Abatacept - Uses, Dosage, Side Effects, Drug Warnings, and Precautions

Overview

Abatacept is a selective costimulation modulator used for treating patients with moderate to severe rheumatoid arthritis. It was approved by the United States Food and Drug Administration (USFDA) in 2005 and by the European Medicines Agency (EMA) on 21st May 2007.

How Does Abatacept Work?

T-cells are white blood cells that develop from the bone marrow and are part of the immune system. T-cells are responsible for inflammation in rheumatoid, polyarticular juvenile idiopathic, and psoriatic arthritis. T-cells get activated by the signaling molecules attached to the receptors on the cells. Abatacept is a protein that acts by suppressing the activation of T-cells by attaching to the signal molecules and reducing inflammation and other symptoms.

What are the Indications of Abatacept?

Abatacept is indicated in the following conditions:

• Abatacept may be used alone or concomitantly with other disease-modifying anti-rheumatic drugs (DMARDs) for reducing signs and symptoms, improving physical function, and inhibiting the progression of the disease in moderate to severe rheumatoid arthritis in adults.

• Abatacept is used alone or along with Methotrexate (MTX) in pediatric patients above six years of age with moderate to severely active polyarticular juvenile idiopathic arthritis.

Limitations: Abatacept must not be administered concomitantly with TNF antagonists and with other biological rheumatoid arthritis (RA) therapy like Anakinra.

What Is the Recommended Dosage of Abatacept?

Abatacept is available as a lyophilized (freeze-dried) powder for intravenous infusion in 250 mg single-use vials and as a solution for subcutaneous injection in 125 mg/ml single-dose prefilled glass syringes. Abatacept must be stored in the refrigerator at two to eight degrees Celsius, in the original package, and away from light. It must not be frozen and should be safely disposed if it is no longer needed or is outdated.

• In adult patients with rheumatoid arthritis, it may be administered as an intravenous or subcutaneous injection as monotherapy or with DMARDs other than TNF antagonists. In pediatric patients with juvenile idiopathic arthritis, the dose is calculated based on the patient's body weight.

• Intravenous administration is a 30 minute infusion, depending on the weight range dosing specifications; it should be administered two and four weeks after the first therapy and every four weeks following it. Unused portions must be immediately discarded

• Subcutaneous administration is once weekly, which may or may not be initiated with an intravenous loading dose. If initiated with an IV loading dose, Abatacept must be started with a single IV infusion followed by the first 125 mg subcutaneous administration within a day of IV infusion.

• For intravenous administration, doses up to 50 mg/kg can be recommended without apparent toxic effects; in case of overdose, the patient must be monitored for any adverse reactions, and appropriate treatment must be considered.

• In pediatric patients of less than 75 kg, the Abatacept dose is calculated at 10 mg/kg based on the patient’s body weight for intravenous administration. For patients weighing more than 75 kg, Abatacept must be administered following the adult dosing regimen for intravenous administration, not exceeding 1000 mg.

What Are the Warnings and Precautions of Abatacept?

• Clinical trials demonstrated that concomitant administration of Abatacept with TNF antagonist to patients resulted in more infections than treatment with only TNF antagonist therapy; therefore, patients must be monitored for signs of infection during the transition from TNF antagonist therapy to Abatacept.

• Anaphylaxis and anaphylactoid reactions were rarely reported during clinical trials; it was observed only in patients with intravenous (IV) Abatacept. Other uncommon (less than one percent) hypersensitivity reactions that occurred within 24 hours of Abatacept infusion were hypotension, urticaria, and dyspnea. However, appropriate medical support must be available to manage the hypersensitivity reactions that may occur after infusion and may be life-threatening; in such cases, the administration of Abatacept must be immediately stopped, and any further use must be permanently discontinued.

• Patients must be screened for latent tuberculosis infection before initiating treatment with Abatacept, and if found positive, the condition must be treated before the treatment with Abatacept. Anti-rheumatic therapy may be associated with the reactivation of hepatitis B infection; thus, patients must be screened for viral hepatitis before initiating Abatacept therapy.

• Serious infections such as pneumonia and sepsis were reported with Abatacept; various infections in patients were also seen on concomitant immunosuppressive treatment making them further susceptible to infections. Therefore, patients must be closely monitored during Abatacept treatment, and the drug must be discontinued if the patient develops a serious infection.

• Abatacept may reduce the effectiveness of the immunizations; therefore, live vaccines must not be concomitantly administered or within three months of discontinuing the drug. Pediatric patients must be up-to-date with all the immunizations before Abatacept therapy.

• Abatacept must be used with caution along with close monitoring in patients with rheumatoid arthritis and chronic obstructive pulmonary disease to prevent worsening of respiratory condition.

• Abatacept may cause immunosuppression due to inhibition of T-cell activation, which may affect the host defense mechanism and increase the risk of infections.

What Are the Adverse Reactions of Abatacept?

The most serious adverse reactions reported with Abatacept include infections and malignancies; most frequent infections, such as pneumonia, bronchitis, herpes zoster, and localized infections, resulted in the discontinuation of the drug. Other commonly reported adverse events include;

• Headache and dizziness.

• Nasopharyngitis.

• Nausea.

• Pain in the extremities.

• Rash.

• Urinary tract infections.

• Back pain.

• Dyspepsia.

• Cough.

• Hypertension.

For Patients

What Is Rheumatoid Arthritis?

Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory disorder (the body’s immune system attacks the healthy cells in the body) affecting the joints of the hands, wrists, and knees. The lining of the joints becomes inflamed, damaging the joint tissues and causing chronic (long-lasting pain), lack of unsteadiness, and deformity. It can also affect vital organs such as the lungs, heart, and eyes. The exact cause of the disease is unknown; it is associated with symptoms such as pain and stiffness of the joint, weight loss, fever, fatigue, and weakness.

What Is Abatacept?

Abatacept is a prescription medicine used alone or with other rheumatoid arthritis medications other than TNF antagonists to treat adult patients with moderate to severe rheumatoid arthritis, including those patients in whom the other medicines for rheumatoid arthritis have not been effective. It helps to prevent further damage to the bones and joints and may improve the ability to perform daily activities. It is also used alone or with Methotrexate in children above six years of age with moderate to severe polyarticular juvenile idiopathic arthritis.

Instructions for Taking Abatacept

Abatacept is administered by the healthcare provider through a vein in the arm, and it may take about 30 minutes to administer the dose. It may also be given as an injection under the skin. The treatment is administered two and four weeks after and every four weeks following the first therapy.

Things to Inform the Doctor of Before Taking Abatacept

• Patients must inform the doctor if they are suffering from any kind of infection, as it may worsen or increase the chance of side effects.

• In case of allergy to Abatacept or other medications, the doctor must be informed.

• The patients must inform the doctor of any history of liver inflammation, and the healthcare provider may examine the liver for infection or hepatitis before starting the treatment with Abatacept.

• In case of a history of breathing problems, such as chronic obstructive pulmonary disease (COPD), lung infections, tuberculosis, or symptoms such as fever, persistent cough, night sweats, and weight loss, the doctor must be informed, and a healthcare provider may examine for tuberculosis or advise a skin test.

• Female patients must inform the doctor if they are pregnant or planning pregnancy, as it is unknown if Abatacept may harm the fetus. Nursing mothers must also inform the doctor before initiating therapy as it is unknown if Abatacept can pass into the breast milk, which may harm the infant.

• Before starting treatment with Abatacept, the doctor must be informed if the patient is taking any medicines, over-the-counter (OTC) medications, vitamins, or herbal supplements, especially if the patients are under medications such as Etanercept, Anakinra, Rituximab, Golimumab, Tocilizumab, or other biologic medicines to treat rheumatoid arthritis or JIA as it may increase the susceptibility to serious infections.

What Are the Side Effects of Abatacept?

• Allergic reactions may occur during the therapy, including symptoms such as itchy skin bumps, difficulty breathing, and swollen face, lips, eyelids, and tongue.

• Patients may be prone to serious infections and experience symptoms such as cough, fever, tiredness, and red, warm skin.

• In patients with COPD, respiratory problems may develop during the treatment with Abatacept, and symptoms may worsen, causing cough and breathing difficulty.

• Abatacept may cause vaccines to be less effective; hence vaccinations must not be received during the treatment.

• Side effects such as headache, sore throat, upper respiratory tract infections, and nausea are common during the treatment with Abatacept. In children, Abatacept may cause diarrhea, fever, cough, and abdominal pain.

For Doctors

Description

Abatacept is a soluble fusion protein produced by recombinant DNA technology and composed of human cytotoxic T-lymphocyte associated antigen 4(CTLA-4), linked to a modified Fc portion of human immunoglobulin G1 (IgG1). It is supplied as a lyophilized powder for intravenous administration. A single-use vial contains Abatacept 250 mg, maltose 500 mg, monobasic sodium phosphate, and sodium chloride. It is supplied as a sterile, preservative-free solution without maltose for subcutaneous administration. A single dose for subcutaneous administration contains Abatacept 125 mg, dibasic sodium phosphate anhydrous, monobasic sodium phosphate monohydrate, poloxamer, and sucrose.

Mechanism of Action

Abatacept is a selective costimulation modulator that acts by inhibiting the activation of T-cells by binding to CD80 and CD86 and blocking the interaction with CD28, which requires a costimulatory signal for activation of T-cells. In vitro, Abtatacept acts by decreasing T-cell proliferation, thereby inhibiting the production of cytokines, TNF alpha, interferon, and interleukin.

Pharmacodynamics

During the clinical trials, the administration of 10 mg/kg of Abatacept demonstrated decreased serum levels of interleukins, rheumatoid factor, C-reactive protein, TNF alpha, and matrix metalloproteinase. The relationship of these biomarkers to the mechanism of Abatacept in rheumatoid arthritis is unknown.

Pharmacokinetics

• In patients with rheumatoid arthritis, after multiple doses of intravenous infusions, Abatacept demonstrated a proportional increase in the maximum concentration and area under the curve (AUC) over the dose range of 2 mg/kg to 10 mg/kg. The serum concentration reached a steady state by day 60 with a mean concentration of 24 mcg/mL; no systemic accumulation occurred upon continued treatment with 10 mg/kg at monthly intervals in rheumatoid arthritis patients. Concomitant administration of Methotrexate, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and TNF-blocking agents did not affect the clearance of Abatacept.

• In patients of 6 to 17 years of age, Abatacept showed mean steady-state serum peak and trough concentrations of 217 mcg/mL and 11.9 mcg/mL. The range of clearance was 0.4 mL/h/kg in patients with juvenile idiopathic arthritis.

• On subcutaneous administration, after 85 days of treatment, Abatacept demonstrated a mean range of minimum plasma concentration (Cmin) of 32.5 mcg/mL and a maximum serum concentration (Cmax) of 48.1 mcg/mL, respectively. The bioavailability is around 78.6 percent, with a mean systemic clearance of 0.28 mL/h/kg, a volume of distribution of 0.111 L/kg, and a terminal half-life of 14.3 days.

Drug Interactions

• Concomitant administration of TNF antagonists with Abatacept is not recommended as it may be associated with an increased risk of serious infections compared to using TNF antagonists alone.

• The safety and efficacy data of Abatacept with other biologic rheumatoid arthritis therapy, such as Anakinra, is insufficient; therefore, such administration is not recommended.

• When IV administration of Abatacept, blood glucose monitoring must be advised, and methods that do not react with maltose must be considered because parenteral drug products contain maltose which may interfere with the blood glucose test values.

Results of Clinical Studies:

• In adults with RA, the use of Abatacept was tested across six randomized controlled trials with double blinding, involving patients with RA either not responding to Methotrexate or DMARDs.The trials involved the administration of Abatacept or placebo intravenously, starting with weeks 0, 2, and 4. It was later followed up with injections every four weeks. The dose was 500 mg for those weighing 60 kgs or less and 750 mg for patients between 60 - 100 kgs, and 1000 mg for those weighing 100 kg or more. According to the American College of Rheumatology (ACR) classification, the diagnosis of RA is based on the symptom duration, distribution of joints involved, serology, and ESR and CRP values.

• A score of more than or equal to six is needed for diagnosing RA in a patient with swollen joints that any other disease cannot explain. The studies demonstrated a significant increase in the improvement at the end of six months compared to those receiving a placebo. Another study was conducted to verify the suitability of subcutaneous injection; the results showed a non-inferiority in the criteria to those receiving intravenous therapy. In those receiving a combination of Abatacept and Methotrexate, a comparison was made for the radiological improvement at the end of two years to those receiving placebo or Methotrexate, and 51 percent had no significant progression of the disease; greater levels of improvement were observed in patients receiving Abatacept. Similarly, in the pediatric population, in patients with juvenile RA, the studies demonstrated a significant improvement in the patients treated with Abatacept.

Non-clinical Toxicology

• Carcinogenicity: In a mouse carcinogenicity study, on weekly administration of subcutaneous injections of 20,65 and 200 mg/kg of Abatacept for 84 weeks in males and 88 weeks in females, an increase in the incidence of malignant lymphomas and mammary gland tumors were seen. The doses produced exposures of 0.8, 2.0, and 3.0 times higher than those with the maximum recommended human dose (MHRD) of 10 mg/kg based on AUC.

• Fertility: No adverse effects were seen on male or female fertility in rats at doses up to 200 mg/kg of Abatacept every three days, at 11 times the MHRD exposure based on AUC.

• Toxicity: No significant drug-related toxicity was reported in a one-year toxicity study in monkeys with Abatacept administered weekly once intravenously at doses up to 50 mg/kg (nine times the MHRD exposure). In a juvenile study conducted in rats from 4 to 94 days of age with Abatacept increased incidence of infections that lead to death was observed compared to the controls. Altered levels of T-cell subsets, including an increase in T - helper cells and a decrease in T- regulatory cells, were observed. Lymphocytic inflammation of the thyroid and pancreatic islets were observed upon following these animals till adulthood.

• Mutagenicity: In vitro bacterial reverse mutation (Ames) tests, no mutations or chromosomal aberrations were observed in human lymphocytes treated with or without metabolic activation of Abatacept.

Uses of Abatacept in Specific Populations

• Pregnancy: Adequate data is not available on the use of Abatacept in pregnant women; animal studies have demonstrated that the drug crosses the placenta and alterations occurred in immune function; however, Abatacept was not teratogenic in pregnant mice at doses up to 300 mg/kg, and the administration of Abatacept to female rats during the early gestation and lactation period did not produce any significant adverse effects in the offsprings.

• Nursing Mothers: As many drugs are excreted in human milk, there may be a potential for serious adverse reactions in the infants, so a decision must be made whether to discontinue nursing or discontinue the treatment with Abatacept, taking into consideration the importance of the drug to the mother.

• Pediatric Use: Abatacept is not recommended for patients below six years of age as the safety and effectiveness of the drug have not been established. Subcutaneous administration in patients below 18 years of age is not recommended as the safety and efficacy of the drug have not been studied.

• Geriatric Use: No overall differences were observed in safety and effectiveness between the young and old patients treated with Abatacept; however, the frequency of serious infection and malignancy is higher in patients above 65 years than in younger patients.