Chemical formula: C₃₄₉₈H₅₄₅₈N₉₂₂O₁₀₉₀S₃₂ Molecular mass: 92,300 g/mol
Abatacept interacts in the following cases:
Abatacept has not been studied in these patient populations. No dose recommendations can be made.
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 higher than a human 10 mg/kg dose based on AUC.
Abatacept should not be used during pregnancy unless the clinical condition of the woman requires treatment with abatacept. Women of childbearing potential have to use effective contraception during treatment and up to 14 weeks after the last dose of abatacept.
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 unknown whether abatacept is excreted in human milk.
A risk to the newborns/infants cannot be excluded.
Breast-feeding should be discontinued during treatment 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 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:
Infections and infestations | 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, musculoskeletal infections, skin abscess, pyelonephritis, rhinitis, ear infection | |
Rare | Tuberculosis, bacteraemia, gastrointestinal infection, pelvic inflammatory disease | |
Neoplasms benign, malignant and unspecified (incl. cysts and polyps) | Uncommon | Basal cell carcinoma, skin papilloma |
Rare | Lymphoma, lung neoplasm malignant, squamous cell carcinoma | |
Blood and lymphatic system disorders | Uncommon | Thrombocytopenia, leukopenia |
Immune system disorders | Uncommon | Hypersensitivity |
Psychiatric disorders | Uncommon | Depression, anxiety, sleep disorder (including insomnia) |
Nervous system disorders | Common | Headache, dizziness |
Uncommon | Migraine, paraesthesia | |
Eye disorders | Uncommon | Conjunctivitis, dry eye, visual acuity reduced |
Ear and labyrinth disorders | Uncommon | Vertigo |
Cardiac disorders | Uncommon | Palpitations, tachycardia, bradycardia |
Vascular disorders | Common | Hypertension, blood pressure increased |
Uncommon | Hypotension, hot flush, flushing, vasculitis, blood pressure decreased | |
Respiratory, thoracic and mediastinal disorders | Common | Cough |
Uncommon | Chronic obstructive pulmonary disease exacerbated, bronchospasm, wheezing, dyspnoea, throat tightness | |
Gastrointestinal disorders | Common | Abdominal pain, diarrhoea, nausea, dyspepsia, mouth ulceration, aphthous stomatitis, vomiting |
Uncommon | Gastritis | |
Hepatobiliary disorders | Common | Liver function test abnormal (including transaminases increased) |
Skin and subcutaneous tissue disorders | Common | Rash (including dermatitis) |
Uncommon | Increased tendency to bruise, dry skin, alopecia, pruritus, urticaria, psoriasis, acne, erythema, hyperhidrosis | |
Musculoskeletal and connective tissue disorders | Uncommon | Arthralgia, pain in extremity |
Reproductive system and breast disorders | Uncommon | Amenorrhea, menorrhagia |
General disorders and administration site conditions | Common | Fatigue, asthenia, local injection site reactions, systemic injection reactions* |
Uncommon | Influenza like illness, weight increased |
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.
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 annualised incidence rate remained stable.
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 annualised 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 dyspnoea. 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 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.
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 (short-term 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 electrochemiluminescence (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 pharmacokinetics.
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, dyspnoea) have been received following the use of subcutaneous abatacept.
Abatacept is the first selective co-stimulation modulator.
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 occured 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 1).
Abatacept has been studied in patients with pJIA in 2 clinical trials (ongoing pJIA SC study and pJIA IV study). The pJIA SC study included 46 patients in the 2 to 5 year age cohort and 173 patients in the 6 to 17 year age cohort. The pJIA IV study included 190 patients in the 6 to 17 year age cohort. During the first 4-month open-label period, the overall safety profile in these 409 pJIA patients was similar to that observed in the RA population with the following exceptions in the pJIA patients:
Infections were the most commonly reported adverse events in patients with pJIA. The types of infections were consistent with those commonly seen in outpatient paediatric populations. During the first 4-month treatment period of intravenous and subcutaneous abatacept in 409 patients with pJIA, the most common adverse reactions were nasopharyngitis (3.7% patients) and upper respiratory tract infection (2.9% patients). Two serious infections (varicella and sepsis) were reported during the initial 4 months of treatment with abatacept.
Of the 219 patients with pJIA treated with subcutaneous abatacept during the first 4-month abatacept treatment, the frequency of local injection reactions was 4.6% (10/219); injection site pain and injection site erythema were the most frequently reported local injection reactions. No systemic hypersensitivity reactions were reported.
Antibodies directed against the entire abatacept molecule or to the CTLA-4 Antibodies directed against the whole abatacept molecule or to the CTLA-4 portion of abatacept were assessed by an ECL assay in patients with pJIA following repeated treatment with subcutaneous abatacept. Overall, 6.9% (15/218) of subjects (cohorts combined) had a positive immunogenicity response relative to baseline during the cumulative period, including the 4-month short-term treatment period, 20-month extension treatment period and the 6-month post abatacept follow-up period. In the 6 to 17 year age cohort, the overall rate of seropositivity during the cumulative period including post abatacept follow-up was 4.7% (8/172): 2.3% (4/172) on treatment and 13.6% (6/44) after discontinuation of abatacept (≥28 days after the last dose). In the 2 to 5 year age cohort, the overall rate of seropositivity during the cumulative period including post abatacept follow-up was 15.2% (7/46): 10.9% (5/46) on treatment and 37.5% (3/8) after discontinuation of abatacept (≥28 days after the last dose).
Overall antibodies against abatacept were generally transient and of low titer. The absence of concomitant methotrexate did not appear to be associated with a higher rate of seropositivity. The significance of the higher incidence in the 2 to 5 year age cohort is unknown, taking into account the difference in sample size. The presence of antibodies was not associated with adverse reactions, or with changes in efficacy or serum abatacept concentrations, in either cohort.
During the extension period of the pJIA studies (20 months in the pJIA ongoing SC study and 5 years in the pJIA IV study), the safety profile in the pJIA patients aged 6 to 17 years was comparable to that seen in adult patients. One patient was diagnosed with multiple sclerosis while in the extension period of the pJIA IV study. One serious adverse reaction of infection (limb abscess) was reported in the 2 to 5 year age cohort during the 20-month extension period of the pJIA SC study.
Long-term safety data in 2 to 5 year age cohort with pJIA was limited, but the existing evidence did not reveal any new safety concern in this younger paediatric population. During the 24-month cumulative period of the pJIA SC study (4-month short-term period plus 20-month extension period), a higher frequency of infections was reported in the 2 to 5 year age cohort (87.0%) compared to that reported in the 6 to 17 year age cohort (68.2%). This was mostly due to non-serious upper respiratory tract infections in the 2 to 5 year age cohort.
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