Source: European Medicines Agency (EU) Revision Year: 2017 Publisher: Bristol-Myers Squibb Pharma EEIG, Uxbridge Business Park, Sanderson Road, Uxbridge UB8 1DH, United Kingdom
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Severe and uncontrolled infections such as sepsis and opportunistic infections (see section 4.4).
There is limited experience with use of abatacept in combination with TNF-inhibitors (see section 5.1). In placebo-controlled clinical trials, in comparison with patients treated with TNFinhibitors and placebo, patients who received combination TNF-inhibitors with abatacept experienced an increase in overall infections and serious infections (see section 4.5). Abatacept is not recommended for use in combination with TNF-inhibitors.
While transitioning from TNF-inhibitor therapy to ORENCIA therapy, patients should be monitored for signs of infection (see section 5.1, Study VII).
Allergic reactions have been reported uncommonly with abatacept administration in clinical trials, where patients were not required to be pretreated to prevent allergic reactions (see section 4.8).
Anaphylaxis or anaphylactoid reactions can occur after the first infusion and can be life-threatening. In postmarketing experience, a case of fatal anaphylaxis following the first infusion of ORENCIA has been reported. If any serious allergic or anaphylactic reaction occurs, intravenous or subcutaneous ORENCIA therapy should be discontinued immediately and appropriate therapy initiated, and the use of ORENCIA should be permanently discontinued (see section 4.8).
Medicinal products which affect the immune system, including ORENCIA, may affect host defences against infections and malignancies, and affect vaccination responses.
Co-administration of ORENCIA with biologic immunosuppressive or immunomodulatory agents could potentiate the effects of abatacept on the immune system (see section 4.5).
Serious infections, including sepsis and pneumonia, have been reported with abatacept (see section 4.8). 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 infections. Treatment with ORENCIA should not be initiated in patients with active infections until infections are controlled. Physicians should exercise caution when considering the use of ORENCIA in patients with a history of recurrent infections or underlying conditions which may predispose them to 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.
No increase of tuberculosis was observed in the pivotal placebo-controlled studies; however, all ORENCIA patients were screened for tuberculosis. The safety of ORENCIA in individuals with latent tuberculosis is unknown. There have been reports of tuberculosis in patients receiving ORENCIA (see section 4.8). Patients should be screened for latent tuberculosis prior to initiating ORENCIA. The available medical guidelines should also be taken into account.
Anti-rheumatic 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.
Treatment with immunosuppressive therapy, such as ORENCIA, may be associated with progressive multifocal leukoencephalopathy (PML). If neurological symptoms suggestive of PML occur during ORENCIA therapy, treatment with ORENCIA should be discontinued and appropriate diagnostic measures initiated.
In the placebo-controlled clinical trials, the frequencies of malignancies in abatacept- and placebotreated patients were 1.2% and 0.9%, respectively (see section 4.8). Patients with known malignancies were not included in these clinical trials. In carcinogenicity studies in mice, an increase in lymphomas and mammary tumours were noted. The clinical significance of this observation is unknown (see section 5.3). The potential role of abatacept in the development of malignancies, including lymphoma, in humans is unknown. There have been reports of non-melanoma skin cancers in patients receiving ORENCIA (see section 4.8). Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Patients treated with ORENCIA may receive concurrent vaccinations, except for live vaccines. Live vaccines should not be given concurrently with abatacept or within 3 months of its discontinuation. Medicinal products that affect the immune system, including abatacept, may blunt the effectiveness of some immunisations (see section 4.5).
A total of 404 patients 65 years of age and older, including 67 patients 75 years and older, received intravenous abatacept in placebo-controlled clinical trials. A total of 270 patients 65 years of age and older, including 46 patients 75 years and older, received subcutaneous abatacept in controlled clinical trials. The frequencies of serious infection and malignancy relative to placebo among intravenous abatacept-treated patients over age 65 were higher than among those under age 65. Similarly, the frequencies of serious infection and malignancy among subcutaneous abatacept-treated patients over age 65 were higher than among those under age 65. Because there is a higher incidence of infections and malignancies in the elderly in general, caution should be used when treating the elderly (see section 4.8).
There is a theoretical concern that treatment with abatacept might increase the risk for autoimmune processes in adults, for example deterioration of multiple sclerosis. In the placebo-controlled clinical trials, abatacept treatment did not lead to increased autoantibody formation, such as antinuclear and anti-dsDNA antibodies, relative to placebo treatment (see sections 4.8 and 5.3).
This medicinal product contains 0.014 mmol sodium (0.322 mg) per pre-filled syringe, i.e. essentially ‘sodium-free’.
There is limited experience with the use of abatacept in combination with TNF-inhibitors (see section 5.1). While TNF-inhibitors did not influence abatacept clearance, in placebo-controlled clinical trials, patients receiving concomitant treatment with abatacept and TNF-inhibitors experienced more infections and serious infections than patients treated with only TNF-inhibitors. Therefore, concurrent therapy with ORENCIA and a TNF-inhibitor is not recommended.
Population pharmacokinetic analyses did not detect any effect of methotrexate, NSAIDs, and corticosteroids on abatacept clearance (see section 5.2). No major safety issues were identified with use of abatacept in combination with sulfasalazine, hydroxychloroquine, or leflunomide.
Co-administration of ORENCIA with biologic immunosuppressive or immunomodulatory agents could potentiate the effects of abatacept on the immune system. There is insufficient evidence to assess the safety and efficacy of ORENCIA in combination with anakinra or rituximab (see section 4.4).
Live vaccines should not be given concurrently with abatacept or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. Medicinal products that affect the immune system, including ORENCIA, may blunt the effectiveness of some immunisations (see sections 4.4 and 4.6).
Exploratory studies to assess the effect of abatacept on the antibody response to vaccination in healthy subjects as well as the antibody response to influenza and pneumococcal vaccines in rheumatoid arthritis patients suggested that abatacept may blunt the effectiveness of the immune response, but did not significantly inhibit the ability to develop a clinically significant or positive immune response.
Abatacept was evaluated in an open-label study in rheumatoid arthritis patients administered the 23-valent pneumococcal vaccine. After pneumococcal vaccination, 62 of 112 abatacept-treated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine.
Abatacept was also evaluated in an open-label study in rheumatoid arthritis patients administered the seasonal influenza trivalent virus vaccine. After influenza vaccination, 73 of 119 abatacept-treated patients without protective antibody levels at baseline were able to mount an adequate immune response of at least a 4-fold increase in antibody titers to trivalent influenza vaccine.
There are no adequate data from use of abatacept in pregnant women. In pre-clinical embryo-fetal development studies no undesirable effects were observed at doses up to 29-fold a human 10 mg/kg dose based on AUC. In a pre- and postnatal development study in rats, limited changes in immune function were observed at 11-fold higher than a human 10 mg/kg dose based on AUC (see section 5.3). ORENCIA should not be used in pregnant women unless clearly necessary. Women of child-bearing potential should use effective contraception during treatment with ORENCIA and up to 14 weeks after the last dose of abatacept treatment.
Abatacept may cross the placenta into the serum of infants born to women treated with abatacept during pregnancy. Consequently, these infants may be at increased risk of infection. The safety of administering live vaccines to infants exposed to abatacept in utero is unknown. Administration of live vaccines to infants exposed to abatacept in utero is not recommended for 14 weeks following the mother’s last exposure to abatacept during pregnancy.
Abatacept has been shown to be present in rat milk. It is not known whether abatacept is excreted in human milk. Women should not breastfeed while treated with ORENCIA and for up to 14 weeks after the last dose of abatacept treatment.
Formal studies of the potential effect of abatacept on human fertility have not been conducted. In rats, abatacept had no undesirable effects on male or female fertility (see section 5.3).
Based on its mechanism of action, abatacept is expected to have no or negligible influence on the ability to drive and use machines. However, dizziness and reduced visual acuity have been reported as common and uncommon adverse reactions respectively from patients treated with ORENCIA, therefore if a patient experiences such symptoms, driving and use of machinery should be avoided.
Abatacept has been studied in patients with active rheumatoid arthritis in placebo-controlled clinical trials (2,653 patients with abatacept, 1,485 with placebo). In placebo-controlled clinical trials with abatacept, adverse reactions (ARs) were reported in 49.4% of abatacept-treated patients and 45.8% of placebo-treated patients. The most frequently reported adverse reactions (≥5%) among abatacept-treated patients were headache, nausea, and upper respiratory tract infections (including sinusitis). The proportion of patients who discontinued treatment due to ARs was 3.0% for abatacept-treated patients and 2.0% for placebo-treated patients.
Listed in Table 1 are adverse reactions observed in clinical trials and post-marketing experience presented by system organ class and frequency, using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1. Adverse Reactions:
Very Common: Upper respiratory tract infection (including tracheitis, nasopharyngitis, and sinusitis)
Common: Lower respiratory tract infection (including bronchitis), urinary tract infection, herpes infections (including herpes simplex, oral herpes, and herpes zoster), pneumonia, influenza
Uncommon: Tooth infection, onychomycosis, sepsis, muskuloskeletal infections, skin abscess, pyelonephritis, rhinitis, ear infection
Rare: Tuberculosis, bacteraemia, gastrointestinal infection, pelvic inflammatory disease
Uncommon: Basal cell carcinoma, skin papilloma
Rare: Lymphoma, lung neoplasm malignant, squamous cell carcinoma
Uncommon: Thrombocytopenia, leukopenia
Uncommon: Hypersensitivity
Uncommon: Depression, anxiety, sleep disorder (including insomnia)
Common: Headache, dizziness
Uncommon: Migraine, paraesthesia
Uncommon: Conjunctivitis, dry eye, visual acuity reduced
Uncommon: Vertigo
Uncommon: Palpitations, tachycardia, bradycardia
Common: Hypertension, blood pressure increased Uncommon Hypotension, hot flush, flushing, vasculitis, blood pressure decreased
Common: Cough
Uncommon: Chronic obstructive pulmonary disease exacerbated, bronchospasm, wheezing, dyspnea, throat tightness
Common: Abdominal pain, diarrhoea, nausea, dyspepsia, mouth ulceration, aphthous stomatitis, vomiting
Uncommon: Gastritis
Common: Liver function test abnormal (including transaminases increased)
Common: Rash (including dermatitis)
Uncommon: Increased tendency to bruise, dry skin, alopecia, pruritus, urticaria, psoriasis, acne, erythema, hyperhidrosis
Uncommon: Arthralgia, pain in extremity
Uncommon: Amenorrhea, menorrhagia
Common: Fatigue, asthenia, local injection site reactions, systemic injection reactions*
Uncommon: Influenza like illness, weight increased
* (e.g. pruritus, throat tightness, dyspnea)
In the placebo-controlled clinical trials with abatacept, infections at least possibly related to treatment were reported in 22.7% of abatacept-treated patients and 20.5% of placebo-treated patients.
Serious infections at least possibly related to treatment were reported in 1.5% of abatacept-treated patients and 1.1% of placebo-treated patients. The type of serious infections was similar between the abatacept and placebo treatment groups (see section 4.4).
The incidence rates (95% CI) for serious infections was 3.0 (2.3, 3.8) per 100 patient-years for abatacept-treated patients and 2.3 (1.5, 3.3) per 100 patient-years for placebo-treated patients in the double-blind studies.
In the cumulative period in clinical trials in 7,044 patients treated with abatacept during 20,510 patient-years, the incidence rate of serious infections was 2.4 per 100 patient-years, and the annualized incidence rate remained stable.
In placebo-controlled clinical trials, malignancies were reported in 1.2 % (31/2,653) of abatacepttreated patients, and in 0.9% (14/1,485) of placebo-treated patients. The incidence rates for malignancies was 1.3 (0.9, 1.9) per 100 patient-years for abatacept-treated patients and 1.1 (0.6, 1.9) per 100 patient-years for placebo-treated patients.
In the cumulative period 7,044 patients treated with abatacept during 21,011 patient-years (of which over 1,000 were treated with abatacept for over 5 years), the incidence rate of malignancy was 1.2 (1.1, 1.4) per 100 patient-years, and the annualized incidence rates remained stable.
The most frequently reported malignancy in the placebo-controlled clinical trials was non-melanoma skin cancer; 0.6 (0.3, 1.0) per 100 patient-years for abatacept-treated patients and 0.4 (0.1, 0.9) per 100 patient-years for placebo-treated patients and 0.5 (0.4, 0.6) per 100 patient-years in the cumulative period.
The most frequently reported organ cancer in the placebo-controlled clinical trials was lung cancer 0.17 (0.05, 0.43) per 100 patient-years for abatacept-treated patients, 0 for placebo-treated patients and 0.12 (0.08, 0.17) per 100 patient-years in the cumulative period. The most common hematologic malignancy was lymphoma 0.04 (0, 0.24) per 100 patient-years for abatacept-treated patients, 0 for placebo-treated patients, and 0.06 (0.03, 0.1) per 100 patient-years in the cumulative period.
In Study IV, there were 37 patients with COPD treated with intravenous abatacept and 17 treated with placebo. The COPD patients treated with abatacept developed adverse reactions more frequently than those treated with placebo (51.4% vs. 47.1%, respectively). Respiratory disorders occurred more frequently in abatacept-treated patients than in placebo-treated patients (10.8% vs. 5.9%, respectively); these included COPD exacerbation, and dyspnea. A greater percentage of abatacept- than placebotreated patients with COPD developed a serious adverse reaction (5.4% vs. 0%), including COPD exacerbation (1 of 37 patients [2.7%]) and bronchitis (1 of 37 patients [2.7%]).
Abatacept therapy did not lead to increased formation of autoantibodies, i.e., antinuclear and antidsDNA antibodies, compared with placebo.
The incidence rate of autoimmune disorders in abatacept-treated patients during the double-blind period was 8.8 (7.6, 10.1) per 100 person-years of exposure and for placebo-treated patients was 9.6 (7.9, 11.5) per 100 person-years of exposure. The incidence rate in abatacept-treated patients was 3.8 per 100 person-years in the cumulative period. The most frequently reported autoimmune-related disorders other than the indication being studied during the cumulative period were psoriasis, rheumatoid nodule, and Sjogren’s syndrome.
Antibodies directed against the abatacept molecule were assessed by ELISA assays in 3,985 rheumatoid arthritis patients treated for up to 8 years with abatacept. One hundred and eighty-seven of 3,877 (4.8%) patients developed anti-abatacept antibodies while on treatment. In patients assessed for anti-abatacept antibodies after discontinuation of abatacept (>42 days after last dose), 103 of 1,888 (5.5%) were seropositive.
Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies. Twenty-two of 48 evaluable patients showed significant neutralizing activity. The potential clinical relevance of neutralizing antibody formation is not known.
Overall, there was no apparent correlation of antibody development to clinical response or adverse events. However, the number of patients that developed antibodies was too limited to make a definitive assessment. Because immunogenicity analyses are product-specific, comparison of antibody rates with those from other products is not appropriate.
Study SC-I compared the immunogenicity to abatacept following subcutaneous or intravenous administration as assessed by ELISA assay. During the initial double blind 6 months period (shortterm period), 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 effect of immunogenicity on pharmacokinetics, safety, or efficacy.
Immunogenicity to abatacept following long-term subcutaneous administration was assessed by a new ECL assay. Comparison of incidence rates across different assays is not appropriate, as the ECL assay was developed to be more sensitive and drug tolerant than the previous ELISA assay. The cumulative immunogenicity frequency to abatacept by the ECL assay with at least one positive sample in the short-term and long-term periods combined was 15.7% (215/1369) while on abatacept, with a mean duration of exposure of 48.8 months, and 17.3% (194/1121) after discontinuation (>21 days up to 168 days after last dose). The exposure adjusted incidence rate (expressed per 100 person-years) remained stable over the treatment duration.
Consistent with previous experience, titers and persistence of antibody responses were generally low and did not increase upon continued dosing (6.8% subjects were seropositive on 2 consecutive visits), and there was no apparent correlation of antibody development to clinical response, adverse events, or PK.
In Study SC-III, similar immunogenicity rates were seen in patients on treatment for the abatacept+MTX, and abatacept monotherapy groups (2.9% (3/103) and 5.0% (5/101), respectively) during the double-blind 12 month period. As in Study SC-I, there was no effect of immunogenicity on safety or efficacy.
A study in the subcutaneous program was conducted to investigate the effect of withdrawal (three months) and restart of abatacept subcutaneous treatment on immunogenicity. Upon withdrawal of abatacept subcutaneous treatment, the increased rate of immunogenicity was consistent with that seen upon discontinuation of abatacept administered intravenously. Upon reinitiating therapy, there were no injection reactions and no other safety concerns 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 the treatment arm that reinitiated therapy without an intravenous loading dose was also consistent with that observed in the other studies.
In SC-III, increased rates of immunogenicity were observed in subjects tested during 6 months of complete drug withdrawal in the abatacept+MTX and abatacept monotherapy groups (37.7% [29/77] and 44.1% [27/59], respectively) with generally low titer antibody responses. No clinical impact of these antibody responses was detected, and no safety concerns were observed upon reinitiation of abatacept therapy.
Study SC-I 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 subcutaneous placebo group (intravenous abatacept), respectively. All injection site reactions were described as mild to moderate (hematoma, pruritus, or erythema) and generally did not necessitate drug discontinuation. During the cumulative study period when all subjects treated with abatacept in 7 SC studies were included, the frequency of injection site reactions was 4.6% (116/2,538) with an incidence rate of 1.32 per 100 person-years. Postmarketing reports of systemic injection reactions (e.g. pruritus, throat tightness, dyspnea) have been received following the use of subcutaneous ORENCIA.
Abatacept is the first selective co-stimulation modulator. Information on the relative safety in a clinical trial versus infliximab is summarized in section 5.1.
Abatacept has been studied in patients with active psoriatic arthritis in two placebo-controlled clinical trials (341 patients with abatacept, 253 patients with placebo) (see Section 5.1). During the 24-week placebo-controlled period in the larger study PsA-II, the proportion of patients with adverse reactions was similar in the abatacept and placebo treatment groups (15.5% and 11.4%, respectively). There were no adverse reactions that occurred at ≥2% in either treatment group during the 24-week placebocontrolled period. The overall safety profile was comparable between studies PsA-I and PsA-II and consistent with the safety profile in rheumatoid arthritis (Table 1).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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