Abatacept

Subcutaneous administration exhibited a bioavailability of 78.6% when compared to intravenous administration.The volume of distribution varies among different administration methods. For RA patients receiving intravenous administration, the volume of distribution is 0.07 L/kg, while healthy subjects receiving intravenous administration have a volume of distribution of 0.09 L/kg. RA patients undergoing subcutaneous administration have a volume of distribution of 0.11 L/kg.Comprehensive information regarding the metabolism of abatacept is not provided, leaving its metabolic processes undisclosed.Abatacept's elimination involves both kidney and liver processes, contributing to its clearance from the body.

Abatacept functions as a selective modulator of co-stimulation, similar to CTLA-4. The drug has demonstrated the ability to hinder the activation of T-cells (T lymphocytes) by binding to CD80 and CD86, effectively preventing their interaction with CD28. By blocking this interaction, the delivery of the crucial second co-stimulatory signal needed for T-cell activation is inhibited. This leads to the suppression of autoimmune T-cell activation, which is known to play a role in the development of rheumatoid arthritis.

When administered intravenously to healthy subjects, a single 10 mg/kg infusion of abatacept yielded a peak plasma concentration (Cmax) of 292 mcg/mL. In rheumatoid arthritis (RA) patients, multiple 10 mg/kg doses led to a Cmax of 295 mcg/mL.

• Graft-versus-host disease, acute, prophylaxis
• Psoriatic arthritis
• Rheumatoid arthritis

• Graft-versus-host disease, acute, prophylaxis
• Psoriatic arthritis
• Rheumatoid arthritis

Graft-versus-Host Disease, Acute, Prophylaxis:

Please take note: This approach should be combined with a calcineurin inhibitor and methotrexate. Before administering abatacept, begin antiviral prophylaxis to prevent reactivation of Epstein-Barr virus (EBV), following clinical or institutional guidelines. Continue antiviral prophylaxis for six months post-hematopoietic stem cell transplant (HSCT). Also, consider prophylactic antiviral treatment for cytomegalovirus (CMV) infection/reactivation during abatacept therapy and for six months post-HSCT.

• Intravenous (IV): Administer 10 mg/kg (maximum: 1,000 mg/dose) the day before transplant (day -1), followed by 10 mg/kg (maximum: 1,000 mg/dose) on days 5, 14, and 28 post-transplant (Ref).

Psoriatic Arthritis:

Please note: IV dosing is determined by body weight. After the initial IV infusion using weight-based dosing, repeat the IV infusion with the same weight-based dosing at 2 weeks and 4 weeks after the first infusion, and subsequently every four weeks.

• IV:
• <60 kg: 500 mg.
• 60 to 100 kg: 750 mg.
• 100 kg: 1,000 mg.
• Subcutaneous (SUBQ): 125 mg once weekly. Please administer without an IV loading dose. When transitioning from IV to SUBQ therapy, administer the first SUBQ dose instead of the next scheduled IV dose.

Rheumatoid Arthritis:

Please note: This is an option for those who have not responded to maximal methotrexate treatment, or as an alternative to methotrexate for treatment-naive patients with moderate to high disease activity. IV dosing is based on body weight. After the initial IV infusion using weight-based dosing, repeat the IV infusion with the same weight-based dosing at 2 weeks and 4 weeks after the first infusion, and subsequently every four weeks.

• IV:
• <60 kg: 500 mg.
• 60 to 100 kg: 750 mg.
• 100 kg: 1,000 mg.
• Subcutaneous (SUBQ): 125 mg once weekly. SUBQ dosing can be initiated with or without an IV loading dose. If beginning with an IV loading dose, administer the initial IV infusion using weight-based dosing. Then, within 24 hours of the infusion, administer 125 mg subcutaneously, followed by 125 mg subcutaneously once weekly. When transitioning from IV to SUBQ therapy, administer the first SUBQ dose instead of the next scheduled IV dose.

• Injectable Infusion : 250 mg/vial
• Subcutaneous Injection : 125mg/prefilled syringe or auto-injector

Graft-versus-host disease, acute; prevention in patients undergoing hematopoietic stem cell transplantation (HSCT):

Please note: Use in conjunction with calcineurin inhibitors and methotrexate. Before administering abatacept, initiate antiviral prophylaxis for reactivation of Epstein-Barr virus (EBV) as per clinical or institutional practice guidelines; continue antiviral prophylaxis for 6 months post-HSCT. Consider prophylactic antivirals for cytomegalovirus (CMV) infection/reactivation during abatacept therapy and for 6 months post-HSCT. Efficacy demonstrated in patients undergoing HSCT from a well-matched donor or a donor with a single allele mismatch.

For Children aged 2 to under 6 years:

Intravenous (IV) infusion: 15 mg/kg on day -1 (the day before transplantation), followed by 12 mg/kg on days 5, 14, and 28 after transplantation.

For Children aged 6 years and Adolescents:

Intravenous (IV) infusion: 10 mg/kg on day -1, followed by 10 mg/kg on days 5, 14, and 28 post-transplantation; maximum dose: 1,000 mg per dose.

Regarding Juvenile Idiopathic Arthritis:

Dosing varies based on the route of administration (IV or SUBQ), with special care needed.

For Intravenous (IV) administration in Children aged 6 years and Adolescents:

The dosage is determined by body weight at each administration. After the initial IV infusion, the IV dose is repeated at 2 weeks, 4 weeks after the initial infusion, and subsequently every 4 weeks.

Patient weight:

• <75 kg: IV: 10 mg/kg.
• 75 to 100 kg: IV: 750 mg.
• 100 kg: IV: 1,000 mg.

For Subcutaneous (SUBQ) administration in Children aged 2 years and Adolescents:

Please note: Administer without an IV loading dose and adhere to the following weight-based dosing. The subcutaneous autoinjector has not been studied in patients under 18 years old.

Patient weight:

• 10 to <25 kg: SUBQ: 50 mg once weekly.
• ≥25 to <50 kg: SUBQ: 87.5 mg once weekly.
• ≥50 kg: SUBQ: 125 mg once weekly.

• Concomitant Use with TNF Antagonists:

In clinical trials involving adult RA patients, the combined use of intravenous Abatacept and TNF antagonist therapy led to a higher incidence of infections (63%) and serious infections (4.4%) compared to patients treated solely with TNF antagonists (43% and 0.8%, respectively). These trials did not demonstrate significant additional effectiveness with concurrent Abatacept and TNF antagonist administration. Therefore, it is not recommended to use Abatacept and a TNF antagonist concurrently. During the transition from TNF antagonist therapy to Abatacept therapy, close monitoring for signs of infection is advised.

• Hypersensitivity:

In controlled clinical trials, anaphylaxis and anaphylactoid reactions were rare (<0.1%) and observed only in patients receiving intravenous Abatacept. Other reactions potentially linked to drug hypersensitivity, such as hypotension, urticaria, and dyspnea occurring within 24 hours of Abatacept infusion, were uncommon (<1%). Among patients with juvenile idiopathic arthritis, one case of a hypersensitivity reaction (0.5%) was observed. Immediate medical support measures should be available in case of hypersensitivity reactions. Anaphylaxis or anaphylactoid reactions can occur after the first infusion and may be life-threatening. If a serious allergic reaction occurs, Abatacept administration should be halted and appropriate therapy initiated, followed by permanent discontinuation of Abatacept.

• Infections:

Serious infections, including sepsis and pneumonia, have been reported in patients using Abatacept, with some leading to fatality. Many of these severe infections occurred in patients on immunosuppressive therapy, which, combined with their underlying condition, could increase infection susceptibility. Caution is advised when considering Abatacept use in patients with histories of recurrent infections, predisposing conditions, or chronic/latent/localized infections. Patients developing new infections during Abatacept treatment should be closely monitored. Abatacept administration should be ceased in cases of serious infections. In adult RA patients, concurrent TNF antagonists and Abatacept use has been associated with a higher rate of serious infections.

• Tuberculosis Screening and Hepatitis B:

Before initiating immunomodulatory therapies, including Abatacept, tuberculosis screening and hepatitis B testing in accordance with guidelines are recommended. Patients with positive tuberculosis screens should receive appropriate treatment before Abatacept therapy, as the safety of Abatacept in individuals with latent tuberculosis is unknown. Those testing positive for hepatitis are typically excluded from Abatacept studies.

• Immunizations:

Concurrent administration of live vaccines with Abatacept or within three months of discontinuation is not advised. The secondary transmission of infection from those receiving live vaccines to Abatacept patients has no available data. Abatacept's impact on vaccine efficacy is unknown, and its mechanism may diminish the effectiveness of certain immunizations. Juvenile idiopathic arthritis patients should be up-to-date with immunizations as per guidelines before starting Abatacept therapy.

• Use in Patients with COPD:

Adult COPD patients treated with Abatacept exhibited adverse events more frequently than those on placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. The use of Abatacept in patients with both RA and COPD should be approached cautiously, with monitoring of respiratory status for potential deterioration.

• Immunosuppression:

Drugs inhibiting T cell activation, including Abatacept, have the potential to affect host defenses against infections and malignancies, given that T cells mediate cellular immune responses. The impact of Abatacept treatment on malignancy development and course is not fully understood. Clinical trials in adult RA patients demonstrated a higher infection rate in those treated with Abatacept compared to placebo.

There are no specific alcohol-related warnings associated with the use of abatacept mentioned in the provided information. However, it's important to note that combining alcohol with medications, including abatacept, can sometimes have unpredictable effects.

The presence of Abatacept in human milk and its systemic absorption by nursing infants after ingestion are currently unknown. Nevertheless, abatacept has been found in rat milk. Given that numerous medications are eliminated through human milk and considering the potential for significant adverse effects on nursing infants from Abatacept, a choice should be carefully deliberated between discontinuing breastfeeding or discontinuing the medication. This decision should factor in the significance of the drug for the mother's well-being.

Pregnancy category C:Abatacept is generally not known to have significant interactions with food.

Adequate and well-controlled investigations regarding the utilization of Abatacept in pregnant women are lacking. In animals, abatacept has demonstrated the ability to cross the placenta, and studies on animal reproduction have disclosed immune function modifications. The administration of Abatacept during pregnancy should be contemplated solely if the potential benefits for the mother outweigh the potential risks for the developing fetus.

Administration of abatacept to pregnant mice at doses up to 300 mg/kg, and to pregnant rats and rabbits at doses up to 200 mg/kg daily, has not displayed teratogenic effects. These doses represent around 29 times the exposure associated with the highest recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve).

When administered to female rats every three days during early gestation and throughout the lactation phase, abatacept caused no negative outcomes in offspring at doses up to 45 mg/kg, equivalent to 3 times the exposure linked to the MRHD of 10 mg/kg based on AUC. Nevertheless, at 200 mg/kg, representing exposure 11 times greater than the MRHD, alterations in immune function emerged. These included a 9-fold increase in T-cell dependent antibody response in female pups and thyroid inflammation in one female pup. While the implications of these findings for the development of autoimmune diseases in humans exposed to abatacept in utero remain uncertain, exposure to abatacept in juvenile rats, which may more closely resemble the fetal immune system state in humans, yielded immune system irregularities such as thyroid and pancreas inflammation.

Common:

● Headache

● Nasopharyngitis

● Nausea

● Infection

Less Common:

● Dizziness

● Cough

● Back pain

● Hypertension

● Dyspepsia

● Urinary Tract Infection

● Rash

● Pain in extremity

Rare:

● Acute lymphocytic leukemia

● Anaphylaxis

● Cellulitis

● COPD exacerbation

● Disease flare

● Diverticulitis

● Dyspnea

● Flushing

● Hypersensitivity

● Hypotension

● Joint wear

● Lung cancer

● Lymphoma

● Malignancies

● Ovarian cyst

● Pruritus

● Pyelonephritis

● Rhonchi

● Urticaria

● Varicella infection

● Wheezing

Interaction with TNF Antagonists:

Concurrently administering a TNF antagonist with Abatacept has been linked to an elevated risk of severe infections and negligible added effectiveness compared to using TNF antagonists independently. It is not recommended to combine therapy with Abatacept and TNF antagonists.

Interaction with Other Biologic RA Therapy:

There is an insufficient amount of experience to evaluate the safety and efficacy of concurrently administering Abatacept with other biologic RA therapies, like anakinra. Consequently, such concurrent use is not advisable.

Blood Glucose Testing:

Parenteral drug products containing maltose can potentially interfere with the readings of blood glucose monitors that employ test strips using glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). Systems based on GDH-PQQ for glucose monitoring may react with the maltose found in intravenously administered Abatacept, leading to falsely elevated blood glucose readings on the day of infusion. Individuals undergoing intravenous administration of Abatacept and needing blood glucose monitoring should explore methods that do not interact with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods. Notably, Abatacept for subcutaneous administration does not contain maltose; hence, patients need not modify their glucose monitoring practices.

● Headache

● Nasopharyngitis (inflammation of the nose and throat)

● Nausea

● Infection

Pregnancy category C:

Adequate and well-controlled investigations regarding the utilization of Abatacept in pregnant women are lacking. In animals, abatacept has demonstrated the ability to cross the placenta, and studies on animal reproduction have disclosed immune function modifications. The administration of Abatacept during pregnancy should be contemplated solely if the potential benefits for the mother outweigh the potential risks for the developing fetus.

Administration of abatacept to pregnant mice at doses up to 300 mg/kg, and to pregnant rats and rabbits at doses up to 200 mg/kg daily, has not displayed teratogenic effects. These doses represent around 29 times the exposure associated with the highest recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve).

When administered to female rats every three days during early gestation and throughout the lactation phase, abatacept caused no negative outcomes in offspring at doses up to 45 mg/kg, equivalent to 3 times the exposure linked to the MRHD of 10 mg/kg based on AUC. Nevertheless, at 200 mg/kg, representing exposure 11 times greater than the MRHD, alterations in immune function emerged. These included a 9-fold increase in T-cell dependent antibody response in female pups and thyroid inflammation in one female pup. While the implications of these findings for the development of autoimmune diseases in humans exposed to abatacept in utero remain uncertain, exposure to abatacept in juvenile rats, which may more closely resemble the fetal immune system state in humans, yielded immune system irregularities such as thyroid and pancreas inflammation.

Lactation:

The presence of Abatacept in human milk and its systemic absorption by nursing infants after ingestion are currently unknown. Nevertheless, abatacept has been found in rat milk. Given that numerous medications are eliminated through human milk and considering the potential for significant adverse effects on nursing infants from Abatacept, a choice should be carefully deliberated between discontinuing breastfeeding or discontinuing the medication. This decision should factor in the significance of the drug for the mother's well-being.

Intravenous Abatacept is prescribed for alleviating signs and symptoms in pediatric patients aged 6 years and older with moderately to severely active polyarticular juvenile idiopathic arthritis. Abatacept can be administered as monotherapy or in conjunction with methotrexate.

Research conducted on juvenile rats exposed to Abatacept prior to the maturation of their immune systems revealed immune system irregularities, including a heightened occurrence of fatal infections, along with inflammation of the thyroid and pancreas. Similar findings were not demonstrated in studies involving adult mice and monkeys. However, since the rat's immune system is still developing during the initial weeks after birth, the applicability of these outcomes to humans older than 6 years, where the immune system is considerably developed, remains uncertain.

Using Abatacept is not recommended for patients below 6 years of age. The safety and effectiveness of Abatacept in pediatric patients below 6 years of age have not been verified. Furthermore, the safety and efficacy of Abatacept for indications other than juvenile idiopathic arthritis have not been established.

The safety and effectiveness of subcutaneous Abatacept have not been assessed in patients under the age of 18.

A collective of 323 patients aged 65 and above, with 53 of them aged 75 and beyond, participated in clinical trials involving Abatacept. While no broad disparities in safety or efficacy emerged between these older patients and their younger counterparts, the limited sample size does not entirely dismiss the potential for discrepancies. Among individuals above 65 who received Abatacept, there was a heightened occurrence of severe infections and malignancies compared to those under 65. Given the naturally elevated prevalence of infections and malignancies in the elderly demographic, prudence is advised when administering treatment to this age group.

Abatacept stands as a trailblazer in a fresh category of pharmaceuticals termed Selective Co-stimulation Modulators. Functioning as a recombinant fusion protein, this medication is crafted from the human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) extracellular domain linked to a modified Fc component of human immunoglobulin G1 (IgG1). Within this Fc component, the hinge region, CH2 domain, and CH3 domain of IgG1 are encompassed. The intricate landscape of pathways and cellular entities at play in the development of rheumatoid arthritis is widely acknowledged. Existing evidence points towards the pivotal role of T-cell activation in the immunopathology of this ailment. Ordinarily, complete T-cell activation necessitates the engagement of the T-cell receptor with an antigen-MHC complex on the surface of an antigen-presenting cell, alongside a co-stimulatory signal facilitated by the binding of the CD28 protein on the T-cell surface with the CD80/86 proteins present on the antigen-presenting cell. CTLA4 emerges as a naturally occurring protein, surfacing on T-cells after a certain span following full T-cell activation. It possesses an enhanced capacity to bind to CD80/86 on antigen-presenting cells in comparison to CD28. The interaction of CTLA4-Ig with CD80/86 induces a negative feedback mechanism, leading to the deactivation of T-cells. The origins of Abatacept trace back to the efforts of Bristol-Myers-Squibb, and it is granted a license in the United States for addressing Rheumatoid Arthritis in instances where the response to anti-TNF-alpha therapy is insufficient.

Absorption:

● Intravenous Administration in Healthy Subjects: A single 10 mg/kg intravenous infusion of abatacept in healthy subjects resulted in a peak plasma concentration (Cmax) of 292 mcg/mL.

● Multiple Doses in Rheumatoid Arthritis (RA) Patients: Multiple doses of 10 mg/kg administered to RA patients led to a Cmax of 295 mcg/mL.

● Subcutaneous Administration: The bioavailability of abatacept following subcutaneous administration, compared to intravenous administration, is 78.6%.

Volume of Distribution:

● RA Patients, IV Administration: The volume of distribution for RA patients receiving intravenous administration is 0.07 L/kg.

● Healthy Subjects, IV Administration: In healthy subjects receiving intravenous administration, the volume of distribution is 0.09 L/kg.

● RA Patients, Subcutaneous Administration: For RA patients undergoing subcutaneous administration, the volume of distribution is 0.11 L/kg.

Protein Binding:

● Binding Not Available: The extent of protein binding for abatacept is not available.

Metabolism:

● Metabolism Not Available: Detailed information about the metabolism of abatacept is not provided.

Route of Elimination:

● Kidney and Liver: Abatacept is eliminated from the body through both kidney and liver processes.