Orencia Drug Information

Dosage in Adult Rheumatoid Arthritis

For adult patients with RA, administer as an intravenous infusion or as a subcutaneous injection. ORENCIA may be used as monotherapy or concomitantly with disease-modifying antirheumatic drugs (DMARDs) other than JAK inhibitors or bDMARDs (e.g., TNF antagonists). Intravenous Dosage Reconstitute ORENCIA lyophilized powder and administer after dilution as a 30-minute intravenous infusion utilizing the weight range-based dosing recommended in Table 1.

Following the initial intravenous infusion, administer as an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter. Table 1: Dose of ORENCIA for Intravenous Infusion in Adult RA Patients 4 Subcutaneous Dosage Prior to the first subcutaneous dose, an optional loading dose may be administered as a single intravenous infusion (as per body weight categories in Table 1). If an intravenous loading dose is used, administer the first subcutaneous injection within one day of the infusion.

Administer ORENCIA 125 mg in prefilled syringes or in ORENCIA ClickJect™ autoinjector by subcutaneous injection once weekly. For patients switching from ORENCIA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Dosage in Polyarticular Juvenile Idiopathic Arthritis

For pediatric patients with pJIA, either administer ORENCIA as an intravenous infusion (only patients 6 years of age and older) or as a subcutaneous injection (only patients 2 years of age and older). Intravenous Dosage Administer ORENCIA as a 30-minute intravenous infusion based on body weight: • For body weight less than 75 kg, administer a dose of 10 mg/kg. • For body weight of 75 kg or greater, administer as per the recommendations in Table 1 (follow the adult intravenous dosing regimen), not to exceed a maximum dose of 1,000 mg. Immediately discard any unused portion in the vials.

Subcutaneous Dosage Administer ORENCIA for subcutaneous injection, without an intravenous loading dose, utilizing the weight range-based dosing as recommended in Table 2. Subsequently administer once weekly. Table 2: Dose of ORENCIA for Subcutaneous Administration in Patients 2 Years of Age and Older with pJIA Patients with pJIA may self-inject with ORENCIA or the patient’s caregiver may administer ORENCIA if both the healthcare practitioner and the parent/legal guardian determine it is appropriate.

The ability of pediatric patients to self-inject with the autoinjector has not been tested.

Dosage in Psoriatic Arthritis Adult Patients

ORENCIA may be used with or without non-biologic DMARDs. Subcutaneous Dosage Administer 125 mg of ORENCIA subcutaneously once weekly (no intravenous loading dose is needed). Pediatric Patients Administer ORENCIA as a subcutaneous injection in pediatric patients 2 years of age and older with psoriatic arthritis.

Intravenous administration is not approved for pediatric patients with psoriatic arthritis. Subcutaneous Dosage Administer ORENCIA for subcutaneous injection weekly, utilizing the weight range-based dosage as recommended in Table 3.

Dosage in Prophylaxis of Acute

Graft versus Host Disease in Adults and Pediatric Patients Aged 2 Years and Older Antiviral Prophylactic Treatment Before administering ORENCIA, administer recommended antiviral prophylactic treatment for Epstein-Barr Virus (EBV) reactivation, and continue for six months following HSCT. In addition, consider prophylactic antivirals for Cytomegalovirus (CMV) infection/reactivation during treatment and for six months following HSCT. For a full dose, less than the full contents of one vial or more than one vial may be needed.

Using aseptic technique, reconstitute, dilute, and then administer ORENCIA as follows: Reconstitution 1 Use the vial only if the vacuum is present. 2 Reconstitute each vial of supplied ORENCIA lyophilized powder (each vial supplies 250 mg of abatacept) with 10 mL of Sterile Water for Injection, USP (direct the stream toward the inside wall of the vial) to obtain a concentration of 25 mg/mL. Use only the provided silicone-free syringe with an 18- to 21-gauge needle: a. If the ORENCIA lyophilized powder is accidently reconstituted using a siliconized syringe, the solution may develop a few translucent particles (discard any solutions prepared using siliconized syringes). b.

If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe. To obtain new silicone-free syringes, contact Bristol-Myers Squibb at 1-800-ORENCIA. 3 Gently swirl the vial to minimize foam formation, until the contents are completely dissolved. Do not shake.

Avoid prolonged or vigorous agitation. 4 Upon complete dissolution of the lyophilized powder, vent the vial with a needle to dissipate any foam that may be present. 5 Visually inspect the reconstituted solution (the solution should be clear and colorless to pale yellow). Dilution 7 Must further dilute the reconstituted ORENCIA solution to 100 mL as follows: a. From a 100 mL infusion bag or bottle of 0.9% Sodium Chloride Injection, USP, withdraw a volume equal to the volume of the reconstituted ORENCIA solution required for the patient’s dose. b.

Slowly add the reconstituted ORENCIA solution(s) into the infusion bag or bottle using the silicone-free disposable syringe provided with each vial. c. 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 abatacept added, but will be no more than 10 mg/mL. Immediately discard any unused portion in the ORENCIA vial. Administration 8 Prior to administration, visually inspect the ORENCIA diluted solution for particulate matter and discoloration.

Discard the diluted solution if any particulate matter or discoloration is observed. 9 Using an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 μm to 1.2 μm), administer the entire diluted ORENCIA solution over: • 30 minutes for RA, pJIA, and adults with PsA • 60 minutes for aGVHD prophylaxis 10 Must complete the infusion of the diluted ORENCIA solution within 24 hours of reconstitution of the ORENCIA vials. Do not infuse ORENCIA 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 drugs.

Storage of Diluted ORENCIA Solution May store the diluted ORENCIA solution at room temperature or refrigerate at 2ºC to 8ºC (36ºF to 46ºF) up to 24 hours before use. Discard the diluted solution if not administered within 24 hours.

Recommendations for Subcutaneous Administration

ORENCIA prefilled syringes and ORENCIA ClickJect autoinjectors are intended for: • Subcutaneous use only and are not intended for intravenous infusion. • Use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient or the patient’s caregiver may administer a subcutaneous injection of ORENCIA (ClickJect autoinjector or prefilled syringe) if a healthcare practitioner determines that it is appropriate. Instruct patients and/or caregivers to follow the directions provided in the Instructions for Use for additional details on administration.

Specifically instruct them to inject the full amount (which provides the proper dose of ORENCIA), rotate injection sites, and to avoid injections into areas where the skin is tender, bruised, red, or hard. Do not use ORENCIA prefilled syringes or ORENCIA ClickJect autoinjectors exhibiting particulate matter or discoloration. ORENCIA should be clear to slightly opalescent and colorless to pale yellow.

Clinical Trials Experience

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. Adverse Reactions in Adult Patients with RA Adverse Reactions in Adult Patients with RA Treated with Intravenous ORENCIA The data from placebo-controlled studies described herein reflect exposure to ORENCIA administered intravenously in patients with active RA (1955 patients with ORENCIA, 989 with placebo) (Studies I through VI). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF antagonist (204 patients with ORENCIA, 134 with placebo).

The concomitant use of ORENCIA with a TNF antagonist is not recommended. 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 antagonist, 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 reactions 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%), 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%). Most Common Adverse Reactions in Adult Patients with RA Treated with Intravenous ORENCIA Adverse reactions occurring in 3% or more of patients and at least 1% more frequently in ORENCIA-treated patients (intravenous) during placebo-controlled RA studies are summarized in Table 4. Table 4: Most Common Adverse Reactions* During Placebo-Controlled RA Studies of Intravenous ORENCIA Infections in Adult Patients with RA Treated with Intravenous ORENCIA In the placebo-controlled trials in patients with RA, infections were reported in 54% of intravenous 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. Serious infections were reported in 3% 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. Malignancies in Adult Patients with RA Treated with Intravenous ORENCIA In the placebo-controlled portions of the clinical trials (1955 patients treated for RA 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). 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. The potential role of ORENCIA in the development of malignancies in humans is unknown.

Infusion-Related Reactions and Hypersensitivity Reactions in Adult Patients with RA Treated with Intravenous ORENCIA Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V 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.

In clinical trials of 2688 adult RA patients treated with intravenous ORENCIA, there were two cases (<0.1%) of anaphylaxis. Other reactions 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.

Adverse Reactions in Patients with COPD Treated for RA with Intravenous ORENCIA In Study V, there were 37 and 17 patients with chronic obstructive pulmonary disease (COPD) who were treated for RA with ORENCIA and placebo, respectively. The COPD patients treated with ORENCIA for RA 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 and pneumonia. Adverse Reactions in Methotrexate-Naive Patients with RA Treated with Intravenous ORENCIA Study VI was an active-controlled clinical trial in methotrexate-naive patients. The safety experience in these patients was consistent with the patients in Studies I-V.

Adverse Reactions in Adult Patients with RA Treated with Subcutaneous or Intravenous ORENCIA The data described below are derived from Study SC-1. Study SC-1 was a randomized, double-blind, double-dummy, non-inferiority study that compared the safety of ORENCIA administered subcutaneously or intravenously in 1457 patients with RA, who received background methotrexate, and experienced an inadequate response to methotrexate (MTX-IR). The adverse reaction profile in patients treated with subcutaneous ORENCIA was similar to the adverse reaction profile in patients treated with intravenous ORENCIA and consistent with intravenous ORENCIA administered in Studies I-VI.

Injection Site Reactions in Adult RA Patients Treated with Subcutaneous ORENCIA The overall frequency of injection site reactions in Study SC-1 was for the subcutaneous ORENCIA group and the subcutaneous placebo group (given intravenous ORENCIA), respectively. All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation. Adverse Reactions in Adult Patients with PsA Adverse Reactions in Adult Patients with PsA Treated with Intravenous or Subcutaneous ORENCIA The safety of ORENCIA was evaluated in 594 patients with PsA (341 patients on ORENCIA and 253 patients on placebo), in two randomized, double-blind, placebo-controlled trials.

Of the 341 patients who received ORENCIA, 128 patients received intravenous ORENCIA (PsA-I) and 213 patients received subcutaneous ORENCIA (PsA-II). The safety profile was comparable between ORENCIA given intravenously in Study PsA-I and ORENCIA given subcutaneously in Study PsA-II and also consistent with the safety profile of ORENCIA in patients with RA. Adverse Reactions in Patients with pJIA Adverse Reactions in Patients with pJIA Treated with Intravenous ORENCIA In general, the adverse events in pediatric patients with polyarticular JIA (pJIA) treated with intravenous ORENCIA were similar in frequency and type to those seen in adult patients with RA treated with intravenous ORENCIA.

Study JIA-1 was a three-part study including an open-label extension that assessed the safety of intravenous ORENCIA in 190 pediatric patients, 6 to 17 years of age, with pJIA. 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%. 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 were reported during the initial 4 months of treatment with intravenous ORENCIA. Of the 190 pediatric patients with pJIA treated with intravenous 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. Adverse Reactions in Patients with pJIA Treated with Subcutaneous ORENCIA Study JIA-2 was an open-label study with a 4-month short-term period and a long-term extension period that assessed the safety of subcutaneous ORENCIA in 205 pediatric patients, 2 to 17 years of age with pJIA.

The adverse reaction profile in patients with pJIA treated with ORENCIA administered subcutaneously in Study JIA-2 were consistent with the adverse reaction profile in patients with pJIA treated with intravenous Study JIA-1. There were no reported cases of hypersensitivity reactions. Local injection‑site reactions occurred at a frequency of 4.4%.

Adverse Reactions in Patients Undergoing Unrelated-Donor Hematopoietic Stem Cell Transplantation (HSCT) with Intravenous ORENCIA The data described herein were from one clinical study of ORENCIA (GVHD-1) for aGVHD prophylaxis in patients 6 years and older with hematologic malignancies who were undergoing unrelated HSCT wherein all patients were receiving calcineurin inhibitor and methotrexate as the standard of care for aGVHD prophylaxis. The safety information from the date of first dose of ORENCIA up to Day 225 post-transplantation from this study is presented below. The incidence of adverse reactions was determined based on pooled data of ORENCIA-treated patients from the 2 study cohorts (n=116).

Permanent discontinuation of ORENCIA due to an adverse reaction occurred in two patients (1.7%) due to one case each of pneumonia and allergic reaction. The most common (≥10%) adverse reactions in the ORENCIA treated patients were anemia, hypertension, CMV reactivation/CMV infection, pyrexia, pneumonia, epistaxis, CD4 lymphocytes decreased, hypermagnesemia, and acute kidney injury. Table 5 summarizes the frequency of adverse reactions reported in the study of ORENCIA in GVHD-1.

Table 5: Adverse Reactions (≥10%) in Patients with aGVHD Who Received ORENCIA with a Difference Between Arms of > Clinically relevant adverse reactions in <10% of patients who received ORENCIA in combination with calcineurin inhibitor and methotrexate in Study GVHD-1 included EBV reactivation.

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other abatacept products may be misleading. Immunogenicity in Adult Patients with RA Treated with Intravenous ORENCIA 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 intravenous ORENCIA. Thirty-four of 1993 (2%) 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. 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 anti-abatacept antibody development to clinical response or adverse events was observed. Immunogenicity in Adult RA Patients Treated with Subcutaneous or Intravenous ORENCIA Study SC-1 compared the immunogenicity to abatacept following subcutaneous or intravenous ORENCIA administration.

The overall immunogenicity frequency to abatacept was 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 in Adult RA Patients Treated with Subcutaneous ORENCIA Monotherapy Study SC-2 was conducted to determine the effect of subcutaneous monotherapy use of ORENCIA on immunogenicity (without an intravenous loading dose) in 100 RA patients, who had not previously received ORENCIA or other CTLA4Ig.

Patients in this study received either subcutaneous ORENCIA plus methotrexate (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed anti-abatacept antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies.

Immunogenicity in Adult RA Patients After Treatment, Withdrawal, and then Restart of Subcutaneous ORENCIA Study SC-3 was conducted to investigate the immunogenicity in adult RA patients after treatment, withdrawal (three months), and restart of ORENCIA subcutaneous treatment (patients were 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).

Half of the patients who received subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. 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 compared to those who remained on subcutaneous therapy (these results occurred in those who received or did not receive an intravenous loading dose). Immunogenicity in Patients with pJIA Treated with Intravenous ORENCIA Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with pJIA following repeated treatment with intravenous 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. Immunogenicity in Patients Treated for Prophylaxis of aGVHD with Intravenous ORENCIA Immunogenicity was assessed in patients undergoing HSCT.

Overall, immunogenicity incidence and associated antibody titers were low from the 4-dose intravenous ORENCIA regimen used in this study. Of the 114 immunogenicity evaluable subjects in the ORENCIA groups, none were positive during the ORENCIA treatment period (Day -1 to Day 28 following transplant). In this study, immunogenicity positive subjects only had ADA positive samples on Day 180 (off-treatment period) and thus due to the timing of the response, the impact on PK, safety, or efficacy could not be determined.

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 with ORENCIA, the following adverse reactions have been identified: • Vasculitis (including cutaneous vasculitis and leukocytoclastic vasculitis) • New or worsening psoriasis • Non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma) • Angioedema reactions During postmarketing experience with intravenous ORENCIA, systemic infusion reactions were similar to that seen in the clinical trial experience with intravenous ORENCIA with the exception of one case of fatal anaphylaxis.

Postmarketing reports of systemic injection reactions (e.g., pruritus, throat tightness, dyspnea) have occurred following the use of subcutaneous ORENCIA.

Immunosuppressants

Concomitant 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. There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic RA therapy, such as anakinra, or other biologic PsA therapy, and JAK inhibitors 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 pyrroloquinoline quinone (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 intravenous ORENCIA, 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.

Pregnancy Risk Summary The data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. However, there are clinical considerations for administering live vaccines to infants who were exposed to ORENCIA while in utero (see Clinical Considerations). In reproductive toxicology studies in rats and rabbits, no fetal malformations were observed with intravenous administration of ORENCIA during organogenesis at doses that produced exposures approximately 29 times the exposure at the maximum recommended human dose (MRHD) of 10 mg/kg/month on an AUC basis.

However, in a pre- and postnatal development study in rats, ORENCIA altered immune function in female rats at 11 times the MRHD on an AUC basis. Clinical Considerations Infants and Administration of Live Vaccines It is unknown if abatacept can cross the placenta into the fetus when a woman is treated with ORENCIA during pregnancy. Abatacept is an immunomodulatory agent.

It is unknown if the immune response of an infant who was exposed in utero to abatacept and subsequently administered a live vaccine is impacted. Risks and benefits should be considered prior to vaccinating such infants. Data Human Data There are no adequate and well-controlled studies of ORENCIA use in pregnant women.

No adverse effects were observed at approximately 3 times the MRHD (a maternal dose of 45 mg/kg). It is not known if immunologic perturbations in rats are relevant indicators of a risk for development of autoimmune diseases in humans exposed in utero to abatacept. 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.

Pediatric Use Polyarticular Juvenile Idiopathic Arthritis The safety and effectiveness of ORENCIA for reducing signs and symptoms in patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA) have been established (ORENCIA may be used as monotherapy or concomitantly with methotrexate). Use of ORENCIA for this indication is supported by evidence from the following studies: Intravenous Use: A randomized withdrawal efficacy, safety, and pharmacokinetic study of intravenous ORENCIA in 190 pediatric patients 6 to 17 years of age with pJIA. Given that population pharmacokinetic (PK) analyses (after intravenous ORENCIA administration) showed that clearance of abatacept increased with baseline body weight, intravenous ORENCIA is administered either weight-based or weight ranged based.

Intravenous ORENCIA administration has not been studied in patients younger than 6 years of age. Subcutaneous Use: An open-label PK and safety study of subcutaneous ORENCIA in 205 pediatric patients aged 2 to 17 years old with pJIA, extrapolation of effectiveness of intravenous ORENCIA in patients with pJIA and subcutaneous ORENCIA in patients with RA. Given that population PK analyses (after subcutaneous ORENCIA injection) in pJIA patients showed that there was a trend toward higher clearance of abatacept with increasing body weight, subcutaneous ORENCIA dosage is weight range-based.

The safety and effectiveness of ORENCIA use in pJIA in pediatric patients less than two years of age have not been established. Acute Graft Versus Host Disease Prophylaxis The safety and effectiveness of ORENCIA for the prophylaxis of Acute Graft Versus Host Disease (aGVHD), in combination with a calcineurin inhibitor and methotrexate, in pediatric patients aged 2 years of age and older undergoing HSCT from a matched or 1 allele-mismatched unrelated donor have been established. Furthermore, the course of disease is sufficiently similar in pediatric patients aged 2 years to less than 6 years to that of patients aged 6 years and older to allow extrapolation of data to younger pediatric patients.

No new safety signals were observed in pediatric patients aged 6 years and older in Study GVHD-1. The safety and effectiveness of ORENCIA for this indication have not been established in pediatric patients less than 2 years of age. Psoriatic Arthritis Subcutaneous Administration The safety and effectiveness of subcutaneous ORENCIA have been established for treatment of psoriatic arthritis in pediatric patients 2 to 17 years old.

Use of ORENCIA in this age group is supported by evidence from adequate and well-controlled studies of ORENCIA in adults with PsA, pharmacokinetic data from adult patients with RA, adult patients with PsA, and pediatric patients with pJIA, and safety data from clinical studies in pediatric patients 2 to 17 years old with pJIA using the subcutaneous formulation. The observed pre-dose (trough) concentrations are generally comparable between adults with RA and PsA and pediatric patients with JIA with active polyarthritis, and the PK exposure is expected to be comparable between adult PsA and pediatric patients with PsA. The safety and effectiveness of subcutaneous ORENCIA have not been established in pediatric patients less than 2 years old with psoriatic arthritis.

Intravenous Administration The safety and effectiveness of intravenous ORENCIA in pediatric patients with psoriatic arthritis have not been established. Juvenile Animal Toxicity Data A juvenile animal study conducted in rats dosed with abatacept from 4 to 94 days of age (prior to immune system maturity) showed an increase in the incidence of infections leading to death at all doses compared with controls. Altered T-cell subsets including increased T-helper cells and reduced T-regulatory cells were observed.

In addition, inhibition of T-cell-dependent antibody responses (TDAR) was observed. Upon following these animals into adulthood, lymphocytic inflammation of the thyroid and pancreatic islets was observed. In contrast, 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 is unknown.

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.