Antithymocyte globulin (rabbit) (ATG [rabbit]), a polyclonal antibody preparation, is an immunosuppressive agent.1, 8
Antithymocyte globulin (rabbit) (ATG [rabbit]) is used in conjunction with other immunosuppressive agents for the treatment of acute rejection of renal allografts.1, 8 In a randomized, multicenter, double-blind, prospective study, ATG (rabbit) was more effective than antithymoglobulin (equine) (ATG [equine]) in reversing acute rejection episodes in renal transplant patients 15-73 years of age.1, 2 Patients had biopsy-proven acute rejection and were randomized to receive 7-14 days of therapy with ATG (rabbit) (1.5 mg/kg once daily) or ATG (equine) (15 mg/kg once daily); other immunosuppressive agents (e.g., azathioprine, prednisone, cyclosporine) were continued in all patients according to usual protocols, although dosages in some patients were temporarily reduced during ATG therapy.2 Reversal of graft rejection, the primary end point of the study, was defined as a decrease in serum creatinine concentrations to baseline or lower after completion of ATG therapy or 14 days after initiation of ATG therapy.2 There was reversal of graft rejection in 88% of those who received ATG (rabbit) and 76% of those who received ATG (equine) (intent-to-treat analysis).2 In addition, the rate of recurrent rejection at 90 days was lower in those who received ATG (rabbit) (17%) than in those who received ATG (equine) (36%).2
ATG (rabbit) has been used in conjunction with other immunosuppressive agents to prevent or delay the onset of renal allograft rejection†.4, 5 In a double-blind study in adult renal transplant recipients, patients were randomized to receive induction immunosuppression with ATG (rabbit) (1.5 mg/kg daily for at least 7 days) or ATG (equine) (15 mg/kg daily for at least 7 days) initiated at the time of transplant in conjunction with a maintenance immunosuppressive regimen (azathioprine or mycophenolate mofetil; corticosteroids; and cyclosporine or tacrolimus).5 The primary end points of the study were the rates of rejection at 6 and 12 months, patient survival, and graft survival.5 At 6 and 12 months, the rates of rejection were lower in patients receiving ATG (rabbit) than in those receiving ATG (equine) and there was some evidence that acute rejection episodes were less severe in those who received ATG (rabbit).5 The rate of rejection was 4% at both 6 or 12 months in those who received ATG (rabbit) compared with 17% at 6 months and 25% at 12 months in those who received ATG (equine).5 Patient survival at 6 and 12 months was 98 or 94% in those who received ATG (rabbit) or ATG (equine), respectively.5 When graft failure from all causes was considered, graft survival was 98 or 83% in those who received ATG (rabbit) or ATG (equine), respectively.5
Myelodysplastic Syndrome and Aplastic Anemia
ATG (rabbit) has been designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome†;3 safety and efficacy of ATG (rabbit) (3.75 mg/kg daily for 4 days) in patients with myelodysplastic syndrome are being evaluated in an ongoing open-label, randomized study.9
Although safety and efficacy have not been established, ATG (rabbit) has been used for the treatment of aplastic anemia† in a limited number of patients.7, 9 In 1 uncontrolled, multicenter study, ATG (rabbit) (3.5 mg/kg daily for 5 days) given in conjunction with cyclosporine and granulocyte colony-stimulating factor (G-CSF) was used in patients who failed to respond to a regimen that included ATG (equine) in conjunction with cyclosporine and G-CSF; 77% of these patients achieved transfusion independence after a median of 95 days and overall survival was 93% after 914 days of follow-up.7
Reconstitution and Administration
Antithymocyte globulin (rabbit) (ATG [rabbit]) is administered by IV infusion.1 Initial IV infusions of ATG (rabbit) should be given over at least 6 hours and subsequent infusions given over at least 4 hours.1 In addition, to prevent or ameliorate acute infusion reactions to ATG (rabbit), the manufacturer recommends that patients receive a pretreatment regimen consisting of a corticosteroid (e.g., IV methylprednisolone 2-5 mg/kg), oral acetaminophen (500-650 mg) and/or an antihistamine (e.g., oral or IV diphenhydramine 25 mg), 1 hour prior to each dose of the drug.1, 9 If manifestations of infusion reactions (e.g., chills, fever) occur or if the patient is receiving ATG (rabbit) dosages greater than 1.5 mg/kg daily, additional doses of corticosteroid can be given or the infusion time prolonged to greater than 12 hours.9
Commercially available ATG (rabbit) lyophilized powder must be reconstituted and diluted prior to administration using proper aseptic technique.1 ATG (rabbit) solutions should be prepared immediately before use.1 The manufacturer states that reconstituted solutions of ATG (rabbit) are stable for up to 24 hours at room temperature;9 however, the drug does not contain any preservatives or bacteriostatic agents and generally should be used within 4 hours after reconstitution if stored at room temperature.1 Reconstituted vials of ATG (rabbit) should be entered only once.9
Based on the indicated dosage of ATG (rabbit), the appropriate number of vials of the drug should be reconstituted using the sterile water for injection diluent supplied by the manufacturer; vials of the drug and diluent should be allowed to reach room temperature before reconstitution.1 Each vial of lyophilized ATG (rabbit) labeled as containing 25 mg of ATG (rabbit) should be reconstituted by adding 5 mL of the diluent supplied by the manufacturer to provide a solution containing 5 mg/mL.1 During reconstitution, the sterile water diluent should be directed toward the side of the vial using a sterile syringe and needle and the contents gently swirled until the lyophilized powder is completely dissolved.1 The reconstituted solution should be inspected visually for particulate matter while in the vial and, if such matter is present, the vial should be gently rotated until the particulates are not present; solutions should be discarded if particulate matter remains.1 The reconstituted solution should be clear and should not be used if discolored or opaque or if particles are present.1, 9 (1,9) The appropriate dosage of reconstituted ATG (rabbit) should then be diluted in 0.9% sodium chloride or 5% dextrose injection; each reconstituted vial of ATG (rabbit) should be diluted in 50 mL of infusion solution and the total volume of infusion solution required generally is 50-500 mL.1 The final concentration of the reconstituted and diluted ATG (rabbit) solution should be approximately 0.5 mg/mL.9 The diluted ATG (rabbit) solution should be gently mixed by inverting the infusion bag only once or twice.1
ATG (rabbit) should be infused through a 0.22-µm inline membrane filter into a high-flow vein.1 The initial dose of ATG (rabbit) should be infused IV over a period of at least 6 hours and subsequent doses infused over a period of at least 4 hours.1
The manufacturer states that no incompatibilities have been observed between ATG (rabbit) solutions and glass bottles or polyvinyl chloride bags and administration sets.9 Information on the physical and/or chemical compatibility of ATG (rabbit) with other IV infusion fluids or other drugs is not available, and the manufacturer recommends that ATG (rabbit) not be admixed with other drugs or infused in the same IV line with other agents (piggybacked).9
For the treatment of acute renal transplant rejection, the usual adult dosage of ATG (rabbit) is 1.5 mg/kg once daily for 7-14 days.1 Other immunosuppressive agents used for the treatment of acute renal transplant rejection (e.g., azathioprine, prednisone, cyclosporine) usually are continued in patients receiving ATG (rabbit).1, 2 (See Drug Interactions: Immunosuppressive Agents.)
Laboratory Monitoring and Dosage Adjustment
Lymphocyte counts (i.e., total lymphocytes and/or T-cell subsets) should be monitored to assess the level of T-cell depletion in patients receiving ATG (rabbit).1 Total leukocyte cell counts (WBCs) and platelet counts also should be monitored and dosage of ATG (rabbit) reduced in patients who develop leukopenia and/or thrombocytopenia.1 If WBCs are 2000-3000/ mm3 or platelet counts are 50,000-75,000/ mm3, dosage of ATG (rabbit) should be reduced by 50%; discontinuance of the drug should be considered in those with WBCs less than 2000/ mm3 or platelet counts less than 50,000/ mm3.1
No special population dosage recommendations at this time.
Known hypersensitivity to rabbit proteins1 or any ingredient in the formulation;(9) history of anaphylaxis following receipt of ATG (rabbit).1 Acute viral illness.1
ATG (rabbit) should be used only by clinicians experienced in use of immunosuppressive therapy for the management of renal transplant patients.1
Close medical supervision is required during and after IV infusion of ATG (rabbit).1
Anaphylaxis has been reported rarely with ATG (rabbit).1 If anaphylaxis or other severe hypersensitivity reaction occurs, the ATG (rabbit) infusion should be discontinued immediately and appropriate therapy initiated (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen, IV fluids, antihistamines, maintenance of blood pressure) as indicated.1
Chills and fever may occur.1 These acute infusion reactions may be minimized by giving initial IV infusions of ATG (rabbit) over at least 6 hours.1 Use of a pretreatment regimen (corticosteroids, acetaminophen, and/or an antihistamine) 1 hour prior to each ATG (rabbit) infusion and/or slowing the infusion rate also may prevent or ameliorate these acute infusion reactions and is recommended by the manufacturer.1, 9 (See Dosage and Administration: Reconstitution and Administration.)
Infectious Complications and Malignancy
Patients receiving ATG (rabbit) as part of an immunosuppressive regimen may be at increased risk of infectious complications and malignancies.1 To decrease the risk of serious infections, the manufacturer recommends that patients receive appropriate anti-infective prophylaxis, including antiviral, antiprotozoal, and/or antifungal agents.1 Prolonged use or overdosage of ATG (rabbit) in conjunction with other immunosuppressive agents may increase the risk of lymphoma or posttransplant lymphoproliferative disease (PTLD); 2 patients developed lymphoma and one patient was diagnosed with leukemia during 1-year follow-up after receiving ATG (rabbit) for treatment of acute rejection of renal transplant.1, 9
T-cell Depletion, Leukopenia, and Thrombocytopenia
A decrease in T cells occurs during ATG (rabbit) therapy; lymphocyte counts (i.e., total lymphocyte and/or T-cell subsets) should be used to monitor the level of T-cell depletion.1 Reversible leukopenia or thrombocytopenia may occur; dosage adjustment or discontinuance of ATG (rabbit) may be necessary.1 (See Laboratory Monitoring and Dosage Adjustment under Dosage and Administration: General Dosage.)
Development of anti-rabbit antibodies occurred in up to 68% of patients who received ATG (rabbit) for 7-14 days for treatment of acute rejection of renal transplant in one study; these anti-rabbit antibodies were still present in 24% of patients at 90 days.1, 6 Although presence of anti-rabbit antibodies did not correlate with treatment success or failure of ATG (rabbit) in these patients,6 the possible effect(s) of these antibodies on efficacy of the drug during subsequent use has not been evaluated.1
Potential interference with rabbit antibody-based immunoassays and with cross-match or panel-reactive antibody cytotoxicity assays.1
Category C. (See Users Guide.)
Not known whether ATG (rabbit) is distributed into milk.1 However, many drugs are distributed into human milk, including antibodies; also consider potential for adverse effects.1 Discontinue nursing or drug, taking into account the importance of the drug to the mother.1
Safety and efficacy of ATG (rabbit) not established in children younger than 18 years of age.1, 9 A limited number of pediatric patients 2.5-18 years of age have received ATG (rabbit) (1.5-2.5 mg/kg daily for 5 days) in conjunction with other immunosuppressive agents to prevent or delay the onset of renal allograft rejection;4, 9, 10 adverse effects in these patients appear to be similar to those reported in adults.1
Infectious complications, including sepsis, urinary tract infections, and cytomegalovirus (CMV) infections, have been reported in 37-50% of patients receiving ATG (rabbit) in conjunction with other immunosuppressive agents for the treatment of acute rejection of renal allografts.1, 2 In one study, 29% of patients developed bacterial infections, 21% developed viral infections, and 9% developed fungal infections.2
Fever,1 chills,1 and leukopenia1 have been reported in 57-63% of patients receiving ATG (rabbit).1 Adverse effects reported in 27-46% of patients include abdominal pain,1 nausea,1 diarrhea,1 asthenia,1 dyspnea,1 headache,1 hyperkalemia,1 hypertension,1 pain,1 peripheral edema,1 tachycardia,1 and thrombocytopenia.1 Dizziness1 and malaise1 were reported in about 8-13% of patients.1
Potential pharmacologic interaction (additive immunosuppressive effects). ATG (rabbit) usually is used in conjunction with other immunosuppressive agents; this may predispose patients to over-immunosuppression.1 Consideration should be given to decreasing maintenance immunosuppressive therapy during ATG (rabbit) therapy.1
Antithymocyte globulin (rabbit) (ATG [rabbit]), a polyclonal antibody preparation, is an immunosuppressive agent.1, 8 ATG (rabbit) contains immunoglobulin G (gamma globulin, IgG) prepared from the sera of healthy rabbits hyperimmunized against antigens expressed on human thymocytes.1 The exact mechanism(s) of immunosuppressive action of ATG (rabbit) has not been fully elucidated; however, it appears to involve clearance of peripheral antigen-reactive T lymphocytes (T cells) and modulation of T-cell activation, homing, and cytotoxicity.1, 8 ATG (rabbit) contains antibodies that bind T-cell surface receptors such as CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, HLA-DR, HLA class I heavy chains, and β2 microglobulin.1, 8 Following initiation of ATG (rabbit) therapy in transplant recipients, T-cell depletion generally occurs within a day.1 ATG (rabbit) has not been shown to be effective for treating antibody-mediated (humoral) transplant rejections.1
Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 25 mg |
1. Sangstat Medical Corporation. Thymoglobulin®; (anti-thymocyte globulin [rabbit]) prescribing information. Menlo Park, CA; 1998 Dec.
2. Gaber AO, First MR, Tesi RJ et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation . 1998; 66:29-37. [PubMed 9679818]
3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97?414). Rockville, MD; 2001 May. From FDA web site. [Web]
4. Broyer M, Gagnadoux MF, Guest G et al. Triple therapy including cyclosporine A versus conventional regimen-a randomized prospective study in pediatric kidney transplantation. Transplant Proc . 1987; 19: 3582-85. [PubMed 3313862]
5. Brennan DC, Flavin K, Lowell JA et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation . 1999; 67:1011-8. [PubMed 10221486]
6. Regan JF, Campbell K, Smith LV et al. Sensitization following Thymoglobulin and Atgam rejection therapy as determined with a rapid enzyme-linked immunosorbent assay. Transpl Immunol . 1999; 7:115-21. [PubMed 10544442]
7. Di Bona E, Rodeghiero F, Bruno B et al for the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Rabbit Antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Br J Haematol . 1999; 107:330-4. [PubMed 10583220]
8. Ormrod D, Jarvis B. Antithymocyte globulin (rabbit): a review of the use of Thymoglobulin in the prevention and treatment of acute renal allograft rejection. Biodrugs . 2000; 14:255-73.
9. Sangstat. Fremont, CA: Personal communication.
10. Brophy PD, Thomas SE, McBryde KD et al. Comparison of polyclonal induction agents in pediatric renal transplantation. Pediatr Transplant . 2001; 5:174-8. [PubMed 11422819]