Antithymocyte Globulin (Rabbit)

Class: Immunosuppressive Agents
ATC Class: L04AA04
VA Class: IM600
Brands: Thymoglobulin

Warning(s)

  • Should be used only by clinicians experienced in immunosuppressive therapy for the management of renal transplant patients.b

Introduction

Antithymocyte globulin (rabbit) (ATG [rabbit]); rabbit-derived polyclonal antibody preparation; immunosuppressive agent.2 8 a b g

Uses for Antithymocyte Globulin (Rabbit)

Renal Allotransplantation

Treatment of acute rejection of renal allografts in conjunction with other immunosuppressive agents.2 8 a b e g

ATG (rabbit) found to be more effective than ATG (equine) in reversing acute rejection episodes (88% compared with 76%) and preventing recurrent rejection episodes in renal transplant recipients.2 b

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Has also been used successfully as induction therapy in conjunction with maintenance immunosuppressive therapy for the prevention of renal allograft rejection.4 5 a d g m n o p q r s u w x

Hepatic Allotransplantation

Induction therapy to prevent hepatic allograft rejection and minimize maintenance immunosuppression in pediatric patients (designated an orphan drug by FDA for this use)j t and in adults.v

Myelodysplastic Syndrome and Aplastic Anemia

Has been used for the treatment of myelodysplastic syndrome (designated an orphan drug by FDA for this use).j k

Has been used for the treatment of aplastic anemia, usually in conjunction with cyclosporine.7 9 a l

Antithymocyte Globulin (Rabbit) Dosage and Administration

General

  • To reduce the incidence and intensity of infusion-related adverse effects, the manufacturer and some clinicians recommend premedication with corticosteroids, acetaminophen, and/or an antihistamine (e.g., diphenhydramine) 1 hour prior to each infusion.2 9 a b q u (See Infusion-related Effects under Cautions.)

  • The manufacturer recommends prophylactic antiviral therapy (e.g., acyclovir, ganciclovir, valganciclovir) during ATG (rabbit) therapy.9 a b m (See Infectious Complications under Cautions.)

Administration

IV Administration

For drug compatibility information, see Compatibility under Stability.

ATG (rabbit) is administered by IV infusion.1 a b g The manufacturer states that ATG (rabbit) should be infused through an inline 0.22-μm filter into a high-flow vein.a b g Has also been administered via a peripheral vein in some patients, but safety not fully established and may increase risk of thrombophlebitis and DVT.g h i

Administer in conjunction with other immunosuppressive agents.b

Reconstitution

Allow vial to reach room temperature before reconstituting.a b Reconstitute vial containing 25 mg of the drug with 5 mL of sterile water for injection to provide a solution containing 5 mg/mL.a b Gently rotate vial until powder is completely dissolved.a b Use reconstituted solution immediately.b (See Storage under Stability.)

Dilution

Dilute appropriate dosage of reconstituted ATG (rabbit) in 0.9% sodium chloride or 5% dextrose injection.a b Each reconstituted vial should be diluted in 50 mL of infusion solution; total volume of infusion solution required generally is 50–500 mL.a b Recommended final concentration approximately 0.5 mg/mL.9 a Mix diluted solution by gently inverting infusion bag only once or twice.a b

Rate of Administration

Administer initial dose over ≥6 hours and subsequent doses over ≥4 hours.b g Slowing infusion rate may help prevent or ameliorate acute infusion reactions.9 a b (See Infusion-related Effects under Cautions.)

Dosage

Appropriate dosage for Thymoglobulin differs from dosages for other antithymocyte globulin (ATG) preparations since protein composition and concentrations vary depending on source of ATG used.b Exercise care to ensure prescribed dose is appropriate for the ATG preparation being administered.b

Reduce ATG (rabbit) dosage by 50% if WBC is ≥2000 but ≤3000/mm3 or platelet count is ≥50,000 but ≤75,000/m3.b Consider drug discontinuance if WBC <2000/mm3 or platelet count <50,000/mm3.b (See Hematologic Effects and Clinical/Laboratory Monitoring under Cautions.)

Pediatric Patients

Renal Allotransplantation
Prevention of Renal Allograft Rejection (Induction Therapy)
IV Infusion

Optimum dosage not established; 1.5–2.5 mg/kg once daily for 5–10 days has been given.4 9 10 m n p q

Adults

Renal Allotransplantation
Treatment of Allograft Rejection
IV Infusion

1.5 mg/kg once daily for 7–14 days.2 a b r Usually continue other immunosuppressive agents used for treatment of acute renal transplant rejection (e.g., azathioprine, corticosteroids, cyclosporine) during therapy.2 a b r (See Interactions.)

Prevention of Renal Allograft Rejection (Induction Therapy)
IV Infusion

Optimum dosage not established; 1.5 mg/kg once daily for 5–14 days or 3 mg/kg once daily on day 1 then 1.5 mg/kg once daily on days 2 and 3 has been given.5 9 g r u Intermittent dosage regimens based on CD3+ lymphocyte countsw and regimens in which the first dose is administered intraoperatively also have been given.5 r s u

Myelodysplastic Syndrome and Aplastic Anemia
Myelodysplastic Syndrome
IV Infusion

Optimum dosage not established; 3.75 mg/kg once daily for 5 days has been given.k

Aplastic Anemia
IV Infusion

Optimum dosage not established; 3.5 mg/kg once daily for 5 days has been given.7 a l

Special Populations

No special population dosage recommendations at this time.b

Cautions for Antithymocyte Globulin (Rabbit)

Contraindications

  • Known hypersensitivity to rabbit proteinsa b or any ingredient in the formulation;a 9 history of anaphylaxis following ATG (rabbit) administration.a b

  • Active or acute infections that contraindicate any additional immunosuppression.b

Warnings/Precautions

Warnings

See Boxed Warning.

Close medical supervision required during and after IV infusion of ATG (rabbit).a b

Cytokine Release Syndrome

Severe cytokine release syndrome (CRS), an immune-mediated reaction, reported.b Severe, acute CRS may cause serious cardiorespiratory effects and/or death.b

Infectious Complications

Possible increased risk of infections (bacterial, fungal, viral, and protozoal), reactivation of infections (particularly cytomegalovirus [CMV]), and sepsis when ATG (rabbit) is used in combination with multiple immunosuppressive agents.2 5 b m n r u Severe, acute infections may be fatal.b The manufacturer recommends careful patient monitoring and appropriate anti-infective prophylaxis.b

Sensitivity Reactions

Anaphylaxis

Serious and fatal anaphylactic reactions reported.a b

If anaphylaxis or other severe hypersensitivity reaction occurs, discontinue ATG (rabbit) infusion immediately and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen, IV fluids, antihistamines, maintenance of BP).a b

Patients with a history of anaphylaxis to ATG (rabbit) should not receive the drug again.b

General Precautions

Malignancies

Possible increased risk of malignancies with immunosuppressive therapy, including rabbit ATG (e.g., lymphoma, posttransplant lymphoproliferative disease [PTLD]).9 a b m n r u

Hematologic Effects and Clinical/Laboratory Monitoring

T cells decrease during ATG (rabbit) therapy.b Monitor lymphocyte counts (i.e., total lymphocytes and/or T-cell subsets) to assess level of T-cell depletion in patients receiving the drug.b

Thrombocytopenia and/or leukopenia (including lymphopenia and neutropenia) commonly reported.2 5 a b g r u Monitor WBC and platelet count; reduce dosage and/or consider drug discontinuance in patients who develop leukopenia and/or thrombocytopenia.b (See Dosage under Dosage and Administration.)

Antibody Formation

Anti-rabbit antibodies developed in 68% of renal transplant patients who received ATG (rabbit) for 7–14 days for treatment of acute rejection; these antibodies were still present in 24% of patients at 90 days.6 a b Presence of anti-rabbit antibodies not correlated with treatment success or failure in these patients;6 a possible effects of these antibodies on drug’s efficacy during subsequent use not evaluated.b

Infusion-related Effects

Risk of infusion-related effects (e.g., fever, chills and/or rigors, dyspnea, nausea and/or vomiting, diarrhea, hypotension or hypertension, malaise, rash, and/or headache); may occur as soon as first or second infusion during a single course of treatment.a b

May minimize or prevent infusion-related effects by administering initial ATG (rabbit) infusions over ≥6 hours, administering a pretreatment regimen (corticosteroid, acetaminophen, and/or an antihistamine) 1 hour prior to each ATG (rabbit) infusion, and/or slowing the infusion rate.2 9 a b q u (See General and see Administration under Dosage and Administration.)

Immunization

Safety of attenuated live vaccine administration following ATG (rabbit) therapy not established.b Manufacturer states that immunization with attenuated live vaccines not recommended in patients who recently received the drug.b

Laboratory Test Interference

Potential interference with rabbit antibody-based immunoassays and with cross-match or panel-reactive antibody cytotoxicity assays.a b

Specific Populations

Pregnancy

Category C.b

Lactation

1 Not known whether ATG (rabbit) is distributed into milk; however, other immunoglobulins are distributed into human milk.b Discontinue nursing or the drug.b

Pediatric Use

The manufacturer states that safety and efficacy not established in children <18 years of age in controlled trials.a 9 b However, ATG (rabbit) has been used as induction therapy in conjunction with maintenance immunosuppressive therapy to prevent renal or hepatic allograft rejection in pediatric patients 5 months–18 years of age.4 9 10 a m n o p q t (See Hepatic Allotransplantation under Uses.)

Dosage, efficacy, and adverse effect profile in pediatric patients generally appear to be the same as in adults.b n p q t

Common Adverse Effects

Infectious complications (including sepsis, urinary tract infections, and CMV infections),5 a b n r u fever,b chills,b leukopenia,5 b u lymphopenia,5 d g r thrombocytopenia,b g u cytokine release syndrome,g abdominal pain,b nausea,b diarrhea,b asthenia,b dyspnea,b headache,b pain,b hyperkalemia,b hypertension,b peripheral edema,b tachycardia,b dizziness,b infusion site pain/swelling/erythema.b

Interactions for Antithymocyte Globulin (Rabbit)

No formal drug interaction studies to date.b

Specific Drugs

Drug

Interaction

Comments

Basiliximab

No increase in adverse effectsf

Daclizumab

Limited experiencec

Immunosuppressive agents

Risk of oversuppression of the immune system and associated susceptibility to infection and malignancies, including lymphomaa b

Consider decreasing maintenance immunosuppressive therapy during concurrent usea b

Vaccines

Safety data not available on the effects of immunization with live vaccines during ATG (rabbit) therapyb

Avoid use of live vaccines in patients who have recently received ATG (rabbit)b

Antithymocyte Globulin (Rabbit) Pharmacokinetics

Absorption

Onset

T-cell depletion usually observed within 1 day after initiating therapy.b g

Plasma Concentrations

Average 21.5 and 87 mcg/mL 4–8 hours post-infusion after first and last IV doses, respectively, when given for 7–11 days.b

Duration

Lymphopenia may persist ≥1–2 years after ATG (rabbit) administration.5 g r

Distribution

Extent

Not known whether ATG (rabbit) distributes into human milk; however, other immunoglobulins are distributed into human milk.a b

Elimination

Half-life

2–3 days after first dose;b may increase after multiple-dose administration.2 y

Stability

Storage

Parenteral

Powder for Injection

2–8°C; do not freeze.b Protect from light.b

Although reconstituted solutions are stable at room temperature for up to 24 hours, room temperature storage is not recommended by the manufacturer since the preparation contains no preservatives; use immediately.b

Use diluted solutions immediately.b

Discard any unused drug after infusion.b

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Drug CompatibilityHID
Admixture Compatibility

Variable

Heparin sodium with hydrocortisone sodium succinate

Y-Site Compatibility

Compatible

Hydrocortisone sodium succinate

Variable

Heparin sodium

Incompatibility not observed with polyvinyl chloride bags or infusion sets.9 a z

Actions

  • Rabbit-derived polyclonal antibody; immunosuppressive agent.2 8 a b g

  • Exact mechanism of immunosuppressive action not fully elucidated; appears to involve clearance of peripheral antigen-reactive T lymphocytes (T cells) and modulation of T-cell activation, homing, and cytotoxicity.8 a b g

  • ATG (rabbit) contains antibodies that bind T-cell surface receptors, including CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, HLA-DR, HLA class I heavy chains, and β2-microglobulin.8 a b g

  • Induces profound depletion of CD2, CD3, CD4, CD8, CD16, CD25, and CD45 lymphocytes within 24 hours of first dose administration.b g

  • Not effective for treating antibody-mediated (humoral) transplant rejections.b

Advice to Patients

  • Importance of informing patients about the potential benefits of ATG (rabbit) and attendant risks of immunosuppressive therapy.b

  • Risk of decreased number of platelets and/or WBCs, including lymphocytes.b Necessity of administration under supervision of a clinician with regular monitoring of platelet and WBC counts.b

  • Potential for reduction of lymphocyte counts, which could increase risk of infection or malignancy.b Importance of informing clinicians promptly if any signs or symptoms of infection or malignancy occur.b

  • Advise patient of risk of possible fever, chills, itching, and/or rash during ATG (rabbit) infusion and that medication will be given to help control these reactions.b

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal or nutritional supplements, as well as any concomitant illnesses.b

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.b

  • Importance of informing patients of other important precautionary information.b (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Antithymocyte Globulin (Rabbit)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

25 mg

Thymoglobulin

Genzyme

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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. [IDIS 410978] [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 ()

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: 3582-5. [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. [IDIS 427773] [PubMed 10221486]

6. Regan JF, Campbell K, Van Smith L et al. Sensitization following Thymoglobulin and Atgam rejection therapy as determined with a rapid enzyme-linked immunosorbent assay: US Thymoglobulin Multi-Center Study Group. 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]

a. www.ahfsdruginformation.com. Antithymocyte globulin (rabbit). Accessed February 2008.

b. Genzyme Corporation. Thymoglobulin (anti-thymocyte globulin [rabbit]) prescribing information. Cambridge, MA; 2007 Sep.

c. Hoffmann-La Roche Inc. Zenapax (daclizumab) sterile concentrate for injection prescribing information. Nutley, NJ; 2005 Sep.

d. Hardinger KL, Schnitzler MA, Miller B et. al. Five-year follow up of Thymoglobulin versus ATGAM induction in adult renal transplantation. Transplantation. 2004; 78:136-41. [PubMed 15257052]

e. Schnitzler MA, Woodward RS, Lowell JA et. al. Economics of the antithymocyte globulins Thymoglobulin and Atgam in the treatment of acute renal transplant rejection. Pharmacoeconomics. 2000; 17:287-93. [PubMed 10947303]

f. Novartis Pharmaceuticals Corporation. Simulect (basiliximab) for injection prescribing information. East Hanover, NJ; 2005 Sep.

g. Hardinger KL. Rabbit antithymocyte globulin induction therapy in adult renal transplantation. Pharmacotherapy. 2006; 26:1771-83. [PubMed 17125438]

h. Marvin MR, Droogan C, Sawinski D et al. Administration of rabbit antithymocyte globulin (thymoglobulin) in ambulatory renal-transplant patients. Transplantation. 2003; 76:488-9.

i. Mathis AS, Rao V. Deep vein thrombosis during rabbit antithymocyte globulin administration. Transplant Proc. 2004; 36:3250-1. [PubMed 15686740]

j. 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; 2007 Oct. From FDA web site ()

k. Stadler M, Germing U, Kliche KO et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs. rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia. 2004; 18:460-5. [PubMed 14712285]

l. Scheinberg P, Nunez O, Young NS. Retreatment with rabbit antithymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia. Br J Haematol. 2006; 133:622-7. [PubMed 16704436]

m. Khositseth S, Matas A, Cook ME et al. Thymoglobulin versus ATGAM induction therapy in pediatric kidney transplant recipients: a single-center report. Transplantation. 2005; 79:958-63. [PubMed 15849550]

n. Schwartz JJ, Ishitani MB, Weckwerth J et al. Decreased incidence of acute rejection in adolescent kidney transplant recipients using antithymocyte induction and triple immunosuppression. Transplantation. 2007; 84:715-21. [PubMed 17893604]

o. Buchler M, Hurault de Ligny B, Madec C et al. Induction therapy by antithymocyte globulin (rabbit) in renal transplantation: a 1-yr follow-up of safety and efficacy. Clin Transplantation. 2003; 17:539-45.

p. Kamel MH, Mohan P, Little DM et al. Rabbit antithymocyte globulin as induction immunotherapy for pediatric deceased donor kidney transplantation. J Urol. 2005; 174:703-7. [PubMed 16006954]

q. Ault BH, Honaker MR, Gaber AO et al. Short term outcomes of thymoglobulin induction in pedatric renal transplant recipients. Pediatr Nephrol. 2002; 17:815-8. [PubMed 12376809]

r. Hardinger KL, Schnitzler MA, Miller B et. al. Five-year follow up of Thymoglobulin versus ATGAM induction in adult renal transplantation. Transplantation. 2004; 78:136-41. [PubMed 15257052]

s. Agha IA, Rueda J, Alvarez A et. al. Short course induction immunosuppression with Thymoglobulin for renal transplant recipients. Transplant. 2002; 73:473-5.

t. Shah A, Agarwal A, Mangus R et al. Induction immunosuppression with rabbit antithymocyte globulin in pediatric liver transplantation. Liver Transpl. 2006; 12:1210-4. [PubMed 16868953]

u. Brennan DC, Daller JA, Lake KD et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006; 355:1967-7. [PubMed 17093248]

v. Bajjoka I, Hsaiky L, Brown K et al. Preserving renal function in liver transplant recipients with rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitors. Liver Transpl. 2008; 14:66-72. [PubMed 18161842]

w. Peddi VR, Bryant M, Roy-Chaudhury P et al. Safety, efficacy, and cost analysis of thymoglobulin induction therapy with internittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients. Transplantation. 2002; 73:1514-8. [PubMed 12023634]

x. Guttmann RD, Flemming C. Sequential biological immunosuppression: induction therapy with rabbit antithymocyte globulin. Clin Transplant. 1997; 11:185-92. [PubMed 9193840]

y. Bieber CP, Griepp RB, Oyer PE et al. Use of rabbit antithymocyte globulin in cardiac transplantation: relationship of clearance rates to clinical outcome. Transplantation. 1976; 22:478-88. [PubMed 793103]

z. Genzyme Corporation. Cambridge, MA: Personal communication.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:167-8.

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