Anti-Thymocyte Globulin

Approved Indications:

A. Organ Transplantation:

• Renal Transplantation – Induction Therapy:
  For prevention of acute rejection in renal allograft recipients, especially those at high immunologic risk (e.g., repeat transplantation, sensitized recipients).
• Renal Transplantation – Treatment of Acute Rejection:
  Used to manage moderate to severe corticosteroid-resistant acute cellular rejection episodes.

B. Hematologic Conditions:

• Severe Aplastic Anemia (SAA):
  In combination with cyclosporine, it is approved as first-line immunosuppressive therapy in patients with acquired SAA who are not candidates for bone marrow transplantation.

Clinically Accepted Off-Label Uses:

C. Hematopoietic Stem Cell Transplantation:

• Graft-versus-Host Disease (GVHD):
  Used for GVHD prophylaxis during allogeneic stem cell transplantation and in steroid-refractory GVHD.

D. Other Transplants:

• Heart and Liver Transplantation:
  Occasionally used in selected patients for induction or rejection treatment based on transplant center protocol.

E. Autoimmune Disorders (select cases):

• Refractory autoimmune diseases such as systemic lupus erythematosus, pure red cell aplasia, or hemophagocytic lymphohistiocytosis under specialized care.

Route: Intravenous (IV) infusion only
Premedication: Administer antipyretics, corticosteroids, and antihistamines 30–60 minutes prior to infusion to reduce the risk of infusion reactions.

Adults:

• Renal Transplant – Induction:
  1.5 mg/kg/day IV for 4–7 days starting intraoperatively or immediately post-transplant.
• Renal Transplant – Rejection Treatment:
  1.5 mg/kg/day IV for 7–14 days based on clinical response.
• Severe Aplastic Anemia:
  40 mg/kg/day IV for 4 consecutive days (total dose: 160 mg/kg), in combination with cyclosporine.

Pediatrics:

• Same dosing as adults based on body weight (mg/kg basis).
  Close monitoring for hematologic and infectious complications is essential.

Elderly:

• No specific dose adjustment required; however, increased monitoring for infection and organ function is recommended due to comorbidities.

Renal/Hepatic Impairment:

• No routine dose adjustment necessary, but careful monitoring is advised due to the risk of infection, hematologic toxicity, and altered clearance.

Infusion Instructions:

• Dilute in 0.9% NaCl or 5% dextrose to a final concentration of 0.5–1 mg/mL.
• Infuse over 4–12 hours via central or peripheral line under close supervision.
• Avoid rapid infusion to minimize the risk of hypotension and anaphylaxis.

Anti-Thymocyte Globulin is a polyclonal immunoglobulin preparation obtained from rabbits or horses immunized with human thymocytes. It contains antibodies that recognize multiple T-cell surface antigens, including CD2, CD3, CD4, CD8, CD25, HLA-DR, and others. These antibodies exert immunosuppressive effects by depleting circulating T-lymphocytes through complement-mediated lysis and antibody-dependent cellular cytotoxicity. The binding of these antibodies also impairs T-cell activation and proliferation. As a result, ATG inhibits both the cellular immune response (important in graft rejection and aplastic anemia) and modulates cytokine release, thereby suppressing immune-mediated tissue damage.

• Absorption: Not applicable (IV only)
• Distribution: Extensive tissue distribution, particularly within lymphoid organs and bone marrow
• Bioavailability: 100% (IV administration)
• Metabolism: Catabolized via proteolytic enzymes into peptides and amino acids
• Half-life: Approximately 2–4 days; can be prolonged with repeated dosing
• Onset of Action: T-cell depletion usually evident within 24 hours of administration
• Excretion: Eliminated primarily via the reticuloendothelial system; not renally excreted

• Pregnancy:
  Not formally classified under the FDA’s old pregnancy categories.
  Animal studies are inadequate, and human data are limited.
  Use only if clearly needed, balancing maternal benefit against potential fetal risk.
• Lactation:
  It is unknown whether ATG is excreted in human breast milk. Due to its immunosuppressive potential and protein nature, breastfeeding is not recommended during and shortly after treatment.
• Caution:
  Avoid in pregnancy and lactation unless absolutely indicated, and counsel women of reproductive potential appropriately.

• Primary Class: Immunosuppressive Agent
• Subclass: Polyclonal Anti-thymocyte Globulin
• Source: Animal-derived (rabbit or horse)

• Known hypersensitivity to ATG or any excipients
• Allergy to rabbit or horse proteins (depending on formulation)
• Severe acute systemic infection (untreated bacterial, viral, or fungal infections)
• Uncontrolled thrombocytopenia or severe leukopenia unrelated to the underlying disease

• Infusion Reactions:
  May include fever, chills, hypotension, dyspnea, rash, and anaphylaxis. Must premedicate and monitor vital signs during infusion.
• Serum Sickness:
  Delayed hypersensitivity reaction (rash, fever, arthralgia) may occur 5–15 days after initiation; corticosteroid therapy may be required.
• Infections:
  Profound immunosuppression may lead to serious opportunistic infections including CMV, EBV, fungal, or bacterial sepsis. Prophylactic antimicrobials and monitoring are strongly advised.
• Malignancy:
  Long-term use is associated with increased risk of post-transplant lymphoproliferative disorder (PTLD) and other cancers.
• Hematologic Toxicity:
  Neutropenia, thrombocytopenia, and anemia can occur; frequent CBC monitoring required.
• Monitoring:
  CBC with differential, renal/liver function tests, and infection markers should be monitored regularly.

Common Side Effects (>10%):

• General: Fever, chills, malaise, fatigue
• Cardiovascular: Hypotension, tachycardia
• Respiratory: Dyspnea, cough
• Hematologic: Leukopenia, thrombocytopenia, anemia
• GI: Nausea, vomiting, diarrhea
• Skin: Rash, pruritus

Less Common (1–10%):

• Headache, myalgia, arthralgia
• Elevated liver enzymes
• Hypertension

Rare/Serious (<1%):

• Anaphylaxis
• Serum sickness
• Sepsis or septic shock
• Acute respiratory distress syndrome (ARDS)
• PTLD or other lymphoproliferative disorders

Timing:

• Infusion-related side effects typically occur during or shortly after administration.
• Serum sickness appears 5–15 days post-treatment.

• Live Vaccines: Avoid during and for several months after ATG due to immune suppression.
• Other Immunosuppressants (e.g., Cyclosporine, Tacrolimus): Additive immunosuppressive and myelosuppressive effects increase infection risk.
• Myelosuppressive Agents (e.g., chemotherapy): Risk of enhanced bone marrow suppression.

CYP450 Interactions:

• ATG is not metabolized via CYP450 enzymes; minimal risk of enzyme-mediated drug interactions.

Drug-Food and Drug-Alcohol:

• No known significant interactions with food or alcohol, but alcohol should be avoided in immunosuppressed patients.

• FDA & EMA (2023–2024):
• Reinforced need for infection prophylaxis and monitoring during treatment.
• Emphasized black box warning for anaphylaxis and serum sickness.
• KDIGO & EBMT Guidelines:
• Recommended ATG for induction in high-risk transplant recipients.
• Endorsed as first-line for aplastic anemia when stem cell transplant is unavailable.
• Transplant Protocol Revisions:
• Many centers now include ATG in desensitization protocols for highly sensitized transplant candidates.

• Temperature: Store between 2°C to 8°C (refrigerated). Do not freeze.
• Light: Protect from direct light.
• Handling: Do not shake. Use aseptic technique during reconstitution and infusion preparation.
• After Dilution:
• Use immediately, or store diluted solution at 2°C–8°C for up to 24 hours if prepared under sterile conditions.
• Allow refrigerated solution to reach room temperature before infusion. Do not reuse or save partially used vials.