Chemical formula: C₃₄₉₈H₅₄₅₈N₉₂₂O₁₀₉₀S₃₂ Molecular mass: 92,300 g/mol
Abatacept interacts in the following cases:
Co-administration of abatacept 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 abatacept in combination with anakinra or rituximab.
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 a human 10 mg/kg dose based on AUC. Abatacept should not be used in pregnant women unless clearly necessary. Women of child-bearing potential should use effective contraception during treatment with abatacept 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 abatacept 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.
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 abatacept, 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 below 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.
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, 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.
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.
Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in seven pooled intravenous studies 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 abatacept 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.
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%]).
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 abatacept.
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). 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.
abatacept has been studied in 190 paediatric patients, 6 to 17 years of age, with polyarticular JIA. 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 with the following exceptions:
Common: upper respiratory tract infection (including sinusitis, nasopharyngitis and rhinitis), otitis (media and externa), haematuria, pyrexia.
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 abatacept.
Of the 190 patients with JIA treated with abatacept 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.
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 abatacept. 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 abatacept during the double-blind period for up to 6 months, none had an infusion reaction upon re-initiation of abatacept.
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).
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