patients and generally occurred within 24 hours of Orencia infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see Warnings and Precautions (5.2)].

Adverse Reactions in Patients with COPD

In Study V [see Clinical Studies (14.1)], there were 37 patients with chronic obstructive pulmonary disease (COPD) who were treated with Orencia and 17 COPD patients who were treated with placebo. The COPD patients treated with Orencia developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in Orencia-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of Orencia-treated patients 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)].

Other Adverse Reactions

Adverse events occurring in 3% or more of patients and at least 1% more frequently in Orencia-treated patients during placebo-controlled RA studies are summarized in Table 2.

Table 2: Adverse Events Occurring in 3% or More of Patients and at Least 1% More Frequently in Orencia-Treated Patients During Placebo-Controlled RA Studies

Adverse Event (Preferred Term)	Orencia (n=1955)a Percentage	Placebo (n=989)b Percentage
a  Includes 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).
b  Includes 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).
Headache	18	13
Nasopharyngitis	12	9
Dizziness	9	7
Cough	8	7
Back pain	7	6
Hypertension	7	4
Dyspepsia	6	4
Urinary tract infection	6	5
Rash	4	3
Pain in extremity	3	2

Immunogenicity

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

Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cell-based luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.

No correlation of antibody development to clinical response or adverse events was observed.

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

Clinical Experience in Methotrexate-Naive Patients

Study VI was an active-controlled clinical trial in methotrexate-naive patients [see Clinical Studies (14.1)]. The safety experience in these patients was consistent with Studies I-V.

Clinical Experience in Adult RA Patients Treated with Subcutaneous Orencia

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.

Study SC-I was a randomized, double-blind, double-dummy, non-inferiority study that compared the efficacy and safety of abatacept administered subcutaneously (SC) and intravenously (IV) in 1457 subjects with rheumatoid arthritis, receiving background methotrexate, and experiencing an inadequate response to methotrexate (MTX-IR) [see Clinical Studies (14.1)]. The safety experience and immunogenicity for Orencia administered subcutaneously was consistent with intravenous Studies I-VI. Due to the route of administration, injection site reactions and immunogenicity were evaluated in Study SC-I and two other smaller studies discussed in the sections below.

Injection Site Reactions in Adult RA Patients Treated with Subcutaneous Orencia

Study SC-I compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the intravenous abatacept group (subcutaneous placebo), respectively. All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation.

Immunogenicity in Adult RA Patients Treated with Subcutaneous Orencia

Study SC-I compared the immunogenicity to abatacept following subcutaneous or intravenous administration. The overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy.

Immunogenicity and Safety of Subcutaneous Orencia Administration as Monotherapy without an Intravenous Loading Dose

Study SC-II was conducted to determine the effect of monotherapy use of Orencia on immunogenicity following subcutaneous administration without an intravenous load in 100 RA patients, who had not previously received abatacept or other CTLA4Ig, who received either subcutaneous Orencia plus methotrexate (n=51) or subcutaneous Orencia monotherapy (n=49). No patients in either group developed anti-product antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies.

Immunogenicity and Safety of Subcutaneous Orencia upon Withdrawal (Three Months) and Restart of Treatment

Study SC-III in the subcutaneous program was conducted to investigate the effect of withdrawal (three months) and restart of Orencia subcutaneous treatment on immunogenicity in RA patients treated concomitantly with methotrexate. One hundred sixty-seven patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized to either subcutaneous Orencia or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label Orencia treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 patients who continued to receive subcutaneous Orencia developed anti-product antibodies compared to 7/73 (9.6%) of patients who had subcutaneous Orencia withdrawn during this period. Half of the patients receiving subcutaneous placebo during the withdrawal period received a single intravenous infusion of Orencia at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous Orencia, the immunogenicity rates were 1/38 (2.6%) in the group receiving subcutaneous Orencia throughout, and 2/73 (2.7%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in this study was consistent with that observed in the other studies.

Clinical Studies Experience in Juvenile Idiopathic Arthritis

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

Orencia has been studied in 190 pediatric patients, 6 to 17 years of age, with polyarticular juvenile idiopathic arthritis. Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at 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 were consistent with those commonly seen in outpatient pediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain.

A total of 6 serious adverse events (acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare [2], and joint wear) were reported during the initial 4 months of treatment with Orencia.

Of the 190 patients with 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 reported in adults.

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

Immunogenicity

Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with juvenile idiopathic arthritis following repeated treatment with Orencia throughout the open-label period. For patients who were 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). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies.

The presence of antibodies was generally transient and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from Orencia during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of Orencia therapy.

Postmarketing Experience

Adverse reactions have been reported during the postapproval use of Orencia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Orencia. Based on the postmarketing experience in adult RA patients, the following adverse reaction has been identified during postapproval use with Orencia.

• Vasculitis (including cutaneous vasculitis and leukocytoclastic vasculitis)

Drug Interactions

TNF Antagonists

Concurrent administration of a TNF antagonist with Orencia has been associated with an increased risk of serious infections and 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)].

Other Biologic RA Therapy

There is insufficient experience to assess the safety and efficacy of Orencia administered concurrently with other biologic RA therapy, such as anakinra, and therefore such use is not recommended.

Blood Glucose Testing

Parenteral drug products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in Orencia for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving Orencia through intravenous administration, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods.

Orencia for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

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

Abatacept was not teratogenic when administered to pregnant mice at doses up to 300 mg/kg and in pregnant rats and rabbits at doses up to 200 mg/kg daily representing approximately 29 times the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve).

Abatacept administered to female rats every three days during early gestation and throughout the lactation period, produced no adverse effects in offspring at doses up to 45 mg/kg, representing 3 times the exposure associated with the MRHD of 10 mg/kg based on AUC. However, at 200 mg/kg, 11 times the MRHD exposure, alterations in immune function were observed consisting of a 9-fold increase in T-cell dependent antibody response in female pups and thyroid inflammation in one female pup. It is not known whether these findings indicate a risk for development of autoimmune diseases in humans exposed in utero to abatacept. However, exposure to abatacept in the juvenile rat, which may be more representative of the fetal immune system state in the human, resulted in immune system abnormalities including inflammation of the thyroid and pancreas [see Nonclinical Toxicology (13.2)].

Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to Orencia, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972.

Nursing Mothers

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

Pediatric Use

Orencia is indicated for reducing signs and symptoms in pediatric patients with moderately to severely active polyarticular juvenile idiopathic arthritis ages 6 years and older. Orencia may be used as monotherapy or concomitantly with methotrexate.

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

Orencia is not recommended for use in patients below the age of 6 years.

The safety and effectiveness of Orencia in pediatric patients below 6 years of age have not been established. The safety and efficacy of Orencia in pediatric patients for uses other than juvenile idiopathic arthritis have not been established.

Geriatric Use

A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received Orencia in clinical studies. No overall differences in safety or effectiveness were observed between these patients and younger patients, but these numbers are too low to rule out differences. The frequency of serious infection and malignancy among Orencia-treated patients over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.

Overdosage

Doses up to 50 mg/kg have been administered intravenously without apparent toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.

Orencia Description

Orencia® (abatacept) is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in a mammalian cell expression system. The apparent molecular weight of abatacept is 92 kilodaltons.

Orencia lyophilized powder for intravenous infusion is supplied as a sterile, white, preservative-free, lyophilized powder for intravenous administration. Following reconstitution of the lyophilized powder with 10 mL of Sterile Water for Injection, USP, the solution of Orencia is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of Orencia provides 250 mg abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium chloride (14.6 mg) for administration.

Orencia solution for subcutaneous administration is supplied as a sterile, preservative-free, clear, colorless to pale yellow solution with a pH of 6.8 to 7.4. Each single dose of subcutaneous injection provides 125 mg abatacept, dibasic sodium phosphate anhydrous (0.838 mg), monobasic sodium phosphate monohydrate (0.286 mg), poloxamer 188 (8 mg), sucrose (170 mg), and quantity sufficient to 1 mL with water for injection. Unlike the intravenous formulation, Orencia solution for subcutaneous administration contains no maltose.

Orencia - Clinical Pharmacology

Mechanism of Action

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

In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and interleukin-2. In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-γ. The relationship of these biological response markers to the mechanisms by which Orencia exerts its effects in RA is unknown.

Pharmacodynamics

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

Pharmacokinetics

Healthy Adults and Adult RA - Intravenous Administration

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

Table 3: Pharmacokinetic Parameters (Mean, Range) in Healthy Subjects and RA Patients After 10 mg/kg Intravenous Infusion(s)

PK Parameter	Healthy Subjects (After 10 mg/kg Single Dose) n=13	RA Patients (After 10 mg/kg Multiple Dosesa) n=14
a  Multiple intravenous infusions were administered at days 1, 15, 30, and monthly thereafter.
Peak Concentration (Cmax) [mcg/mL]	292 (175-427)	295 (171-398)
Terminal half-life (t1/2) [days]	16.7 (12-23)	13.1 (8-25)
Systemic clearance (CL) [mL/h/kg]	0.23 (0.16-0.30)	0.22 (0.13-0.47)
Volume of distribution (Vss) [L/kg]	0.09 (0.06-0.13)	0.07 (0.02-0.13)

The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady-state by day 60 with a mean (range) trough concentration of 24 (1 to 66) mcg/mL. No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients.

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

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

Juvenile Idiopathic Arthritis

In patients 6 to 17 years of age, the mean (range) steady-state serum peak and trough concentrations of abatacept were 217 (57 to 700) and 11.9 (0.15 to 44.6) mcg/mL. Population pharmacokinetic analyses of the serum concentration data showed that clearance of abatacept increas