Antithymocyte Globulin (Rabbit)
Medically reviewed on March 25, 2018.
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- Antithymocyte Immunoglobulin
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Thymoglobulin: 25 mg (1 ea) [contains glycine, mannitol, sodium chloride]
Brand Names: U.S.
- Immune Globulin
- Immunosuppressant Agent
- Polyclonal Antibody
Antithymocyte globulin (rabbit) is a polyclonal antibody which appears to cause immunosuppression by acting on T-cell surface antigens and depleting CD4 lymphocytes
Onset of Action
T-cell depletion: Within 24 hours (Hardinger 2006)
Duration of Action
Lymphopenia may persist for up to 1 year (Hardinger 2006)
2 to 3 days
Use: Labeled Indications
Renal transplant rejection: Prophylaxis and treatment of acute rejection in renal transplantation (in conjunction with concomitant immunosuppression)
Note: In a multicenter, double-blind, randomized trial, antithymocyte globulin (rabbit) was shown to be superior to antithymocyte globulin (equine) in reversing acute rejection and preventing subsequent episodes (Gaber 1998). Based on data from studies (including 10 years follow up) comparing ATG (rabbit) to ATG (equine) for induction, ATG (rabbit) has emerged as the T-cell lymphocyte depleting induction therapy of choice over ATG (equine) in adult kidney transplantation due to its improved efficacy and lower incidence of acute rejection (Brennan 1999; Hardinger 2008).
Off Label Uses
Chronic graft-versus-host disease (prevention)
Data from a randomized, controlled, multicenter phase III study supports the use of antithymocyte globulin (rabbit; thymoglobulin) for the prevention of chronic graft-versus-host disease (as part of the myeloablative or nonmyeloablative conditioning regimen) in patients receiving a stem cell transplant from unrelated donors [Walker 2016]. Data from another randomized, controlled, multicenter phase III study supports the use of antithymocyte globulin (rabbit; ATG-Fresenius [ATG-F]) for the prevention of chronic graft-versus-host disease (as part of the myeloablative conditioning regimen) in patients receiving an allogeneic peripheral stem cell transplant from an HLA-identical sibling [Kröger 2016].
Based on the Prophylaxis and Treatment of GVHD: EBMT-ELN Working Group Recommendations for a Standardized Practice, antithymocyte globulin (rabbit) may be used to prevent chronic graft-versus-host disease (GVHD) in patients who have received both myeloablative and reduced intensity conditioning regimens [Ruutu 2013].
Heart transplant (induction therapy)
Based on recommendations from a working group of international experts, antithymocyte globulin (rabbit) is recommended as an induction agent in heart transplantation to prevent rejection in certain groups of high risk patients [Zuckermann 2015].
Heart transplant (acute cellular rejection) (treatment)
Based on the International Society of Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients, antithymocyte globulin (rabbit), in combination with intravenous corticosteroids, is effective and recommended in symptomatic acute cellular rejection (ACR) of the cardiac allograft if hemodynamic compromise is present and/or if no clinical improvement has occurred within 12 to 24 hours of intravenous corticosteroid administration. There are currently no large randomized trials evaluating treatments for ACR in cardiac transplantation; recommendations are based on consensus.
Intestinal and multivisceral transplantation (induction therapy)
Data from a retrospective study and clinical experience suggests that antithymocyte globulin (rabbit) (in combination with rituximab, followed by maintenance tacrolimus) may have utility as induction immunosuppression in intestinal and multivisceral transplantation [Trevizol 2012], [Vianna 2008]. Additional data may be necessary to further define the role of antithymocyte globulin (rabbit) in this condition.
Lung transplant (induction therapy)
Data from two single center, randomized, prospective studies in adult lung transplant recipients support the use of antithymocyte globulin (rabbit) for prevention of acute rejection after lung transplant. The incidence of acute rejection was decreased in patients receiving antithymocyte globulin (rabbit), however there was no difference in overall survival [Hartwig 2008], [Palmer 1999]. Additional trails may be necessary to further define the role of antithymocyte globulin (rabbit) for prevention of rejection after lung transplant.
Lung transplant (persistent acute cellular rejection) (treatment)
Clinical experience suggests that antithymocyte globulin (rabbit) is an option for treatment of persistent acute rejection after lung transplantation [Martinu 2000]. Additional data may be necessary to further define the role of antithymocyte globulin (rabbit) in treatment of acute cellular rejection after lung transplantation.
Hypersensitivity (allergy or anaphylaxis) to rabbit proteins or any component of the formulation; active acute or chronic infection which contraindicate additional immunosuppression
Documentation of allergenic cross-reactivity for drugs in this class is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Note: Premedicate with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to infusion to reduce the incidence and severity of infusion-related reactions. Administer antifungal and antibacterial prophylaxis therapy if clinically indicated. Antiviral prophylaxis is recommended in patients who are CMV-seropositive at the time of transplant and for CMV-seronegative patients scheduled to receive a kidney from a CMV-seropositive donor.
Renal transplant (acute rejection treatment): IV: 1.5 mg/kg/day for 7 to 14 days
Renal transplant (induction therapy): IV: 1.5 mg/kg/day for 4 to 7 days; the first dose should be administered prior to reperfusion of the donor kidney
Off-label induction dosing: IV: 1.5 mg/kg once daily for 5 to 7 days (Brennan 1999; Brennan 2006; Hardinger 2008) or 1 mg/kg once daily for 3 to 6 days (Goggins 2003); alternative dosing strategies with higher doses for shorter durations such as 2 mg/kg once daily for 3 days have also been recommended (Hardinger 2010); dosing based on peripheral blood CD3+ lymphocyte counts has also been described with an initial dose of 1.5 mg/kg followed by repeat doses when CD3+ count is >20 cells/mm3 (Peddi 2002)
Chronic graft-versus-host disease (prevention) (off-label use): IV: 0.5 mg/kg administered 2 days prior to transplant and 2 mg/kg administered 1 day before and 1 day after transplant (Walker 2016) or 2.5 mg/kg once daily for 3 days beginning 3 days prior to transplant (Ruutu 2013).
Heart transplant (induction therapy in high risk patients) (off-label use): IV: 1 to 1.5 mg/kg once daily for up to 7 days (Zuckermann 2015)
Heart transplant (acute cellular rejection, treatment) (off-label use): IV: 0.75 to 1.5 mg/kg/day for 5 to 14 days (ISHLT [Costanzo 2010])
Intestinal and multivisceral transplantation (induction therapy) (off-label use): IV: 2 mg/kg/day on postoperative days 0, 2, 4, 6, and 8 (in combination with rituximab) (Vianna 2008). Additional trials data may be necessary to further define the role of antithymocyte globulin (rabbit) in this condition.
Lung transplant (induction therapy) (off-label use): IV: 1.5 mg/kg/day for 3 days; the first dose was administered within 24 hours of transplantation (Palmer 1999; Hartwig 2008). Additional trails may be necessary to further define the role of antithymocyte globulin (rabbit) for prevention of rejection after lung transplant.
Lung transplant (persistent acute cellular rejection, treatment) (off-label use): IV: Pulse treatments have been used to manage persistent acute cellular rejection (Martinu 2000). Additional data may be necessary to further define the role of antithymocyte globulin (rabbit) in treatment of acute cellular rejection after lung transplantation.
Refer to adult dosing.
Renal transplant (induction therapy and acute rejection treatment): Refer to adult dosing.
Dosing: Renal Impairment
There are no dosage adjustments provided in the manufacturer's labeling.
Dosing: Hepatic Impairment
There are no dosage adjustments provided in the manufacturer's labeling.
Dosing: Adjustment for Toxicity
WBC count 2,000 to 3,000 cells/mm3 or platelet count 50,000 to 75,000 cells/mm3: Reduce dose by 50%.
WBC count <2,000 cells/mm3 or platelet count <50,000 cells/mm3: Consider discontinuing treatment.
American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) to calculate mg/kg dosing for hematopoietic stem cell transplant conditioning regimens (Bubalo 2014).
Allow vials to reach room temperature, then reconstitute each vial with SWFI 5 mL to a concentration of 5 mg/mL. Rotate vial gently until completely dissolved. Prior to administration, further dilute for infusion, each 25 mg vial should be diluted in 50 mL NS or D5W (total volume is usually 50 to 500 mL depending on total number of vials needed per dose). Mix by gently inverting infusion bag only once or twice. For peripheral administration, dilution in 500 mL NS (only) with the addition of 1,000 units heparin and 20 mg hydrocortisone has been reported (Trofe-Clark 2012).
IV: Infuse the first dose over at least 6 hours; subsequent doses may be infused over at least 4 hours. Infuse through a high-flow vein (central line). Administer through an in-line 0.22 micron filter. Premedication with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to infusion may reduce the incidence and severity of infusion-related reactions. Reducing the infusion rate may minimize infusion reactions. Infusion rate may vary for off-label uses; refer to specific protocol.
In renal transplantation, administration through a peripheral vein has been reported with the addition of 1,000 units heparin and 20 mg hydrocortisone (in 500 mL NS only) to decrease the risk of thrombosis and phlebitis (Marvin 2003; Trofe-Clark 2012). The first 2 doses were infused over 6 hours and subsequent doses were infused over 4 hours (Trofe-Clark 2012).
Store intact vial at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Reconstituted product is stable for up to 24 hours at room temperature; however, the product contains no preservative and room temperature storage is not recommended; the manufacturer recommends use immediately after reconstitution and preparation for infusion in D5W or NS.
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Belatacept: Antithymocyte Globulin (Rabbit) may enhance the adverse/toxic effect of Belatacept. Specifically, the risk for venous thrombosis of the renal allograft may be increased. Management: A 12-hour interval between administration of these 2 agents is suggested if these agents are to be used concomitantly. Consider therapy modification
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy
Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination
Potential interference with rabbit antibody-based immunoassays and with cross-match or panel-reactive antibody cytotoxicity assays. Has not been shown to interfere with routine clinical laboratory tests which do not use immunoglobulins.
Cardiovascular: Hypertension (27% to 37%), tachycardia (23%), peripheral edema (20%), hypotension (10% to 16%)
Central nervous system: Chills (55% to 57%), headache (27% to 40%), pain (26%), insomnia (12% to 20%), malaise (9% to 13%)
Dermatologic: Skin rash (7% to 13%), diaphoresis (6% to 13%), acne vulgaris (12%)
Endocrine & metabolic: Hyperkalemia (17% to 27%), hypokalemia (12%)
Gastrointestinal: Abdominal pain (17% to 38%), nausea (29% to 37%), diarrhea (20%), vomiting (20%), constipation (15%)
Hematologic & oncologic: Leukopenia (49% to 57%), thrombocytopenia (29% to 37%), leukocytosis (13%), anemia (12%)
Infection: Infection (17%), cytomegalovirus disease (13%), sepsis (12%)
Neuromuscular & skeletal: Myalgia (11% to 20%), arthralgia (15%), weakness (13%), back pain (12%)
Respiratory: Dyspnea (15% to 28%), pulmonary disease (12%)
Miscellaneous: Fever (46%)
1% to 10%:
Cardiovascular: Chest pain (9%), edema (6%)
Central nervous system: Anxiety (7%)
Dermatologic: Pruritus (6%)
Endocrine & metabolic: Acidosis (9%), hypophosphatemia (6%)
Gastrointestinal: Dyspepsia (10%), anorexia (6%), intestinal candidiasis (5%), gastritis (1%)
Hematologic & oncologic: Malignant neoplasm (4%)
Hypersensitivity: Serum sickness (2%)
Infection: Herpes simplex infection (5%)
Respiratory: Increased cough (7%)
Miscellaneous: Drug overdose (6%)
<1%, postmarketing, and/or case reports: Anaphylaxis, blood coagulation disorder, cytokine release syndrome, decreased oxygen saturation, increased liver enzymes, infusion-related reaction, lymphadenopathy, lymphoproliferative disorder (posttransplant), malignant lymphoma, proteinuria, solid tumor
Concerns related to adverse effects:
• Hematologic effects: Reversible leukopenia, neutropenia, thrombocytopenia, and lymphopenia may occur. Monitor blood counts. Leukopenia and/or thrombocytopenia may require dosage adjustment.
• Hypersensitivity: Hypersensitivity and fatal anaphylactic reactions have been reported. Stop infusion immediately if anaphylactic reaction occurs. Immediate treatment (including subcutaneous epinephrine and corticosteroids) should be available during infusion for management of hypersensitivity.
• Infection: Severe infections (bacterial, fungal, viral and/or protozoal) may develop following concomitant use of immunosuppressants with antithymocyte globulin. Reactivation of infections (particularly CMV) and sepsis have been reported. Appropriate antiviral, antibacterial, antiprotozoal, and/or antifungal prophylaxis is recommended. Monitor closely for infection.
• Infusion reactions: Release of cytokines by activated monocytes and lymphocytes may lead to cytokine release syndrome (CRS) during infusion; may cause serious cardiopulmonary events (sometimes fatal). Rapid infusion rates have been associated with CRS (case reports). Other infusion reaction symptoms, including flu-like symptoms (fever, chills, nausea, muscle/joint pain) may also occur. Local infusion site reactions (pain, swelling, skin redness) have been reported.
• Malignancy: Immunosuppressants, including antithymocyte globulins may increase the incidence of malignancies, including lymphoma, post-transplant lymphoproliferative disease (PTLD) or other malignancies; may be fatal.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Immunizations: Patients should not be immunized with attenuated live viral vaccines during or shortly after treatment; safety of immunization following therapy has not been studied.
• Liver transplantation induction: Antithymocyte globulin (rabbit) has been associated with increased adverse effects when used for induction in liver transplantation and should be used cautiously in this population (Boillot 2009)
• Administration: Initial dose must be administered over at least 6 hours into a high flow vein. Reducing the infusion rate (and prolonging the administration time) may minimize infusion reactions. May pretreat with an antipyretic, antihistamine, and/or corticosteroid.
• Experienced physician: [US Boxed Warning]: Should only be used by physicians experienced in immunosuppressive therapy in transplantation. Maintenance immunosuppression may require dosage reduction. Medical surveillance is required during the infusion. Should be administered in combination with other immunosuppressants.
• Product selection: Antithymocyte globulin (ATG) (rabbit) is available (based on region) in different product formulations, ATG-Thymoglobulin and ATG-Fresenius; the dosing differs among the formulations. Dosing of antithymocyte globulin (rabbit) also differs from dosing of other antithymocyte globulin products (eg, ATG [equine]); protein compositions and concentrations are different. Use caution to ensure dose prescribed is intended for product being administered.
Lymphocyte count (total lymphocyte and/or T-cell subset), CBC with differential and platelet count; vital signs during administration; signs and symptoms of infection
Solid organ transplant: Absolute CD3 count (cells/µL) monitoring and CD3 based dosing has been considered in renal and heart transplant recipients. It may be beneficial in certain patient populations but is not routinely recommended or utilized. Dose adjustments have been recommended based on the CD3 count (Krasinska 2002).
Animal reproduction studies have not been conducted. Females of reproductive potential should use effective contraception during and for at least 3 months following treatment.
The Transplant Pregnancy Registry International (TPR) is a registry that follows pregnancies that occur in maternal transplant recipients or those fathered by male transplant recipients. The TPR encourages reporting of pregnancies following solid organ transplant by contacting them at 1-877-955-6877 or https://www.transplantpregnancyregistry.org.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea, vomiting, acne, muscle pain, joint pain, insomnia, sweating a lot, constipation, back pain, lack of appetite, or injection site pain or irritation. Have patient report immediately to prescriber signs of infection, signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of acidosis (confusion, fast breathing, tachycardia, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy), angina, tachycardia, bruising, bleeding, severe headache, severe dizziness, passing out, vision changes, confusion, anxiety, agitation, severe loss of strength and energy, swelling of arm or leg, shortness of breath, severe abdominal pain, severe diarrhea, or signs of cytokine release syndrome (chills, dizziness, loss of strength and energy, fever, headache, passing out, rash, angioedema, difficulty breathing, nausea, vomiting, or wheezing) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
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