Abatacept or Orencia is the first biological medicine available as an intravenous infusion and as a subcutaneous injection designed to reduce the signs and symptoms of rheumatoid arthritis in adult patients. In Europe it is indicated in combination with methotrexate (MTX) to treat adult patients with moderate or severe rheumatoid arthritis who have had an inadequate response or intolerance to other disease-modifying antirheumatic drugs (DMARDs), including at least one factor inhibitor. tumor necrosis (antiTNF). In addition, the intravenous formulation of abatacept is indicated for the treatment of patients from six years of age with arthritis. polyarticular juvenile idiopathic showing an insufficient response to DMARDs, including at least one anti-TNF.
Indications and dosage
Abatacept is used to treat moderate to severe active rheumatoid arthritis in adult patients who have had an inadequate response or intolerance to other disease-modifying antirheumatic drugs (DMARDs) (in combination with methotrexate).
Administración intravenosa
- Pacientes ancianos: no se requieren reajuste de las dosis.
- Pacientes pediátricos: se desconoce la eficacia y seguridad del abatacept en niños o adolescentes.
- Renal and hepatic impairment: Abatacept has not been studied in these patient populations.
Contraindications and precautions
Abatacept is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients. It should not be used in cases of serious and uncontrolled infections such as septicemia.and opportunistic infections. When abatacept was used in combination with TNF-blocking agents, an increase in infections in general and serious infections was observed compared to patients treated with TNF-blocking agents and placebo. The use of abatacept in combination with TNF blocking agents is not recommended. Caution is recommended for patients with a history of allergic reactions to abatacept or any of the excipients. If any severe allergic or anaphylactic reaction occurs, abatacept treatment should be stopped immediately and appropriate treatment initiated. Like all drugs that affect the immune system, including abatacept, the host’s defenses against infections and malignancies can be affected.as well as responses to vaccines . Serious infections have been reported with abatacept. Therefore, treatment with this drug should not be initiated in patients with active infections until they are uncontrolled. Caution is advised when considering the use of abatacept in patients with a history of recurrent infections or underlying conditions that may predispose them to infections. Patients who develop a new infection while receiving abatacept should be closely monitored. If a patient develops a severe infection, abatacept should be discontinued. Antirheumatic treatments have been associated with reactivation of hepatitis B. Therefore, viral hepatitis should be screened before starting abatacept treatment.
There are insufficient data on the use of abatacept in pregnant women. Although no adverse effects were observed in laboratory animal studies, abatacept crosses the barrier and therefore is not recommended for use during pregnancy . During abatacept treatment, women of childbearing potential must use effective contraception until fourteen weeks after the last dose. Mothers should not breastfeed their children during treatment.
Interactions
TNF blockers do not influence the clearance of abatacept: however, patients with concomitant treatment with abatacept and TNF blocking agents have more infections and serious infections than patients treated with TNF blocking agents alone. No effects of methotrexate, NSAIDs, and corticosteroids on abatacept clearance have been observed.
Adverse reactions
In placebo-controlled clinical trials with abatacept, adverse drug reactions were observed in 52.2% of abatacept-treated patients and 46.1% of placebo-treated patients. The most frequently reported adverse drug reactions (≥ 5%) among abatacept-treated patients were headache and nausea. The proportion of patients who discontinued treatment due to adverse reactions was 3.4% for abatacept-treated patients and 2.2% for placebo-treated patients.
The reactions that were more common in patients treated with abatacept compared to placebo were:
- Cardiac disorders (less than 1/1000): tachycardia , bradycardia , palpitations
- Adverse reactions on blood and lymphatic system <1/1000): thrombocytopenia , leukopenia
- Adverse reactions on the nervous system: headaches ; dizziness : paresthesia , vertigo ; depression , anxiety
- Vision disturbances: conjunctivitis , decreased acuity
- Respiratory disorders: cough
- Gastrointestinal disorders: abdominal pain , diarrhea , nausea , dyspepsia ; Gastritis , mouth ulcers , aphthous
- Adverse reactions on the skin and soft tissues: skin rashes including dermatitis, increased tendency to bruise, alopecia , dry skin
- Musculoskeletal and connective tissue disorders: arthralgia, pain in extremities
- Infections and infestations: lower respiratory tract infection (including bronchitis ), urinary tract infection , herpes simplex , upper respiratory tract infection (including tracheitis , nasopharyngitis ), rhinitis . Tooth infection, ulcers.
- Benign , malignant and unspecified neoplasms ( cysts and polyps ): basal cell carcinoma .
- Vascular disorders: hypertension , flushing; Hypotension , hot flashes .
- General disorders: fatigue , asthenia ; flu-like syndrome .
Mechanism of action
Abatacept selectively modulates a key costimulatory signal that is necessary for full activation of lymphocytes T expressing CD28. T lymphocytes require two signals provided by antigen presenting cells: the recognition of a specific antigen by a T lymphocyte receptor, an antigen capable of binding to the antigen-MHC complex present in macrophages and dendritic cells first signal and a second signal costimulatory. A major costimulation pathway involves the binding of CD80 and CD86 molecules on the surface of the cell presenting antigen to the CD28 receptor on T lymphocytes (signal 2). Abatacept selectively inhibits this costimulation pathway through its specific binding to CD80 and CD86. Some studies indicate that abatacept affects naive T cell responses more than memory T cell responses.Abatacept also decreases the production of antigen-specific TNF-α, interferon-γ, and interleukin 2 by lymphocytes. As a consequence of these effects, the CTLA4-Ig fusion protein can suppress autoimmune diseases such as rheumatoid arthritis.
Pharmacokinetics
In studies in patients with rheumatoid arthritis, abatacept showed a linear response of peak plasma concentrations as a function of doses in the range of 2 to 10 mg / kg. At the 10 mg / kg doses, the elimination half-life was 13.1 days (8-25 days). The mean volume of distribution (Vss) was 0.07 l / kg while systemic clearance was approximately 0.22 ml / h / kg. In steady-state, trough concentrations were 25 μg / ml, and mean Cmax values were approximately 290 μg / ml. There was no systemic accumulation of abatacept upon continuation of repeated treatment with 10 mg / kg at monthly intervals in patients with rheumatoid arthritis. In healthy volunteers,abatacept shows similar pharmacokinetic properties to rheumatoid arthritis patients.
Toxicity
Abatacept did not show mutagenic effects in any of the standard mutagenesis tests. In animal carcinogenesis studies such as mice, increases in the incidence of malignant lymphomas or tumors of the mammary glands were observed , which may be associated with decreased control of murine leukemia virus and mammary tumor virus in mice. by prolonged immunomodulation. In contrast, in a one-year toxicity study in cynomolgus monkeys, abatacept was not associated with any major toxicity. In other studies on embryotoxicity with abatacept in mice, rats and rabbits at doses up to 20 to 30 times the dose of 10 mg / kg in humans without observing unwanted effects in the offspring. Abatacept crosses the placenta in rats and rabbits . No undesirable effects have been reported in peri- and postnatal toxicity studies in rats .
Presentation
Orencia 250 mg powder for concentrate for solution for injection.