ORENCIA 250 mg powder for concentrate for solution for infusion.
Each vial contains 250 mg of abatacept.
Each mL contains 25 mg of abatacept, after reconstitution.
Abatacept is a fusion protein produced by recombinant DNA technology in Chinese hamster ovary cells.
Excipient with known effect: sodium: 0.375 mmol (8.625 mg) per vial
For the full list of excipients, see section 6.1.
Powder for concentrate for solution for infusion.
The powder is a white to off-white whole or fragmented cake.
Rheumatoid arthritis
ORENCIA, in combination with methotrexate, is indicated for:
▪ the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who responded inadequately to previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) or a tumour necrosis factor (TNF)-alpha inhibitor.
▪ the treatment of highly active and progressive disease in adult patients with rheumatoid arthritis not previously treated with methotrexate.
A reduction in the progression of joint damage and improvement of physical function have been demonstrated during combination treatment with abatacept and methotrexate.
Psoriatic Arthritis
ORENCIA, alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients when the response to previous DMARD therapy including MTX has been inadequate, and for whom additional systemic therapy for psoriatic skin lesions is not required.
Polyarticular juvenile idiopathic arthritis
ORENCIA in combination with methotrexate is indicated for the treatment of moderate to severe active polyarticular juvenile idiopathic arthritis (JIA) in paediatric patients 6 years of age and older who have had an insufficient response to other DMARDs including at least one TNF inhibitor.
Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis or JIA.
If a response to abatacept is not present within 6 months of treatment, the continuation of the treatment should be reconsidered (see section 5.1).
Posology
Rheumatoid arthritis
Adults
To be administered as a 30-minute intravenous infusion at the dose specified in Table 1. Following the initial administration, ORENCIA should be given 2 and 4 weeks after the first infusion, then every 4 weeks thereafter.
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Table 1: Dose of ORENCIAa
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Body Weight of Patient
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Dose
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Number of Vialsb
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< 60 kg
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500 mg
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2
|
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≥ 60 kg to ≤ 100 kg
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750 mg
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3
|
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> 100 kg
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1,000 mg
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4
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a Approximating 10 mg/kg.
b Each vial provides 250 mg of abatacept for administration.
No dose adjustment is required when used in combination with other DMARDs, corticosteroids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics.
Psoriatic arthritis
Adults
To be administered as a 30-minute intravenous infusion at the dose specified in Table 1. Following the initial administration, ORENCIA should be given 2 and 4 weeks after the first infusion, then every 4 weeks thereafter.
Juvenile Idiopathic Arthritis
Paediatric population
The recommended dose of ORENCIA for patients 6 to 17 years of age with juvenile idiopathic arthritis who weigh less than 75 kg is 10 mg/kg calculated based on the patient's body weight at each administration. Paediatric patients weighing 75 kg or more should be administered ORENCIA following the adult dosing regimen, not to exceed a maximum dose of 1,000 mg. ORENCIA should be administered as a 30-minute intravenous infusion. Following the initial administration, ORENCIA should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter.
The safety and efficacy of ORENCIA in children below 6 years of age have not been studied and therefore, ORENCIA is not recommended for use in children under six years old.
Special population
Elderly patients
No dose adjustment is required (see section 4.4).
Renal and hepatic impairment
ORENCIA has not been studied in these patient populations. No dose recommendations can be made.
Method of administration
The entire, fully diluted ORENCIA solution should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 to 1.2 μm). See section 6.6 for information on reconstitution and dilution.
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).
Combination with TNF-inhibitors
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 TNF-inhibitors 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
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.
Effects on the immune system
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).
Infections
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.
Malignancies
In the placebo-controlled clinical trials, the frequencies of malignancies in abatacept- and placebo-treated 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 for those with risk factors for skin cancer.
Vaccinations
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 ORENCIA, may blunt the effectiveness of some immunisations.
It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy (see section 4.5).
Elderly patients
A total of 404 patients 65 years of age and older, including 67 patients 75 years and older, received abatacept in placebo-controlled clinical trials. Similar efficacy was observed in these patients and in younger patients. The frequencies of serious infection and malignancy relative to placebo among 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).
Autoimmune processes
There is a theoretical concern that treatment with abatacept might increase the risk for autoimmune processes in adults and children, 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).
Blood glucose testing
Parenteral medicinal products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving ORENCIA, 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.
Patients on controlled sodium diet
This medicinal product contains 1.5 mmol (or 34.5 mg) sodium per maximum dose of 4 vials (0.375 mmol or 8.625 mg sodium per vial). To be taken into consideration when treating patients on a controlled sodium diet.
Combination with TNF-inhibitors
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.
Combination with other medicinal products
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.
Combination with other medicinal products that affect the immune system and with vaccinations
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).
Vaccinations
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 eva luated 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 eva luated 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.
Pregnancy and Women of childbearing potential
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.
Breast-feeding
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.
Fertility
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.
Adverse reactions in adults
Summary of the safety profile in rheumatoid arthritis
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.
Tabulated list of adverse reactions
Listed in Table 2 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 2: Adverse Reactions
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Infections and infestations
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Very Common
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Upper respiratory tract infection (including tracheitis, nasopharyngitis, and sinusitis)
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Common
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Lower respiratory tract infection (including bronchitis), urinary tract infection, herpes infections (including herpes simplex, oral herpes, and herpes zoster), pneumonia, influenza
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Uncommon
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Tooth infection, onychomycosis, sepsis, muskuloskeletal infections, skin abscess, pyelonephritis, rhinitis, ear infection
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Rare
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Tuberculosis, bacteraemia, gastrointestinal infection, pelvic inflammatory disease
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Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
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Uncommon
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Basal cell carcinoma, skin papilloma
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Rare
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Lymphoma, lung neoplasm malignant, squamous cell carcinoma
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Blood and lymphatic system disorders
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Uncommon
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Thrombocytopenia, leukopenia
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Immune system disorders
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Uncommon
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Hypersensitivity
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Psychiatric disorders
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Uncommon
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Depression, anxiety, sleep disorder (including insomnia)
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Nervous system disorders
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Common
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Headache, dizziness
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Uncommon
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Migraine, paraesthesia
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Eye disorders
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Uncommon
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Conjunctivitis, dry eye, visual acuity reduced
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Ear and labyrinth disorders
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Uncommon
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Vertigo
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Cardiac disorders
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Uncommon
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Palpitations, tachycardia, bradycardia
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Vascular disorders
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Common
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Hypertension, blood pressure increased
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Uncommon
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Hypotension, hot flush, flushing, vasculitis, blood pressure decreased
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Respiratory, thoracic and mediastinal disorders
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Common
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Cough
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Uncommon
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Chronic obstructive pulmonary disease exacerbated, bronchospasm, wheezing, dyspnea, throat tightness
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Gastrointestinal disorders
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Common
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Abdominal pain, diarrhoea, nausea, dyspepsia, mouth ulceration, aphthous stomatitis, vomiting
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Uncommon
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Gastritis
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Hepatobiliary disorders
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Common
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Liver function test abnormal (including transaminases increased)
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Skin and subcutaneous tissue disorders
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Common
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Rash (including dermatitis)
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Uncommon
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Increased tendency to bruise, dry skin, alopecia, pruritus, urticaria, psoriasis, acne, erythema, hyperhidrosis
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Musculoskeletal and connective tissue disorders
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Uncommon
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Arthralgia, pain in extremity
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Reproductive system and breast disorders
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Uncommon
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Amenorrhea, menorrhagia
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General disorders and administration site conditions
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Common
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Fatigue, asthenia
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Uncommon
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Influenza like illness, weight increased
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Description of selected adverse reactions
Infections
In the placebo-controlled clinical trials, 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.
Malignancies
In placebo-controlled clinical trials, malignancies were reported in 1.2% (31/2,653) of abatacept-treated 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.
Infusion-related reactions
Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in seven pooled intravenous studies (for Studies II, III, IV and V see section 5.1) were more common in the abatacept-treated patients than the placebo-treated patients (5.2% for abatacept, 3.7% for placebo). The most frequently reported event with abatacept (1-2%) was dizziness.
Acute infusion-related events that were reported in > 0.1% and ≤ 1% of patients treated with abatacept included cardiopulmonary symptoms such as hypotension, decreased blood pressure, tachycardia, bronchospasm, and dyspnea; other symptoms included myalgia, nausea, erythema, flushing, urticaria, hypersensitivity, pruritus, throat tightness, chest discomfort, chills, infusion site extravasation, infusion site pain, infusion site swelling, infusion related reaction, and rash. Most of these reactions were mild to moderate.
The occurrence of anaphylaxis remained rare during the double blind and the cumulative period. Hypersensitivity was reported uncommonly. Other reactions potentially associated with hypersensitivity to the medicinal product, such as hypotension, urticaria, and dyspnea, that occurred within 24 hours of ORENCIA infusion, were uncommon.
Discontinuation due to an acute infusion-related reaction occurred in 0.3% of patients receiving abatacept and in 0.1% of placebo-treated patients.
Adverse reactions in patients with chronic obstructive pulmonary disease (COPD)
In Study IV, there were 37 patients with COPD treated with 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 placebo-treated 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%]).
Autoimmune processes
Abatacept therapy did not lead to increased formation of autoantibodies, i.e., antinuclear and anti-dsDNA 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.
Immunogenicity
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 eva luable 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.
Safety information related to the pharmacological class
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.
Summary of the safety profile in psoriatic arthritis
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 placebo-controlled period. The overall safety profile was comparable between studies PsA-I and PsA-II and consistent with the safety profile in rheumatoid arthritis (Table 2).
Adverse reactions in paediatric patients with polyarticular juvenile idiopathic arthritis
ORENCIA has been studied in 190 paediatric patients, 6 to 17 years of age, with polyarticular JIA (see section 5.1). Adverse reactions occurring in the 4 month, lead-in, open-label period of the study were similar in type and frequency to those seen in adults (Table 2) with the following exceptions:
Common: upper respiratory tract infection (including sinusitis, nasopharyngitis and rhinitis), otitis (media and externa), haematuria, pyrexia.
Description of selected adverse reactions
Infections
The types of infections were consistent with those commonly seen in outpatient paediatric populations. The infections resolved without sequelae. One serious infection (varicella) was reported during the initial 4 months of treatment with ORENCIA.
Infusion-related reactions
Of the 190 patients with JIA treated with ORENCIA in this study, one (0.5%) patient discontinued due to non-consecutive infusion reactions, consisting of bronchospasm and urticaria. During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 4%, respectively, and were consistent with the types of reactions reported in adults.
Immunogenicity
Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with polyarticular JIA following repeated treatment with ORENCIA. The rate of seropositivity while patients were receiving abatacept therapy was 0.5% (1/189) during Period A; 13.0% (7/54) during Period B; and 12.8% (19/148) during Period C. For patients in Period B who were randomized to placebo (therefore withdrawn from therapy for up to 6 months) the rate of seropositivity was 40.7% (22/54). Anti-abatacept antibodies were generally transient and of low titer. The absence of concomitant methotrexate (MTX) did not appear to be associated with a higher rate of seropositivity in Period B placebo recipients. The presence of antibodies was not associated with adverse reactions or infusional reactions, or with changes in efficacy or serum abatacept concentrations. Of the 54 patients withdrawn from ORENCIA during the double-blind period for up to 6 months, none had an infusion reaction upon re-initiation of ORENCIA.
Open-label extension period
Upon continued treatment in the open-label extension period, the adverse reactions were similar in type to those seen in adult patients. One patient was diagnosed with multiple sclerosis while in Period C (open-label extension).
Reporting of suspected adverse reactions
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 Yellow Card Scheme.
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
Doses up to 50 mg/kg have been administered without apparent toxic effect. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.
Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AA24
Abatacept is a fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in Chinese hamster ovary cells.
Mechanism of action
Abatacept selectively modulates a key costimulatory signal required for full activation of T lymphocytes expressing CD28. Full activation of T lymphocytes requires two signals provided by antigen presenting cells: recognition of a specific antigen by a T cell receptor (signal 1) and a second, costimulatory signal. A major costimulatory pathway involves the binding of CD80 and CD86 molecules on the surface of antigen presenting cells to the CD28 receptor on T lymphocytes (signal 2). Abatacept selectively inhibits this costimulatory pathway by specifically binding to CD80 and CD86. Studies indicate that naive T lymphocyte responses are more affected by abatacept than memory T lymphocyte responses.
Studies in vitro and in animal models demonstrate that abatacept modulates T lymphocyte-dependent antibody responses and inflammation. In vitro, abatacept attenuates human T lymphocyte activation as measured by decreased proliferation and cytokine production. Abatacept decreases antigen specific TNFα, interferon-γ, and interleukin-2 production by T lymphocytes.
Pharmacodynamic effects
Dose-dependent reductions were observed with abatacept in serum levels of soluble interleukin-2 receptor, a marker of T lymphocyte activation; serum interleukin-6, a product of activated synovial macrophages and fibroblast-like synoviocytes in rheumatoid arthritis; rheumatoid factor, an autoantibody produced by plasma cells; and C-reactive protein, an acute phase reactant of inflammation. In addition, serum levels of matrix metalloproteinase-3, which produces cartilage destruction and tissue remodelling, were decreased. Reductions in serum TNFα were also observed.
Clinical efficacy and safety in adult rheumatoid arthritis
The efficacy and safety of abatacept were assessed in randomised, double-blind, placebo-controlled clinical trials in adult patients with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, V, and VI required patients to have at least 12 tender and 10 swollen joints at randomization. Study IV did not require any specific number of tender or swollen joints.
In Studies I, II, and V the efficacy and safety of abatacept compared to placebo were assessed in patients with an inadequate response to methotrexate and who continued on their stable dose of methotrexate. In addition, Study V investigated the safety and efficacy of abatacept or infliximab relative to placebo. In Study III the efficacy and safety of abatacept were assessed in patients with an inadequate response to a TNF-inhibitor, with the TNF-inhibitor discontinued prior to randomization; other DMARDs were permitted. Study IV primarily assessed safety in patients with active rheumatoid arthritis requiring additional intervention in spite of current therapy with non-biological and/or biological DMARDs; all DMARDs used at enrollment were continued. In Study VI, the efficacy and safety of abatacept were assessed in methotrexate-naive, Rheumatoid Factor (RF) and/or anti-Cyclic Citrullinated Peptide 2 (Anti-CCP2)-positive patients with early, erosive rheumatoid arthritis (≤ 2 years disease duration) who were randomized to receive abatacept plus methotrexate or methotrexate plus placebo. Study SC-II investigated the relative efficacy and safety of abatacept and adalimumab, both given subcutaneously without an intravenous loading dose and with background MTX, in patients with moderate to severely active RA and an inadequate response to previous MTX therapy. In study SC-III, abatacept SC was eva luated in combination with methotrexate (MTX), or as abatacept monotherapy, and compared to MTX monotherapy in induction of remission following 12 months of treatment, and the possible maintenance of drug-free remission after complete drug withdrawal, in adult MTX-naive patients with highly active early, rheumatoid arthritis (mean DAS28-CRP of 5.4; mean symptom duration less than 6.7 months) with poor prognostic factors for rapidly progressive disease (e.g., anti-citrullinated protein antibodies [ACPA+], as measured by anti-CCP2 assay, and/or RF+, baseline joint erosions).
Study I patients were randomized to receive abatacept 2 or 10 mg/kg or placebo for 12 months. Study II, III, IV, and VI patients were randomized to receive a fixed dose approximating 10 mg/kg of abatacept or placebo for 12 (Studies II, IV, and VI) or 6 months (Study III). The dose of abatacept was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg. Study V patients were randomized to receive this same fixed dose of abatacept or 3 mg/kg infliximab or placebo for 6 months. Study V continued for an additional 6 months with the abatacept and infliximab groups only.
Studies I, II, III, IV, V, VI, SC-II, and SC-III eva luated 339, 638, 389, 1441, 431, 509, 646, and 351 adult patients, respectively.
Clinical response
ACR response
The percent of abatacept-treated patients achieving ACR 20, 50, and 70 responses in Study II (patients with inadequate response to methotrexate), Study III (patients with inadequate response to TNF-inhibitor), and Study VI (methotrexate-naive patients) are shown in Table 3.
In abatacept-treated patients in Studies II and III, statistically significant improvement in the ACR 20 response versus placebo was observed after administration of the first dose (day 15), and this improvement remained significant for the duration of the studies. In Study VI, statistically significant improvement in the ACR 20 response in abatacept plus methotrexate-treated patients versus methotrexate plus placebo-treated patients was observed at 29 days, and was maintained through the duration of the study. In Study II, 43% of the patients who had not achieved an ACR 20 response at 6 months developed an ACR 20 response at 12 months.
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Table 3: Clinical Responses in Controlled Trials
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Percent of Patients
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MTX-Naive
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Inadequate Response to MTX
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Inadequate Response to TNF Inhibitor
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Study VI
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Study II
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Study III
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Response Rate
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Abatacepta +MTX
n = 256
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Placebo +MTX
n = 253
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Abatacepta +MTX
n = 424
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Placebo +MTX
n = 214
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Abatacepta +DMARDsb
n = 256
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Placebo +DMARDsb
n = 133
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ACR 20
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|
|
|
|
|
|
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Day 15
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24%
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18%
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23%*
|
14%
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18%**
|
5%
|
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Month 3
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64%††
|
53%
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62%***
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37%
|
46%***
|
18%
|
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Month 6
|
75%†
|
62%
|
68%***
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40%
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50%***
|
20%
|
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Month 12
|
76%‡
|
62%
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73%***
|
40%
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NAd
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NAd
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ACR 50
|
|
|
|
|
|
|
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Month 3
|
40%‡
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23%
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32%***
|
8%
|
18%**
|
6%
|
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Month 6
|
53%‡
|
38%
|
40%***
|
17%
|
20%***
|
4%
|
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Month 12
|
57%‡
|
42%
|
48%***
|
18%
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NAd
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NAd
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ACR 70
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|
|
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|
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Month 3
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19%†
|
10%
|
13%***
|
3%
|
6%††
|
1%
|
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Month 6
|
32%†
|
20%
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20%***
|
7%
|
10%**
|
2%
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Month |
