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This site is intended for US-based Health Care Professionals only.
Overview of Head-to-Head Noninferiority Trial vs adalimumab
The AMPLE 2-Year Trial was a randomized, Phase IIIb,
head-to-head noninferiority trial of adult MTX-IR patients, and
is not contained within the Full Prescribing Information.2
It is a supportive trial to AGREE, which was studied in
MTX-naïve patients and had a different comparator. Patients were
randomized to ORENCIA SC + MTX (n=318) or adalimumab
Overview of Registrational Trial in MTX-naïve* Patients4
The AGREE Registrational Trial was a 12-month,
were randomized to ORENCIA IV + MTX (n=256) or
placebo + MTX
(n=253).
89% of patients were anti-CCP+
while 96.5%
were RF+ in the trial.
AGREE: Study design and co-primary endpoints
*Or prior exposure to MTX ≤10 mg/week for ≤3 weeks with none administered for 3 months prior to enrollment.
Head-to-Head
Noninferiority Trial
In a broad population of MTX-IR patients
with moderate to severe RA
Results from a Head-to-Head Noninferiority Trial vs adalimumab
AMPLE was a 2-year Phase IIIb, head-to-head noninferiority trial of adult MTX-IR patients, and is not contained within the Full Prescribing Information.2 It is a supportive trial to the AGREE Registrational Trial, which was studied in MTX-naïve patients and had a different comparator. For more information on AGREE, please see below and the Full Prescribing Information.
Patients were randomized to ORENCIA SC + MTX (n=318) or adalimumab SC +
MTX (n=328).2
45% and 47% of patients were
Patients were required to have moderate to severe RA for ≤5 years, be MTX-IR and biologic-naïve, and have ≥3.2 DAS28-CRP and a history of ≥1 of the following: seropositivity for anti-CCP or RF, or an elevated ESR or CRP level.7
Key limitations of the trial2
Double blinding was not feasible due to difficulty in masking administration of adalimumab.
- Patients were not blinded to study drug
- However, clinical assessors and radiographic readers were blinded to mitigate this limitation
Patients achieved comparable efficacy with ORENCIA SC + MTX vs adalimumab SC + MTX—ACR rates were sustained from Year 1 to Year 22,7
Selected Endpoints: ORENCIA demonstrated similar response rates to adalimumab in DAS28-CRP <2.6
1 Year:
ORENCIA SC + MTX:
43.3% (37.4% to 49.1%)
adalimumab SC + MTX:
41.9% (36.0% to 47.9%)
2 Years:
ORENCIA SC + MTX:
50.6% (44.4% to 56.8%)
adalimumab SC + MTX:
53.3% (47.0% to 59.5%)
Summary of 2-year cumulative safety results in AMPLE
Cumulative rates at Year 2 in the ORENCIA SC + MTX (n=318) and adalimumab SC + MTX (n=328) groups, respectively
- Serious adverse events (SAEs)—13.8% versus 16.5%
- Discontinuations due to SAEs—1.6% versus 4.9%
- Infections and infestations—3.8% versus 5.8%
- Adverse events (AEs)—92.8% versus 91.5%
- Discontinuations due to AEs—3.8% versus 9.5%
- Overall infections—76.1% versus 71.3%
- Malignancies—2.2% versus 2.1%
- Autoimmune events—3.8% versus 1.8%
- Local injection site reactions*—4.1% versus 10.4%
- Deaths†—0.3% versus 0.3%
*Most common local injection site reactions reported were hematoma, pruritus, erythema, rash, hemorrhage, pain, and reaction.
†There was one death in each of these arms; patients each experienced a cardiovascular event.
Some of the observed safety rates for ORENCIA and adalimumab in AMPLE may differ from those previously reported; please refer to the Full Prescribing Information for each product.
Please see Pooled Safety Results below for ORENCIA IV across 5 clinical trials.
Selected Important
Safety
Information
Infections: Serious infections, including sepsis and pneumonia, were reported in 3% and 1.9% of RA patients treated with intravenous ORENCIA and placebo, respectively. 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. Caution should be exercised in patients with a history of infection or underlying conditions which may predispose them to infections. Treatment with ORENCIA should be discontinued if a patient develops a serious infection. Patients should be screened for tuberculosis and viral hepatitis in accordance with published guidelines, and if positive, treated according to standard medical practice prior to therapy with ORENCIA.
- 646 patients were randomized to ORENCIA SC + MTX (n=318; 125 mg once per week) or adalimumab SC + MTX (n=328; 40 mg every other week)2
- AMPLE was designed to show a 12% noninferiority margin3
- 86.2% of patients using ORENCIA and 82% of those using adalimumab completed Year 1 of the study2
- 79.2% of patients using ORENCIA and 74.7% of those using adalimumab completed the study at 2 years2
Inclusion Criteria3,7
- ≥18 years of age with moderate to severe RA for ≤5 years
- Inadequate response to MTX and biologic naïve
-
≥3.2 DAS28-CRP and a history of ≥1 of the following:
- Seropositivity for anti-CCP or RF
- Elevated ESR or CRP level
Key Exclusion Criteria3
-
Previous treatment with an investigational or
approved
biologic RA therapy - History of active or chronic hepatitis B
-
Subjects with any other rheumatic disease or
with active vasculitis of a major organ
Primary Endpoint2,7
-
Noninferiority of ORENCIA SC vs adalimumab SC,
assessed by ACR 20 at
1 year
Selected Secondary Endpoints2,7
- ACR (50, 70) scores through 2 years
- Proportion of patients achieving DAS28-CRP <2.6 through 2 years
- Radiographic outcomes at Year 1 and Year 2 as measured by change in total modified Sharp score
- Proportion of patients achieving a ≥0.3 improvement from baseline in HAQ-DI through 2 years
Other Efficacy Analyses
Descriptive statistics were provided by treatment for ACR 20, ACR 50, and ACR 70 at each scheduled visit and summarized using point estimates and 95% CIs. The proportion of subjects achieving each response was then plotted over time.
Key Baseline Characteristics2,3
|
ORENCIA SC (n=318) |
adalimumab SC (n=318) |
|
|---|---|---|
| Mean disease duration, yr | 1.9 | 1.7 |
| Anti-CCP+*† | 45% | 47% |
| RF+‡ | 75.5% | 77.4% |
| Mean DAS28-CRP | 5.5 | 5.5 |
| Joint Erosion§ | 93% | 96% |
*Anti-CCP status was reported by patient’s medical history for 488 of the 646 patients.3
†In a post-hoc analysis of serum collected for 508 of 646 patients at baseline, 73.7% of ORENCIA-treated patients and 78.9% of adalimumab-treated patients were anti-CCP+.8
‡Seropositive RF antibodies as reported by patient’s
medical history.2
§Radiographic evidence of joint erosion.2
Selected Important
Safety Information
Immunizations: Prior to initiating ORENCIA in pediatric and adult patients, update vaccinations in accordance with current vaccination guidelines. Live vaccines should not be given concurrently with ORENCIA or within 3 months after discontinuation. ORENCIA may blunt the effectiveness of some immunizations. In addition, 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.
Secondary Endpoint: Change in TSS2,7*
*Based on readings at Year 1, the percentage of radiographic nonprogressors was 87.8% for ORENCIA and 88.6% for adalimumab. Graph shown is based on 2-year readings.2,7
Most patients taking ORENCIA did not have radiographic progression based on change in TSS from baseline at
Years 1 and 2
At Year 1, 87.8% of ORENCIA SC + MTX patients demonstrated no change in TSS from baseline.
At Year 2, 84.8% of ORENCIA SC + MTX patients demonstrated no change in TSS from baseline.2,7
Nonprogression was assessed using the modified
Sharp/van der Heijde scoring system and was defined
as
change in total Sharp score ≤ the smallest
detectable change.2
*Based on readings at Year 1, the percentage of radiographic nonprogressors was 87.8% for ORENCIA and 88.6% for adalimumab. Graph shown is based on 2-year readings.2,7
Selected Important
Safety Information
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 events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. In the study, 97% of COPD patients treated with ORENCIA developed adverse events versus 88% treated with placebo. Respiratory disorders occurred more frequently in patients treated with ORENCIA compared to those on placebo (43% vs 24%, respectively), including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of patients treated with ORENCIA developed a serious adverse event compared to those on placebo (27% vs 6%), including COPD exacerbation [3 of 37 patients (8%)] and pneumonia [1 of 37 patients (3%)]. Use of ORENCIA in patients with COPD should be undertaken with caution, and such patients monitored for worsening of their respiratory status.
Secondary Endpoint: HAQ-DI Response Rates
(≥0.3 improvement)2
54.1% of patients taking ORENCIA SC +
MTX achieved a
HAQ-DI, Heath Assessment Questionnaire-Disability Index.
Selected Important
Safety Information
Immunosuppression: In clinical trials in adult RA patients, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo-treated patients. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood. There have been reports of malignancies, including skin cancer in patients receiving ORENCIA. Periodic skin examinations are recommended for all ORENCIA-treated patients, particularly those with risk factors for skin cancer.
Registrational Trial in
Seropositive Patients
In a 1-year trial of MTX-naïve* patients
with moderate to severe
RA
Results in Predominantly Dual-Seropositive Patients from a Registrational Trial4
The AGREE Registrational Trial was a 12-month, placebo-controlled, double-blind, Phase IIIb trial. Adult patients were randomized to ORENCIA IV + MTX (n=256) or placebo + MTX (n=253). 89% of patients were anti-CCP+ while 96.5% were RF+ in the study.
Adult patients were required to have early (≤2 years) and active RA,
be MTX-naïve,* and ≥12 tender and ≥10 swollen joints,
CRP ≥0.45
mg/dL, RF and/or anti-CCP positivity, and radiographic evidence
of bone erosion of the hands, wrists, and feet.
*Or prior exposure to MTX ≤10 mg/week for ≤3 weeks with none administered for 3 months prior to enrollment.
ORENCIA IV + MTX significantly improved
DAS28-CRP <2.6 response rates and
radiographic results at
| CO-PRIMARY ENDPOINTS4,8 At 1 year |
ORENCIA IV + MTX n=256 |
Placebo + MTX n=253 |
|---|---|---|
| Achieved DAS28-CRP <2.6 (95% CI) |
41% (35.4% to 47.4%) P<0.001 |
23% (18.1% to 28.5%) |
|
Radiographic progression (mean change from baseline TSS)† |
0.6 P=0.04 |
1.1 |
| SELECTED ENDPOINTS4,8 At 1 year |
ORENCIA IV + MTX N=256 |
Placebo + MTX N=253 |
|---|---|---|
| HAQ-DI improvement (≥0.3) (95% CI) |
72% (66.4% to 77.4%) P=0.024 |
62% (56.1% to 68.0%) |
|
Achieved ACR 20 (95% CI) |
76% (71.0% to 81.4%) P<0.001 |
62% (56.1% to 68.0%) |
|
Achieved ACR 50 (95% CI) |
57% (51.4% to 63.5%) P<0.001 |
42% (36.2% to 48.4%) |
|
Achieved ACR 70 (95% CI) |
43% (36.5% to 48.6%) P<0.001 |
27% (21.8% to 32.8%) |
†Mean change in Genant-modified TSS at 1 year. Refers to observed data for patient population.
HAQ-DI, Health Assessment Questionnaire–Disability Index.
Summary of safety at 1-year in the AGREE trial
The AGREE trial was an active-controlled clinical trial in methotrexate-naive patients. The safety experience in these patients was consistent with the patients studied across
5 clinical trials for ORENCIA IV.
Please refer to the Pooled Safety below and
Selected Important Safety Information
Blood Glucose Testing: ORENCIA for intravenous administration contains maltose, which may result in falsely elevated blood glucose readings on the day of infusion when using blood glucose monitors with test strips utilizing glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ). Consider using monitors and advising patients to use monitors 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 (SC) administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.
509 adult patients with early moderate to severe RA (≤2 years) who were MTX-naïve* were randomly assigned to treatment groups: ORENCIA IV + MTX (n=256) and placebo + MTX (n=253). ORENCIA IV (~10 mg/kg based on patient weight) was administered on Days 1, 15, and 29, and every 4 weeks thereafter. MTX was initially dosed at 7.5 mg/week and subsequently increased to 15 mg at Week 4 and to 20 mg at Week 8. Dose reduction was permitted to a minimum of 15 mg/week due to toxicity or intolerability.4
Key Patient Characteristics4
- Mean disease duration: 6.5 months
- Anti-CCP+: 89% of patients
- RF+: 96.5% of patients
- Mean DAS28-CRP: 6.3
- Joint erosion†: 100% of patients
Inclusion Criteria4
- Early (≤2 years) and active RA according to ACR criteria
- ≥18 years of age
-
MTX-naïve or prior exposure of
≤10 mg/week for
≤3 weeks, with none administered for 3 months - ≥12 tender and ≥10 swollen joints, CRP ≥0.45 mg/dL, RF and/or anti-CCP seropositivity, and radiographic evidence of bone erosion of the hands, wrists, and feet
Co-primary Endpoints4
-
Proportion of patients achieving DAS28-CRP <2.6 at
12 months - Radiographic progression measured by Genant-modified TSS at 12 months
Selected Secondary Endpoints4
- ACR 50 response at 12 months
- HAQ-DI improvement (≥ 0.3) at 12 months
Selected Endpoints at 12 Months4,9
- ACR 20/70 responses
*Or prior exposure to MTX ≤10 mg/week for ≤3 weeks with
none administered for 3 months prior to enrollment.
†Radiographic evidence of bone erosion of the hands,
wrists, and feet.
Selected Important
Safety Information
Pregnancy: There are no adequate and well-controlled studies of ORENCIA use in pregnant women and the data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. A pregnancy registry has been established to monitor pregnancy outcomes in women exposed to ORENCIA during pregnancy. Healthcare professionals are encouraged to register patients by calling
ORENCIA IV + MTX improved radiographic results at 1 year vs MTX alone4*
Co-primary Endpoint: Radiographic Progression*
*Mean change in Genant-modified TSS at 1 year. Missing data for the as-observed patient population in Month 6 were imputed by linear extrapolation at 1 year.4
Selected Important
Safety Information
Lactation: There is no information regarding the presence of abatacept in human milk, the effects on the breastfed infant, or the effects on milk production. However, abatacept was present in the milk of lactating rats dosed with abatacept.
ORENCIA IV + MTX improved symptom relief
at 1 year vs MTX alone for
predominantly dual-seropositive patients4,8
Selected Endpoint: ACR 20/50/704,8
ORENCIA IV + MTX significantly improved the ACR 20, 50, and 70 response rates at 1 year vs MTX alone4,8
Selected Important
Safety Information
Most Serious Adverse Reactions: In controlled clinical trials, adult RA patients experienced serious infections (3% ORENCIA vs 1.9% placebo) and malignancies (1.3% ORENCIA vs 1.1% placebo).
Pooled Safety Results9
Based on treatment of 2944 patients (1955 patients treated with ORENCIA IV, 989 with placebo) across 6 double-blind, placebo-controlled studies of 6 months or 1 year (103-002, 101-100, AIM, ASSURE, ATTAIN, AGREE). 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.
Most serious adverse reactions9
The most serious adverse reactions associated with ORENCIA therapy were serious infections and malignancies. In patients taking ORENCIA IV (n=1955),* the rate of serious infections was 3.0% and the rate of malignancies was 1.3%. In patients taking placebo (n=989),† the rate of serious infections was 1.9% and the rate of malignancies was 1.1%.
Adverse reactions most frequently resulting in clinical intervention9
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 reactions9
Adverse reactions occurring in 3% or more of patients and at least 1% more frequently in patients treated with ORENCIA IV during placebo-controlled RA studies:
| ORENCIA IV (n=1955)* | Placebo (n=989)† | |
|---|---|---|
| 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% |
*Includes 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).9
†Includes 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).9
Infections9
In placebo-controlled trials, infections were reported in 54% of ORENCIA-treated patients and 48% of placebo-treated patients.
The most commonly reported infections (5%-13% of patients) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza, and bronchitis.
The safety experience of ORENCIA SC was consistent with that of ORENCIA IV.
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Important Safety Information
for ORENCIA® (abatacept)
Increased Risk of Infection with Concomitant Use with TNF Antagonists, Other Biologic RA/PsA Therapy, or JAK Inhibitors: Concurrent therapy with ORENCIA and a TNF antagonist is not recommended. In controlled clinical trials, adult moderate to severe rheumatoid arthritis (RA) patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63% vs 43%) and serious infections (4.4% vs 0.8%) compared to patients treated with only TNF antagonists, without an important enhancement of efficacy. Additionally, concomitant use of ORENCIA with other biologic RA/PsA therapy or JAK inhibitors is not recommended.
Hypersensitivity Reactions: There were 2 cases (<0.1%; n=2688) of anaphylaxis reactions in clinical trials with adult RA patients treated with intravenous ORENCIA. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in <0.9% of patients. There was one case of a hypersensitivity reaction with ORENCIA in pJIA clinical trials (0.5%; n=190).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. Angioedema reactions have occurred within hours of administration and in some instances had a delayed onset (i.e., days). Appropriate medical support measures for treating hypersensitivity reactions should be available for immediate use. If an anaphylactic or other serious allergic reaction occurs, administration of intravenous or subcutaneous ORENCIA should be stopped immediately and permanently discontinued, with appropriate therapy instituted.
Infections: Serious infections, including sepsis and pneumonia, were reported in 3% and 1.9% of RA patients treated with intravenous ORENCIA and placebo, respectively. 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. Caution should be exercised in patients with a history of infection or underlying conditions which may predispose them to infections. Treatment with ORENCIA should be discontinued if a patient develops a serious infection. Patients should be screened for tuberculosis and viral hepatitis in accordance with published guidelines, and if positive, treated according to standard medical practice prior to therapy with ORENCIA.
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. ORENCIA may blunt the effectiveness of some immunizations. In addition, 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.
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. In the study, 97% of COPD patients treated with ORENCIA developed adverse events versus 88% treated with placebo. Respiratory disorders occurred more frequently in patients treated with ORENCIA compared to those on placebo (43% vs 24%, respectively), including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of patients treated with ORENCIA developed a serious adverse event compared to those on placebo (27% vs 6%), including COPD exacerbation [3 of 37 patients (8%)] and pneumonia [1 of 37 patients (3%)]. Use of ORENCIA in patients with COPD should
be undertaken with caution, and such
patients monitored for worsening of their respiratory status.
Immunosuppression: In clinical trials in adult RA patients, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo-treated patients. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood. There have been reports of malignancies, including skin cancer in
patients receiving ORENCIA. Periodic skin examinations are recommended for all ORENCIA-treated patients, particularly those with risk factors for skin cancer.
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. Of 116 patients who received ORENCIA, 4 patients (3.4%) experienced PTLD. All the PTLD events were associated with Epstein-Barr virus (EBV) infection. The range of time to onset of the event was 49 to 89 days post-transplant. Monitor patients for EBV reactivation in accordance with institutional practices. Before administering ORENCIA, provide recommended prophylaxis for EBV infection and continue for 6 months post-transplantation to prevent EBV-associated PTLD. Cytomegalovirus (CMV) invasive disease occurred in patients who received ORENCIA for aGVHD prophylaxis during unrelated HSCT. Of 116 patients who received ORENCIA, 7% (n=8) experienced CMV invasive diseases up to day 225 post-transplant. The median time to onset of the event was 91 days post-transplant. CMV invasive diseases predominantly involved the gastrointestinal tract. Monitor patients for CMV infection/reactivation for 6 months post-transplant regardless of the results of donor and recipient pre-transplant CMV serology. Consider prophylaxis for CMV infection/reactivation during treatment and for six months following HSCT.
Blood Glucose Testing: ORENCIA for intravenous administration contains maltose, which may result in falsely elevated blood glucose readings on the day of infusion when using blood glucose monitors with test strips utilizing glucose dehydrogenase pyrroloquinoline quinone
Pregnancy: There are no adequate and well-controlled studies of ORENCIA use in pregnant women and the data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. A pregnancy registry has been established to monitor pregnancy outcomes in women exposed to ORENCIA during pregnancy. Healthcare professionals are encouraged to register patients by calling 1-877-311-8972.
Lactation: There is no information regarding the presence of abatacept in human milk, the effects on the breastfed infant, or the effects on milk production. However, abatacept was present in the milk of lactating rats dosed with abatacept.
Most Serious Adverse Reactions: In controlled clinical trials, adult RA patients experienced serious infections (3% ORENCIA vs 1.9% placebo) and malignancies (1.3% ORENCIA vs 1.1% placebo). In the GVHD-1 study, 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%).
Malignancies: The overall frequency of malignancies was similar between adult RA patients treated with ORENCIA or placebo. However, more cases of lung cancer were observed in patients treated with ORENCIA (0.2%) than those on placebo (0%). A higher rate of lymphoma was seen compared to the general population; however, patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. The potential role of ORENCIA in the development of malignancies in humans is unknown.
Most Frequent Adverse Events (≥10%): Headache, upper respiratory tract infection, nasopharyngitis, and nausea were the most commonly reported adverse events in the adult RA clinical studies. Other events reported in ≥5% of pJIA patients were diarrhea, cough, pyrexia, and abdominal
pain. In general, the adverse events in pediatric pJIA and adult PsA patients were similar in frequency and type to those seen in adult RA patients. The most frequent adverse reactions of all grades reported in ≥10% of patients with aGVHD who received ORENCIA with a difference of ≥2% for the 7/8 cohort, 8/8 cohort Orencia arm, and 8/8 cohort placebo arm, respectively, were anemia (56%, 69%, and 57%), CD4 lymphocytes decreased (14%, 14%, and 9%), hypertension (49%, 43%, and 38%), pyrexia (28%, 19%, and 20%), CMV reactivation/CMV infection (26%, 32%, and 22%), pneumonia (19%, 12%, and 10%), epistaxis (12%, 16%, and 10%), acute kidney injury (9%, 15%, and 10%), and hypermagnesemia (5%, 18%, 10%).
Incidence rates of grade 3 or 4 adverse reactions were the same as incidence rates of all grades, with the exception of grade 3 or 4 pyrexia in all arms (9% [7/8 cohort], 10% [8/8 cohort, ORENCIA arm], and 4% [8/8 cohort, placebo arm]), pneumonia in the 8/8 cohort placebo arm (9%) and acute kidney injury in the 7/8 cohort ORENCIA arm (7%). 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.
Note concerning ORENCIA administration options: ORENCIA may be administered as an intravenous infusion only for patients 6 years of age and older. PJIA or pediatric PsA patients may self-inject with ORENCIA or the patient’s caregiver may administer ORENCIA if both the healthcare practitioner and the parent/legal guardian determines it is appropriate. The ability of pediatric patients to self-inject with the autoinjector has not been tested. ORENCIA for the prophylaxis of aGVHD in patients undergoing HSCT may only be administered as an intravenous (IV) infusion. The safety and effectiveness of ORENCIA have not been established in pediatric patients younger than 2 years of age for prophylaxis of aGVHD.
Please click here for Full Prescribing Information
References: 1. Rigby W, Buckner J, Bridges SL, et al. The effect
of HLA-DRB1 risk alleles on the clinical efficacy of abatacept and adalimumab in seropositive biologic-naïve patients with early, moderate-to-severe RA: data from a head-to-head single blinded trial. Poster LB0008. Presented at EULAR Annual European Congress of Rheumatology, Madrid, Spain, June 12-15, 2019. 2. Schiff M, Weinblatt ME, Valente R, et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial. Ann Rheum Dis. 2014;73(1):86-94. 3. Data on File. ABAT 143. Princeton, NJ:
Indications and Usage
Adult Rheumatoid Arthritis: ORENCIA® (abatacept) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA).
Polyarticular Juvenile Idiopathic Arthritis: ORENCIA® (abatacept) is indicated for the treatment of patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA).
Psoriatic Arthritis:
ORENCIA® (abatacept) is indicated for the treatment of patients 2 years of age and older with active psoriatic arthritis (PsA).
Prophylaxis for Acute Graft versus Host Disease: ORENCIA® (abatacept) is indicated for the prophylaxis of acute graft versus host disease (aGVHD), in combination with a calcineurin inhibitor (CNI) and methotrexate (MTX), in adults and pediatric patients 2 years of age or older undergoing hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated-donor.
Limitations of Use: The concomitant use of ORENCIA with other potent immunosuppressants [e.g., biologic disease-modifying antirheumatic drugs (bDMARDS), Janus kinase (JAK) inhibitors] is not recommended.
Important Safety Information for ORENCIA® (abatacept)
Increased Risk of Infection with Concomitant Use with TNF Antagonists, Other Biologic RA/PsA Therapy, or JAK Inhibitors: Concurrent therapy with ORENCIA and a TNF antagonist is not recommended. In controlled clinical trials, adult moderate to severe rheumatoid arthritis (RA) patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections
Hypersensitivity Reactions: There were 2 cases (<0.1%; n=2688) of anaphylaxis reactions in clinical trials with adult RA patients treated with intravenous ORENCIA. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in <0.9% of patients. There was one case of a hypersensitivity reaction with ORENCIA in pJIA clinical trials (0.5%; n=190).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. Angioedema reactions have occurred within hours of administration and in some instances had a delayed onset (i.e., days). Appropriate medical support measures for treating hypersensitivity reactions should be available for immediate use. If an anaphylactic or other serious allergic reaction occurs, administration of intravenous or subcutaneous ORENCIA should be stopped immediately and permanently discontinued, with appropriate therapy instituted.
Infections: Serious infections, including sepsis and pneumonia, were reported in 3% and 1.9% of RA patients treated with intravenous ORENCIA and placebo, respectively. 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. Caution should be exercised in patients with a history of infection or underlying conditions which may predispose them to infections. Treatment with ORENCIA should be discontinued if a patient develops a serious infection. Patients should be screened for tuberculosis and viral hepatitis in accordance with published guidelines, and if positive, treated according to standard medical practice prior to therapy with ORENCIA.
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. ORENCIA may blunt the effectiveness of some immunizations. In addition, 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.
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. In the study, 97% of COPD patients treated with ORENCIA developed adverse events versus 88% treated with placebo. Respiratory disorders occurred more frequently in patients treated with ORENCIA compared to those on placebo (43% vs 24%, respectively), including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of patients treated with ORENCIA developed a serious adverse event compared to those on placebo (27% vs 6%), including COPD exacerbation
Immunosuppression: In clinical trials in adult RA patients, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo-treated patients. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood. There have been reports of malignancies, including skin cancer in patients receiving ORENCIA. Periodic skin examinations are recommended for all ORENCIA-treated patients, particularly those with risk factors for skin cancer.
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. Of 116 patients who received ORENCIA, 4 patients (3.4%) experienced PTLD. All the PTLD events were associated with Epstein-Barr virus (EBV) infection. The range of time to onset of the event was 49 to 89 days post-transplant. Monitor patients for EBV reactivation in accordance with institutional practices. Before administering ORENCIA, provide recommended prophylaxis for EBV infection and continue for 6 months post-transplantation to prevent EBV-associated PTLD. Cytomegalovirus (CMV) invasive disease occurred in patients who received ORENCIA for aGVHD prophylaxis during unrelated HSCT. Of 116 patients who received ORENCIA, 7% (n=8) experienced CMV invasive diseases up to day 225 post-transplant. The median time to onset of the event was 91 days post-transplant. CMV invasive diseases predominantly involved the gastrointestinal tract. Monitor patients for CMV infection/reactivation for 6 months post-transplant regardless of the results of donor and recipient pre-transplant CMV serology. Consider prophylaxis for CMV infection/reactivation during treatment and for six months following HSCT.
Blood Glucose Testing: ORENCIA for intravenous administration contains maltose, which may result in falsely elevated blood glucose readings on the day of infusion when using blood glucose monitors with test strips utilizing glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ). Consider using monitors and advising patients to use monitors 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 (SC) administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.
Pregnancy: There are no adequate and well-controlled studies of ORENCIA use in pregnant women and the data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. A pregnancy registry has been established to monitor pregnancy outcomes in women exposed to ORENCIA during pregnancy. Healthcare professionals are encouraged to register patients by calling
Lactation: There is no information regarding the presence of abatacept in human milk, the effects on the breastfed infant, or the effects on milk production. However, abatacept was present in the milk of lactating rats dosed
with abatacept.
Most Serious Adverse Reactions: In controlled clinical trials, adult RA patients experienced serious infections
Malignancies: The overall frequency of malignancies was similar between adult RA patients treated with ORENCIA or placebo. However, more cases of lung cancer were observed in patients treated with ORENCIA (0.2%) than those on placebo (0%). A higher rate of lymphoma was seen compared to the general population; however, patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. The potential role of ORENCIA in the development of malignancies in humans is unknown.
Most Frequent Adverse Events (≥10%): Headache, upper respiratory tract infection, nasopharyngitis, and nausea were the most commonly reported adverse events in the adult RA clinical studies. Other events reported in ≥5% of pJIA patients were diarrhea, cough, pyrexia, and abdominal pain. In general, the adverse events in pediatric pJIA and adult PsA patients were similar in frequency and type to those seen in adult RA patients. The most frequent adverse reactions of all grades reported in ≥10% of patients with aGVHD who received ORENCIA with a difference of ≥2% for the 7/8 cohort, 8/8 cohort Orencia arm, and 8/8 cohort placebo arm, respectively, were anemia (56%, 69%, and 57%), CD4 lymphocytes decreased (14%, 14%, and 9%), hypertension (49%, 43%, and 38%), pyrexia (28%, 19%, and 20%), CMV reactivation/CMV infection (26%, 32%,and 22%), pneumonia (19%, 12%, and 10%), epistaxis (12%, 16%, and 10%), acute kidney injury (9%, 15%,and 10%), and hypermagnesemia (5%, 18%, 10%).
Incidence rates of grade 3 or 4 adverse reactions were the same as incidence rates of all grades, with the exception of grade 3 or 4 pyrexia in all arms (9% [7/8 cohort], 10% [8/8 cohort, ORENCIA arm], and 4% [8/8 cohort, placebo arm]), pneumonia in the 8/8 cohort placebo arm (9%) and acute kidney injury in the 7/8 cohort ORENCIA arm (7%). 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.
Note concerning ORENCIA administration options: ORENCIA may be administered as an intravenous infusion only for patients 6 years of age and older. PJIA or pediatric PsA patients may self-inject with ORENCIA or the patient’s caregiver may administer ORENCIA if both the healthcare practitioner and the parent/legal guardian determines it is appropriate. The ability of pediatric patients to self-inject with the autoinjector has not been tested. ORENCIA for the prophylaxis of aGVHD in patients undergoing HSCT may only be administered as an intravenous (IV) infusion. The safety and effectiveness of ORENCIA have not been established in pediatric patients younger than 2 years of age for prophylaxis of aGVHD.
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Indications and Usage
Adult Rheumatoid Arthritis: ORENCIA® (abatacept) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA).
Polyarticular Juvenile Idiopathic Arthritis: ORENCIA® (abatacept) is indicated for the treatment of patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA).
Psoriatic Arthritis: ORENCIA® (abatacept) is indicated for the treatment of patients 2 years of age and older with active psoriatic arthritis (PsA).
Prophylaxis for Acute Graft versus Host Disease: ORENCIA® (abatacept) is indicated for the prophylaxis of acute graft versus host disease (aGVHD), in combination with a calcineurin inhibitor (CNI) and methotrexate (MTX), in adults and pediatric patients 2 years of age or older undergoing hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated-donor.
Limitations of Use: The concomitant use of ORENCIA with other potent immunosuppressants [e.g., biologic disease-modifying antirheumatic drugs (bDMARDS), Janus kinase (JAK) inhibitors] is not recommended.
Important Safety Information for ORENCIA® (abatacept)
Increased Risk of Infection with Concomitant Use with TNF Antagonists, Other Biologic RA/PsA Therapy, or JAK Inhibitors: Concurrent therapy with ORENCIA and a TNF antagonist is not recommended. In controlled clinical trials, adult moderate to severe rheumatoid arthritis (RA) patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections
Hypersensitivity Reactions: There were 2 cases (<0.1%; n=2688) of anaphylaxis reactions in clinical trials with adult RA patients treated with intravenous ORENCIA. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in <0.9% of patients. There was one case of a hypersensitivity reaction with ORENCIA in pJIA clinical trials (0.5%; n=190).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. Angioedema reactions have occurred within hours of administration and in some instances had a delayed onset (i.e., days). Appropriate medical support measures for treating hypersensitivity reactions should be available for immediate use. If an anaphylactic or other serious allergic reaction occurs, administration of intravenous or subcutaneous ORENCIA should be stopped immediately and permanently discontinued, with appropriate therapy instituted.
Infections: Serious infections, including sepsis and pneumonia, were reported in 3% and 1.9% of RA patients treated with intravenous ORENCIA and placebo, respectively. 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. Caution should be exercised in patients with a history of infection or underlying conditions which may predispose them to infections. Treatment with ORENCIA should be discontinued if a patient develops a serious infection. Patients should be screened for tuberculosis and viral hepatitis in accordance with published guidelines, and if positive, treated according to standard medical practice prior to therapy with ORENCIA.
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. ORENCIA may blunt the effectiveness of some immunizations. In addition, 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.
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. In the study, 97% of COPD patients treated with ORENCIA developed adverse events versus 88% treated with placebo. Respiratory disorders occurred more frequently in patients treated with ORENCIA compared to those on placebo (43% vs 24%, respectively), including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of patients treated with ORENCIA developed a serious adverse event compared to those on placebo (27% vs 6%), including COPD exacerbation [3 of 37 patients (8%)] and pneumonia [1 of 37 patients (3%)]. Use of ORENCIA in patients with COPD should be undertaken with caution, and such patients monitored for worsening of their respiratory status.
Immunosuppression: In clinical trials in adult RA patients, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo-treated patients. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood. There have been reports of malignancies, including skin cancer in patients receiving ORENCIA. Periodic skin examinations are recommended for all ORENCIA-treated patients, particularly those with risk factors for skin cancer.
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. Of 116 patients who received ORENCIA, 4 patients (3.4%) experienced PTLD. All the PTLD events were associated with Epstein-Barr virus (EBV) infection. The range of time to onset of the event was 49 to 89 days post-transplant. Monitor patients for EBV reactivation in accordance with institutional practices. Before administering ORENCIA, provide recommended prophylaxis for EBV infection and continue for 6 months post-transplantation to prevent EBV-associated PTLD. Cytomegalovirus (CMV) invasive disease occurred in patients who received ORENCIA for aGVHD prophylaxis during unrelated HSCT. Of 116 patients who received ORENCIA, 7% (n=8) experienced CMV invasive diseases up to day 225 post-transplant. The median time to onset of the event was 91 days post-transplant. CMV invasive diseases predominantly involved the gastrointestinal tract. Monitor patients for CMV infection/reactivation for 6 months post-transplant regardless of the results of donor and recipient pre-transplant CMV serology. Consider prophylaxis for CMV infection/reactivation during treatment and for six months following HSCT.
Blood Glucose Testing: ORENCIA for intravenous administration contains maltose, which may result in falsely elevated blood glucose readings on the day of infusion when using blood glucose monitors with test strips utilizing glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ). Consider using monitors and advising patients to use monitors 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 (SC) administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.
Pregnancy: There are no adequate and well-controlled studies of ORENCIA use in pregnant women and the data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. A pregnancy registry has been established to monitor pregnancy outcomes in women exposed to ORENCIA during pregnancy. Healthcare professionals are encouraged to register patients by calling
Lactation: There is no information regarding the presence of abatacept in human milk, the effects on the breastfed infant, or the effects on milk production. However, abatacept was present in the milk of lactating rats dosed
with abatacept.
Most Serious Adverse Reactions: In controlled clinical trials, adult RA patients experienced serious infections (3% ORENCIA vs 1.9% placebo) and malignancies (1.3% ORENCIA vs 1.1% placebo). In the GVHD-1 study, 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%).
Malignancies: The overall frequency of malignancies was similar between adult RA patients treated with ORENCIA or placebo. However, more cases of lung cancer were observed in patients treated with ORENCIA (0.2%) than those on placebo (0%). A higher rate of lymphoma was seen compared to the general population; however, patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. The potential role of ORENCIA in the development of malignancies in humans is unknown.
Most Frequent Adverse Events (≥10%): Headache, upper respiratory tract infection, nasopharyngitis, and nausea were the most commonly reported adverse events in the adult RA clinical studies. Other events reported in ≥5% of pJIA patients were diarrhea, cough, pyrexia, and abdominal pain. In general, the adverse events in pediatric pJIA and adult PsA patients were similar in frequency and type to those seen in adult RA patients. The most frequent adverse reactions of all grades reported in ≥10% of patients with aGVHD who received ORENCIA with a difference of ≥2% for the 7/8 cohort, 8/8 cohort Orencia arm, and 8/8 cohort placebo arm, respectively, were anemia (56%, 69%, and 57%), CD4 lymphocytes decreased (14%, 14%, and 9%), hypertension (49%, 43%, and 38%), pyrexia (28%, 19%, and 20%), CMV reactivation/CMV infection (26%, 32%, and 22%), pneumonia (19%, 12%, and 10%), epistaxis (12%, 16%, and 10%), acute kidney injury (9%, 15%, and 10%), and hypermagnesemia (5%, 18%, 10%).
Incidence rates of grade 3 or 4 adverse reactions were the same as incidence rates of all grades, with the exception of grade 3 or 4 pyrexia in all arms (9% [7/8 cohort], 10% [8/8 cohort, ORENCIA arm], and 4% [8/8 cohort, placebo arm]), pneumonia in the 8/8 cohort placebo arm (9%) and acute kidney injury in the 7/8 cohort ORENCIA arm (7%). 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.
Note concerning ORENCIA administration options: ORENCIA may be administered as an intravenous infusion only for patients 6 years of age and older. PJIA or pediatric PsA patients may self-inject with ORENCIA or the patient’s caregiver may administer ORENCIA if both the healthcare practitioner and the parent/legal guardian determines it is appropriate. The ability of pediatric patients to self-inject with the autoinjector has not been tested. ORENCIA for the prophylaxis of aGVHD in patients undergoing HSCT may only be administered as an intravenous (IV) infusion. The safety and effectiveness of ORENCIA have not been established in pediatric patients younger than 2 years of age for prophylaxis of aGVHD.
Please click here for Full Prescribing Information