Orencia (abatacept) Side Effects, Warnings, and Drug Interactions

Orencia (abatacept) is an injectable, synthetic (man-made) protein produced by recombinant DNA technology that is an immunosuppressant used for treating rheumatoid arthritis.

Common side effects of Orencia include:

• headache,
• upper respiratory tract infections,
• nausea,
• and infusion-related reactions (such as dizziness, headache, high or low blood pressure, wheezing, rash, and shortness of breath).

Serious side effects of Orencia include:

• infections
• and cancer.

Drug interactions of Orencia include:

• tumor necrosis factor (TNF) blockers [for example, Enbrel (etanercept), Humira (adalimumab) and Remicade (infliximab)]
• and live vaccines.

Orencia has not been adequately evaluated in pregnant women. Orencia has not been adequately evaluated in women who are breastfeeding.

The most common side effects of abatacept are:

• headache,
• upper respiratory tract infections and
• nausea.

Because abatacept depresses the immune system it reduces the body's ability to fight infection. Therefore, existing infections may worsen or new ones may develop.

Other important side effects include infusion-related reactions such as:

• dizziness,
• headache,
• hypotension,
• hypertension,
• nausea,
• wheezing,
• rash, and
• shortness of breath.

The most serious side effects are:

• infections
• and cancer.

• 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.
• 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 to abatacept in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Clinical Studies Experience In Adult RA Patients Treated With Intravenous Orencia

• The data described herein reflect exposure to Orencia administered intravenously in patients with active RA in placebo-controlled studies (1955 patients with Orencia, 989 with placebo). The studies had either a double-blind, placebo-controlled period of 6 months (258 patients with Orencia, 133 with placebo) or 1 year (1697 patients with Orencia, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF blocking agent (204 patients with Orencia, 134 with placebo).
• The majority of patients in RA clinical studies received one or more of the following concomitant medications with Orencia: methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF blocking agents, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra.
• The most serious adverse reactions were serious infections and malignancies.
• The most commonly reported adverse events (occurring in ≥10% of patients treated with Orencia) were headache, upper respiratory tract infection, nasopharyngitis, and nausea.
• The adverse events most frequently resulting in clinical intervention (interruption or discontinuation of Orencia) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1.0%), bronchitis (0.7%), and herpes zoster (0.7%). The most frequent infections resulting in discontinuation were pneumonia (0.2%), localized infection (0.2%), and bronchitis (0.1%).

Infections

• In the placebo-controlled trials, infections were reported in 54% of Orencia-treated patients and 48% of placebo-treated patients.
• The most commonly reported infections (reported in 5%-13% of patients) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza, and bronchitis.
• Other infections reported in fewer than 5% of patients at a higher frequency (>0.5%) with Orencia compared to placebo, were rhinitis, herpes simplex, and pneumonia.
• Serious infections were reported in 3.0% of patients treated with Orencia and 1.9% of patients treated with placebo. The most common (0.2%-0.5%) serious infections reported with Orencia were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis.

Malignancies

• In the placebo-controlled portions of the clinical trials (1955 patients treated with Orencia for a median of 12 months), the overall frequencies of malignancies were similar in the Orencia-and placebo-treated patients (1.3% and 1.1%, respectively).
• However, more cases of lung cancer were observed in Orencia-treated patients (4, 0.2%) than placebo-treated patients (0). In the cumulative Orencia clinical trials (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years).
• The rate observed for lymphoma is approximately 3.5-fold higher than expected in an age-and gender-matched general population based on the National Cancer Institute’s Surveillance, Epidemiology, and End Results Database.
• Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Other malignancies included skin, breast, bile duct, bladder, cervical, endometrial, lymphoma, melanoma, myelodysplastic syndrome, ovarian, prostate, renal, thyroid, and uterine cancers. The potential role of Orencia in the development of malignancies in humans is unknown.

Infusion-Related Reactions And Hypersensitivity Reactions

• Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V were more common in the Orencia-treated patients than the placebo patients (9% for Orencia, 6% for placebo). The most frequently reported events (1%-2%) were dizziness, headache, and hypertension.
• Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated with Orencia included cardiopulmonary symptoms, such as hypotension, increased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing.
  • Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of Orencia-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 Orencia-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events.
• In clinical trials of 2688 adult RA patients treated with intravenous Orencia, there were two cases (<0.1%) of anaphylaxis or anaphylactoid reactions. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of Orencia-treated patients and generally occurred within 24 hours of Orencia infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction.

Adverse Reactions In Patients With COPD

• In Study V, there were 37 patients with chronic obstructive pulmonary disease (COPD) who were treated with Orencia and 17 COPD patients who were treated with placebo. The COPD patients treated with Orencia developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively).
• Respiratory disorders occurred more frequently in Orencia-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of Orencia-treated patients developed a serious adverse event compared to placebo-treated patients (27% vs 6%), including COPD exacerbation (3 of 37 patients [8%]) and pneumonia (1 of 37 patients [3%]).

Other Adverse Reactions

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

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

Immunogenicity

• Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in RA patients for up to 2 years following repeated treatment with Orencia.
• Thirty-four of 1993 (1.7%) patients developed binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of abatacept. Because trough levels of abatacept can interfere with assay results, a subset analysis was performed. In this analysis it was observed that 9 of 154 (5.8%) patients that had discontinued treatment with Orencia for over 56 days developed antibodies.
• Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cell-based luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.
• No correlation of antibody development to clinical response or adverse events was observed.
• The data reflect the percentage of patients whose test results were positive for antibodies to abatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to abatacept with the incidence of antibodies to other products may be misleading.

Clinical Experience In Methotrexate-Naive Patients

• Study VI was an active-controlled clinical trial in methotrexate-naive patients. The safety experience in these patients was consistent with Studies I-V.

Clinical Studies Experience In Adult RA Patients Treated With Subcutaneous Orencia

• Study SC-1 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).
• The safety experience and immunogenicity for Orencia administered subcutaneously was consistent with intravenous Studies I-VI.
• Due to the route of administration, injection site reactions and immunogenicity were evaluated in Study SC-1 and two other smaller studies discussed in the sections below.

Injection Site Reactions In Adult RA Patients Treated With Subcutaneous Orencia

• Study SC-1 compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration.
• The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the intravenous abatacept group (subcutaneous placebo), respectively.
• All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation.

Immunogenicity In Adult RA Patients Treated With Subcutaneous Orencia

• Study SC-1 compared the immunogenicity to abatacept following subcutaneous or intravenous administration.
• The overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively.
• The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy.

Immunogenicity And Safety Of Subcutaneous Orencia Administration As Monotherapy Without An Intravenous Loading Dose

• Study SC-2 was conducted to determine the effect of monotherapy use of Orencia on immunogenicity following subcutaneous administration without an intravenous load in 100 RA patients, who had not previously received abatacept or other CTLA4Ig, who received either subcutaneous Orencia plus methotrexate (n=51) or subcutaneous Orencia monotherapy (n=49).
• No patients in either group developed anti-product antibodies after 4 months of treatment.
• The safety observed in this study was consistent with that observed in the other subcutaneous studies.

Immunogenicity And Safety Of Subcutaneous Orencia Upon Withdrawal (Three Months) And Restart Of Treatment

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

Clinical Studies Experience In Juvenile Idiopathic Arthritis Patients Treated With Intravenous Orencia

• In general, the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients.
• Study JIA-1 was a three-part study including an open-label extension that assessed the safety and efficacy of intravenous Orencia 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%.
• The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient pediatric populations.
• Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain.
• A total of 6 serious adverse events (acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare [2], and joint wear) were reported during the initial 4 months of treatment with Orencia.
• Of the 190 patients with juvenile idiopathic arthritis treated with Orencia in clinical trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults.
• Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with multiple sclerosis while on open-label treatment.

Immunogenicity

• Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with juvenile idiopathic arthritis following repeated treatment with Orencia throughout the open-label period.
• For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54).
• Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies.
• The presence of antibodies was generally transient and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept.
• For patients who were withdrawn from Orencia during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of Orencia therapy.

Clinical Studies Experience In Juvenile Idiopathic Arthritis Patients 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 pharmacokinetics (PK), safety, and efficacy of subcutaneous Orencia in 205 pediatric patients, 2 to 17 years of age with juvenile idiopathic arthritis.
• The safety experience and immunogenicity for Orencia administered subcutaneously were consistent with the intravenous Study JIA-1.
• There were no reported cases of hypersensitivity reactions. Local injection-site reactions occurred at a frequency of 4.4%.

Clinical Studies Experience In Adult PsA Patients

• The safety of Orencia was evaluated in 594 patients with psoriatic arthritis (341 patients on Orencia and 253 patients on placebo), in two randomized, double-blind, placebo-controlled trials.
• Of the 341 patients who received Orencia, 128 patients received intravenous Orencia (PsA-I) and 213 patients received subcutaneous Orencia (PsA-II).
• The safety profile was comparable between studies PsA-I and PsA-II and consistent with the safety profile in rheumatoid arthritis.

Postmarketing Experience

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

TNF Antagonists

• Concurrent administration of a TNF antagonist with Orencia has been associated with an increased risk of serious infections and no significant additional efficacy overuse of the TNF antagonists alone.
• Concurrent therapy with Orencia and TNF antagonists is not recommended.

Other Biologic RA Therapy

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

Blood Glucose Testing

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