Orencia Information
Orencia (Abatacept) Dosage And Administration
For adult patients with RA, Orencia (Abatacept) may be administered as an intravenous infusion or a subcutaneous injection.
Orencia (Abatacept) 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 ].
Use aseptic technique.
Orencia (Abatacept) is provided as a lyophilized powder in preservative-free, single-use vials. Each Orencia (Abatacept) vial provides 250 mg of abatacept for administration. The Orencia (Abatacept) powder in each vial must be reconstituted with 10 mL of Sterile Water for Injection, USP, using and an 18- to 21-gauge needle. After reconstitution, the concentration of abatacept in the vial will be 25 mg/mL. If the Orencia (Abatacept) 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 is dropped or becomes contaminated, use a new from inventory. For information on obtaining additional , contact Bristol-Myers Squibb 1-800-Orencia (Abatacept) .
Orencia (Abatacept) Injection, 125 mg/syringe is not intended for intravenous infusion.
Orencia (Abatacept) 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 (Abatacept) 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 (Abatacept) prefilled syringes exhibiting particulate matter or discoloration. Orencia (Abatacept) should be clear and colorless to pale yellow.
Patients using Orencia (Abatacept) for subcutaneous administration should be instructed to inject the full amount in the syringe (1 mL), which provides 125 mg of Orencia (Abatacept) , 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.
Orencia (Abatacept) Contraindications
Orencia (Abatacept) Warnings And Precautions
Prior to initiating immunomodulatory therapies, including Orencia (Abatacept) , patients should be screened for latent tuberculosis infection with a tuberculin skin test. Orencia (Abatacept) has not been studied in patients with a positive tuberculosis screen, and the safety of Orencia (Abatacept) 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 (Abatacept) .
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 (Abatacept) . In clinical studies with Orencia (Abatacept) , patients who screened positive for hepatitis were excluded from study.
Live vaccines should not be given concurrently with Orencia (Abatacept) 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 (Abatacept) . The efficacy of vaccination in patients receiving Orencia (Abatacept) is not known. Based on its mechanism of action, Orencia (Abatacept) 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 (Abatacept) therapy.
Orencia (Abatacept) Adverse Reactions
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 (Abatacept) administered intravenously in patients with active RA in placebo-controlled studies (1955 patients with Orencia (Abatacept) , 989 with placebo). The studies had either a double-blind, placebo-controlled period of 6 months (258 patients with Orencia (Abatacept) , 133 with placebo) or 1 year (1697 patients with Orencia (Abatacept) , 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF blocking agent (204 patients with Orencia (Abatacept) , 134 with placebo).
The majority of patients in RA clinical studies received one or more of the following concomitant medications with Orencia (Abatacept) : 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 (Abatacept) ) were headache, upper respiratory tract infection, nasopharyngitis, and nausea.
The adverse events most frequently resulting in clinical intervention (interruption or discontinuation of Orencia (Abatacept) ) 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%).
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 ]. The safety experience and immunogenicity for Orencia (Abatacept) 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.
In general, the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients [see , ].
Orencia (Abatacept) 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 ]. 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 (Abatacept) .
Of the 190 patients with juvenile idiopathic arthritis treated with Orencia (Abatacept) 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.
Orencia (Abatacept) Drug Interactions
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 (Abatacept) for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving Orencia (Abatacept) 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 (Abatacept) for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.
Orencia (Abatacept) Use In Specific Populations
Orencia (Abatacept) 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 (Abatacept) may be used as monotherapy or concomitantly with methotrexate.
Studies in juvenile rats exposed to Orencia (Abatacept) 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 ]. 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 (Abatacept) is not recommended for use in patients below the age of 6 years.
The safety and effectiveness of Orencia (Abatacept) in pediatric patients below 6 years of age have not been established. The safety and efficacy of Orencia (Abatacept) in pediatric patients for uses other than juvenile idiopathic arthritis have not been established.
Orencia (Abatacept) 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 (Abatacept) 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 (Abatacept) 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 (Abatacept) is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of Orencia (Abatacept) provides 250 mg abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium chloride (14.6 mg) for administration.
Orencia (Abatacept) 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 (Abatacept) solution for subcutaneous administration contains no maltose.
Orencia (Abatacept) Clinical Pharmacology
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
Orencia (Abatacept) Nonclinical Toxicology
In a mouse carcinogenicity study, weekly subcutaneous injections of 20, 65, or 200 mg/kg of abatacept administered for up to 84 weeks in males and 88 weeks in females were associated with increases in the incidence of malignant lymphomas (all doses) and mammary gland tumors (intermediate- and high-dose in females). The mice from this study were infected with murine leukemia virus and mouse mammary tumor virus. These viruses are associated with an increased incidence of lymphomas and mammary gland tumors, respectively, in immunosuppressed mice. The doses used in these studies produced exposures 0.8, 2.0, and 3.0 times higher, respectively, than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). The relevance of these findings to the clinical use of Orencia (Abatacept) is unknown.
In a one-year toxicity study in cynomolgus monkeys, abatacept was administered intravenously once weekly at doses up to 50 mg/kg (producing 9 times the MRHD exposure based on AUC). Abatacept was not associated with any significant drug-related toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphologic changes was observed, despite the presence of a virus (lymphocryptovirus) known to cause these lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of Orencia (Abatacept) is unknown.
No mutagenic potential of abatacept was observed in the bacterial reverse mutation (Ames) or Chinese hamster ovary/hypoxanthine guanine phosphoribosyl-transferase (CHO/HGPRT) forward point mutation assays with or without metabolic activation, and no chromosomal aberrations were observed in human lymphocytes treated with abatacept with or without metabolic activation.
Abatacept had no adverse effects on male or female fertility in rats at doses up to 200 mg/kg every three days (11 times the MRHD exposure based on AUC).
A juvenile animal study was conducted in rats dosed with abatacept from 4 to 94 days of age in which an increase in the incidence of infections leading to death occurred 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 studies of adult mice and monkeys, inhibition of TDAR was apparent. However, infection and mortality, altered T-helper cells, and inflammation of thyroid and pancreas were not observed.
Orencia (Abatacept) Clinical Studies
The efficacy and safety of Orencia (Abatacept) for intravenous administration were assessed in six randomized, double-blind, controlled studies (five placebo-controlled and one active-controlled) in patients ≥18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, IV, and VI required patients to have at least 12 tender and 10 swollen joints at randomization. Study V did not require any specific number of tender or swollen joints. Orencia (Abatacept) or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter in intravenous Studies I, II, III, IV, and VI. The safety and efficacy of Orencia (Abatacept) for subcutaneous administration were assessed in Study SC-I, which was a randomized, double-blind, double-dummy, non-inferiority study that compared abatacept administered subcutaneously and intravenously in 1457 subjects with rheumatoid arthritis (RA), receiving background methotrexate (MTX), and experiencing an inadequate response to methotrexate (MTX-IR).
Study I evaluated Orencia (Abatacept) as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept. In Study II and Study III, the efficacy and safety of Orencia (Abatacept) were assessed in patients with an inadequate response to methotrexate and who were continued on their stable dose of methotrexate. In Study IV, the efficacy and safety of Orencia (Abatacept) were assessed in patients with an inadequate response to a TNF blocking agent, with the TNF blocking agent discontinued prior to randomization; other DMARDs were permitted. Study V primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued. Patients in Study V were not excluded for comorbid medical conditions. In Study VI, the efficacy and safety of Orencia (Abatacept) were assessed in methotrexate-naive patients with RA of less than 2 years disease duration. In Study VI, patients previously naive to methotrexate were randomized to receive Orencia (Abatacept) plus methotrexate or methotrexate plus placebo. In Study SC-I, the goal was to demonstrate the efficacy and safety of Orencia (Abatacept) subcutaneous relative to Orencia (Abatacept) intravenous administration in subjects with moderate to severely active RA and experiencing inadequate response to methotrexate, using a non-inferiority study design.
Study I patients were randomized to receive one of three doses of Orencia (Abatacept) (0.5, 2, or 10 mg/kg) or placebo ending at week 8. Study II patients were randomized to receive Orencia (Abatacept) 2 or 10 mg/kg or placebo for 12 months. Study III, IV, V, and VI patients were randomized to receive a dose of Orencia (Abatacept) based on weight range or placebo for 12 months (Studies III, V, and VI) or 6 months (Study IV). The dose of Orencia (Abatacept) was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg. In Study SC-I, patients were randomized with stratification by body weight (100 kg) to receive Orencia (Abatacept) 125 mg subcutaneous injections weekly, after a single intravenous loading dose of Orencia (Abatacept) based on body weight or Orencia (Abatacept) intravenously on Days 1, 15, 29, and every four weeks thereafter. Subjects continued taking their current dose of methotrexate from the day of randomization.
The safety and efficacy of Orencia (Abatacept) were assessed in a three-part study including an open-label extension in children with polyarticular juvenile idiopathic arthritis (JIA). Patients 6 to 17 years of age (n=190) with moderately to severely active polyarticular JIA who had an inadequate response to one or more DMARDs, such as methotrexate or TNF antagonists, were treated. Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and ESR (mean, 32 mm/h). The patients enrolled had subtypes of JIA that at disease onset included Oligoarticular (16%), Polyarticular (64%; 20% were rheumatoid factor positive), and Systemic (20%). At study entry, 74% of patients were receiving methotrexate (mean dose, 13.2 mg/m per week) and remained on a stable dose of methotrexate (those not receiving methotrexate did not initiate methotrexate treatment during the study).
In Period A (open-label, lead-in), patients received 10 mg/kg (maximum 1000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as ≥30% improvement in at least 3 of the 6 JIA core set variables and ≥30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either Orencia (Abatacept) or placebo for 6 months or until disease flare. Disease flare was defined as a ≥30% worsening in at least 3 of the 6 JIA core set variables with ≥30% improvement in not more than 1 of the 6 JIA core set variables; ≥2 cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in ≥2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare.
At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. Pediatric ACR 30 responses were similar in all subtypes of JIA studied.
During the double-blind randomized withdrawal phase (Period B), Orencia (Abatacept) -treated patients experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on Orencia (Abatacept) was less than one-third than that for patients withdrawn from Orencia (Abatacept) treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]). Among patients who received Orencia (Abatacept) throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders has remained consistent for 1 year.
Orencia (Abatacept) How Supplied/storage And Handling
For Intravenous Infusion
Orencia (Abatacept) lyophilized powder for intravenous infusion is supplied as an individually packaged, single-use vial with a silicone-free disposable syringe, providing 250 mg abatacept in a 15-mL vial: NDC 0003-2187-10.
For Subcutaneous Injection
Orencia (Abatacept) injection solution for subcutaneous administration is supplied as a single-dose disposable prefilled glass syringe with flange extender. The Type I glass syringe has a coated stopper and fixed stainless steel needle (5 bevel, 29-gauge thin wall, ½-inch needle) covered with a rigid needle shield. The prefilled syringe provides 125 mg of abatacept in 1 mL and is provided in a pack of 4 syringes: NDC 0003-2188-31.
Storage
Orencia (Abatacept) lyophilized powder supplied in a vial should be refrigerated at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the vial. Protect the vials from light by storing in the original package until time of use.
Orencia (Abatacept) solution supplied in a prefilled syringe should be refrigerated at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the prefilled syringe. Protect from light by storing in the original package until time of use. Do not allow the prefilled syringe to freeze.
Orencia (Abatacept)
Orencia (Abatacept)
Orencia (Abatacept)
Orencia (Abatacept)
