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ORENCIA is a brand name for Abatacept. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE ORENCIA is a selective T cell costimulation modulator indicated for: • the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). (1.1) • the treatment of patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic…
Verbatim from this product's FDA label. Tap a section to expand.
1) • Prior to the first subcutaneous dose, may administer an optional loading dose as a single intravenous infusion as per body weight categories above. • Administer 125 mg by subcutaneous injection once weekly (within a day of the intravenous infusion if infusion given).
• Patients switching from intravenous use to subcutaneous use, administer first subcutaneous dose instead of next scheduled intravenous dose. 2) • Pediatric patients weighing <75 kg administer 10 mg/kg intravenously and those weighing ≥75 kg administer the adult intravenous dosing regimen (not to exceed a maximum dose of 1,000 mg), as a 30-minute infusion.
• Subsequently administer infusions at 2 and 4 weeks and every 4 weeks thereafter. 3 ) • Administer 125 mg by subcutaneous injection once weekly without an intravenous loading dose. • Patients switching from intravenous use to subcutaneous use, administer first subcutaneous dose instead of next scheduled intravenous dose.
4) • For patients 6 years and older, administer at a 10 mg/kg dose (maximum dose 1,000 mg) as a 60-minute infusion on the day before transplantation, followed by a dose on Day 5, 14, and 28 after transplant. • For patients 2 to less than 6 years old, administer a 15 mg/kg dose as a 60-minute infusion on the day before transplantation, followed by a 12 mg/kg dose as a 60-minute infusion on Day 5, 14, and 28 after transplant.
6 ) • Administer as a 30-minute intravenous infusion for RA, pJIA, and adult PsA. 5) • Administer as a 60-minute intravenous infusion for aGVHD prophylaxis. 5) • See the Full Prescribing Information for preparation and administration instructions for intravenous infusion and recommendations for subcutaneous use.
6) Prepare ORENCIA using only the silicone-free disposable syringe. 1 Dosage in Adult Rheumatoid Arthritis For adult patients with RA, administer as an intravenous infusion or as a subcutaneous injection. , TNF antagonists). 5) ] 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 Body Weight of Adult Patient Dose Number of Vials a 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 1,000 mg 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).
7) ] • Most common adverse events (≥10%) in RA are headache, upper respiratory tract infection, nasopharyngitis, and nausea. 1) • Most common adverse reactions (≥10%) in prophylaxis of aGVHD are anemia, hypertension, CMV reactivation/CMV infection, pyrexia, pneumonia, epistaxis, CD4 lymphocytes decreased, hypermagnesemia, and acute kidney injury.
gov/medwatch . 1 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.
1) ] . 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 antagonist (204 patients with ORENCIA, 134 with placebo).
5) ] . 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. 7%). 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.
5 WARNINGS AND PRECAUTIONS • Concomitant use with a TNF antagonist can increase the risk of infections and serious infections. 1) • Hypersensitivity and anaphylaxis have occurred. 2) • Serious infections reported. Patients with a history of recurrent infections or underlying conditions predisposing to infections may experience more infections.
Discontinue if a serious infection develops. 3) • Screen for latent TB infection prior to initiating therapy. Patients testing positive should be treated prior to initiating ORENCIA. 3) • Screen for viral hepatitis prior to initiating ORENCIA.
3) • Update vaccinations prior to initiating ORENCIA. Live vaccines should not be given concurrently or within 3 months of discontinuation. ORENCIA may blunt the effectiveness of some immunizations. 4) • COPD patients may develop more frequent respiratory adverse reactions.
5) • Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) reactivation in patients treated for aGVHD prophylaxis. 1 Increased Risk of Infection with Concomitant Use of TNF Antagonists, Other Biologic RA/PsA Therapy, or JAK Inhibitors In controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63% vs.
4% vs. 1) ] . These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of ORENCIA with TNF antagonists; 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. Additionally, concomitant use of ORENCIA with other biologic RA/PsA therapy or JAK inhibitors is not recommended.
1%) of anaphylaxis reactions. 9% of ORENCIA-treated patients. 1 )] . In postmarketing experience, fatal anaphylaxis following the first infusion of ORENCIA and life-threatening cases of angioedema have been reported. Angioedema has occurred as early as after the first dose of ORENCIA, but also has occurred with subsequent doses.
4 CONTRAINDICATIONS None. None. (4)
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If an intravenous loading dose is used, administer the first subcutaneous injection within one day of the infusion. 6) ] . For patients switching from ORENCIA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.
4) ] . ORENCIA may be used as monotherapy or concomitantly with methotrexate. 5) ] : • 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.
Following the initial intravenous infusion, administer infusions at 2 and 4 weeks and every 4 weeks thereafter. Immediately discard any unused portion in the vials. 6) ] . Subsequently administer once weekly. 5 mg 50 kg or more 125 mg 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. 3 Dosage in Psoriatic Arthritis Adult Patients For adult patients with psoriatic arthritis, administer as an intravenous infusion or a subcutaneous injection.
ORENCIA may be used with or without non-biologic DMARDs. Intravenous Dosage Administer ORENCIA as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, administer an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter.
6) ] . For patients switching from ORENCIA intravenous infusions to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. 4) ] . ORENCIA may be used as monotherapy or concomitantly with methotrexate.
Intravenous administration is not approved for pediatric patients with psoriatic arthritis. 6) ] . 5 mg 50 kg or more 125 mg Pediatric patients with psoriatic arthritis 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. 4 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.
7) ]. Intravenous Dosing Regimen For patients 6 years and older, administer ORENCIA 10 mg/kg (maximum dose of 1,000 mg) as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation.
For patients 2 to less than 6 years old, administer ORENCIA 15 mg/kg as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by 12 mg/kg as an intravenous infusion over 60 minutes on Days 5, 14, and 28 after transplantation.
5 Preparation and Administration Instructions for Intravenous Infusion Calculate the ORENCIA dose, the total volume of reconstituted solution required, and the number of ORENCIA vials needed. 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).
Do not use if opaque particles, discoloration, or other foreign particles are present. 6) Repeat steps 2) through 5) if two, three, or four vials are needed for a dose (see Table 1). Dilution 7) Must further dilute the reconstituted ORENCIA solution to 100 mL as follows: a.
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. 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. 6 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.
Visually inspect for particulate matter and discoloration prior to administration. 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.
Table 4:
Most Common Adverse Reactions* During Placebo-Controlled RA Studies of Intravenous ORENCIA Intravenous ORENCIA (n=1955) a Placebo (n=989) b * Occurred in ≥3% patients and >1% more frequently in ORENCIA-treated patients. 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% 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. 3) ] . 9% of patients treated with placebo.
3) ] . 1%, respectively). 2%) than placebo-treated patients (0 cases, 0%). 10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). 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. 6) ] . The potential role of ORENCIA in the development of malignancies in humans is unknown. 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. 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.
1%) of anaphylaxis. 9% of ORENCIA-treated patients and generally occurred within 24 hours of ORENCIA infusion. 2) ] . 1) ] , 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.
5) ] . 1) ] . 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.
1) ] . 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.
1) ] . All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation. 3) ]. Of the 341 patients who received ORENCIA, 128 patients received intravenous ORENCIA (PsA-I) and 213 patients received subcutaneous ORENCIA (PsA-II).
1 )]. 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 [see Warnings and Precautions (5 ) and Adverse Reactions (6) ] .
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. 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 intravenous ORENCIA. 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.
4%. 4) ] . Two cohorts were studied at 10 mg/kg (maximum dose of 1,000 mg) as an intravenous infusion over 60 minutes on the day before transplantation (Day-1), followed by administration on Days 5, 14, and 28 after transplantation: 1) A single-arm cohort of ORENCIA-treated patients (n=43) who underwent 7 of 8 Human leukocyte antigen (HLA)-matched HSCT from unrelated donors (7 of 8 cohort) and 2) A randomized cohort comprised of ORENCIA-treated patients (n=73) and placebo-treated patients (n=69) who underwent 8 of 8 HLA-matched HSCT from unrelated donors (8 of 8 cohort).
4) ] . 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).
Serious adverse reactions reported in > 5% of patients who received ORENCIA in combination with a calcineurin inhibitor and methotrexate included pyrexia (20%), pneumonia (8%), acute kidney injury (7%), diarrhea (6%), hypoxia (5%), and nausea (5%).
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 >2% Compared to Placebo in GVHD-1 7 of 8 Cohort 8 of 8 Cohort Adverse Reaction ORENCIA (+CNI and MTX) (N=43) ORENCIA (+CNI and MTX) (N=73) Placebo (+CNI and MTX) (N=69) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Blood and Lymphatic System Disorders Anemia 56 56 69 69 57 57 CD4 lymphocytes decreased 14 14 14 14 9 9 Vascular Disorders Hypertension 49 49 43 43 38 38 General Disorders and Administrative Site Conditions Pyrexia 28 9 19 10 20 4 Infections and Infestations CMV Reactivation/CMV Infection 26 26 32 32 22 22 Pneumonia 19 19 12 12 10 9 Respiratory and Mediastinal Disorders Epistaxis 12 12 16 16 10 10 Renal and Urinary Disorders Acute kidney injury 9 7 15 15 10 10 Metabolism and Nutrition Disorders Hypermagnesemia 5 5 18 18 10 10 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.
2 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.
In the subset analysis, 9 of 154 (6%) patients that had discontinued intravenous ORENCIA treatment 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 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 1% (8/725) and 2% (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 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).
At the end of the withdrawal period, 0/38 (0%) patients who continued to receive subcutaneous ORENCIA developed anti-abatacept antibodies compared to 7/73 (10%) of patients who had subcutaneous ORENCIA withdrawn during this period.
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. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (3%) in the group who received subcutaneous ORENCIA throughout, and 2/73 (3%) 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 compared to those who remained on subcutaneous therapy (these results occurred in those who received or did not receive an intravenous loading dose).
The safety observed in this study was consistent with that observed in the other studies. 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). 6%) were positive for CTLA4 and possibly Ig; 4 of the 6 positive subjects were found to have at least one positive sample with neutralization activity.
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. 3 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. 2) ] . , pruritus, throat tightness, dyspnea) have occurred following the use of subcutaneous ORENCIA.
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.
In the subset analysis, 9 of 154 (6%) patients that had discontinued intravenous ORENCIA treatment 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 anti-abatacept antibody development to clinical response or adverse events was observed.
, days). Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction. If an anaphylactic or other serious allergic reaction occurs, administration of intravenous or subcutaneous ORENCIA should be stopped immediately with appropriate therapy instituted, and the use of ORENCIA should be permanently discontinued.
1) ] . 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.
1) ] . Healthcare providers 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. Prior to initiating ORENCIA, patients should be screened for latent tuberculosis (TB) infection according to current TB guidelines.
ORENCIA has not been studied in patients with a positive TB screen, and the safety of ORENCIA in individuals with latent TB infection is unknown. Patients testing positive in TB 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.
4 Immunizations Prior to initiating ORENCIA in pediatric and adult patients, update vaccinations in accordance with current vaccination guidelines. ORENCIA-treated patients may receive current non-live vaccines. Live vaccines should not be given concurrently with ORENCIA or within 3 months after discontinuation.
No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. 1) ] . Based on its mechanism of action, ORENCIA may blunt the effectiveness of some immunizations. 5 Increased Risk of Adverse Reactions When Used in Patients with Chronic Obstructive Pulmonary Disease (COPD) In Study V, adult COPD patients treated with ORENCIA for RA developed adverse reactions more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea.
1) ] . Use of ORENCIA in patients with COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status. 6 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.
1) ] . 1) ] . 3) ] . Periodic skin examinations are recommended for all ORENCIA-treated patients, particularly those with risk factors for skin cancer. 7 Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Reactivation in aGVHD Prophylaxis after Hematopoietic Stem Cell Transplant (HSCT) Post-Transplant Lymphoproliferative Disorder (PTLD) occurred in patients who received ORENCIA for aGVHD prophylaxis during unrelated HSCT.
4%) experienced PTLD. All the PTLD events were associated with Epstein-Barr virus (EBV) infection. Three of the four patients were EBV serology positive at baseline; one patient had negative baseline EBV serology with donor EBV serology unknown.
Three of the 4 patients discontinued acyclovir prophylaxis at day 30 post-transplant. The range of time to onset of the events was 49 to 89 days post-transplant. Monitor patients for EBV reactivation in accordance with institutional practices.
4) ] . Cytomegalovirus (CMV) invasive disease occurred in patients who received ORENCIA for aGVHD prophylaxis during unrelated HSCT. Of 116 patients who received ORENCIA, 7% experienced CMV invasive diseases up to day 225 post-transplant.
All the patients who experienced CMV invasive disease were CMV serology positive at baseline. The median time to onset of the event was 91 days post-transplant. 1) ] . Monitor patients for CMV infection/reactivation for 6 months post-transplant regardless of the results of donor and recipient pre-transplant CMV serology.
4) ] .