Antithymocyte Globulin (Equine)

Brand names: Atgam
Drug class: Antineoplastic Agents

Usage of Antithymocyte Globulin (Equine)

Renal Allotransplantation

Treatment of acute rejection of renal allografts, usually in conjunction with other immunosuppressive therapy.

Adjunctive ATG (equine) therapy successfully reverses most initial episodes of acute rejection in renal allograft recipients, including a high percentage of episodes severe enough to require hemodialysis.

Also may be effective for recurrent episodes of acute rejection and acute rejection episodes unresponsive to high-dose corticosteroid therapy.

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

Also used as induction therapy in conjunction with other immunosuppressive therapy to prevent or delay onset of renal allograft rejection. However, improved graft survival has not been consistently demonstrated.

Aplastic Anemia

Treatment of moderate to severe aplastic anemia in patients unsuitable for bone marrow transplantation.

When combined with conventional supportive therapy in patients with aplastic anemia, ATG (equine) may induce a partial or complete hematologic remission.

Safety and efficacy not fully evaluated in patients with aplastic anemia who are suitable candidates for bone marrow transplantation or in those with aplastic anemia secondary to neoplastic disease, storage disease, myelofibrosis, Fanconi's syndrome, or exposure to myelotoxic agents or radiation.

Graft-versus-host Disease

Treatment of corticosteroid-refractory and/or moderate to severe acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation or bone marrow transplantation† [off-label].

Also has been used for the prevention of GVHD following bone marrow transplantation† [off-label].

Other Organ Transplants

Has been used with some success to prevent and/or manage cardiac allograft rejection† [off-label] in combination with other immunosuppressive medications.

Also has been used for induction therapy or treatment of rejection in lung transplantation† [off-label] and combined heart-lung transplantation† [off-label].

Has been used in skin allotransplantation†.

Pure Red Cell Aplasia

Has been used for treatment of pure red cell aplasia (PRCA) in some patients refractory to other therapies†.

Relate drugs

How to use Antithymocyte Globulin (Equine)

General

Usually administered in conjunction with other immunosuppressive agents (e.g., azathioprine and corticosteroids).

Intradermal Sensitivity Testing

  • Because of risk of severe systemic reaction (e.g., anaphylaxis), intradermal sensitivity testing is recommended in all individuals prior to administration of initial ATG (equine) dose.
  • Skin test procedure: Inject intradermally 0.1 mL of a 1:1000 dilution of ATG (equine) concentrate for injection in 0.9% sodium chloride (5 mcg of equine IgG); only use fresh diluted ATG (equine). Administer control test of 0.9% sodium chloride injection contralaterally to facilitate interpretation of results.
  • Observe patient and skin test site every 15–20 minutes during the first hour after intradermal injection of drug for positive reaction (wheal and/or area of erythema ≥10 mm in diameter, with or without pseudopod formation, and itching or marked local swelling) and question patient about occurrence of systemic manifestations.
  • If intradermal skin test is positive, seriously consider alternative forms of therapy and weigh risk of administration against risk of withholding ATG (equine). If therapy considered appropriate following a positive skin test reaction, administer drug only in a setting in which facilities for intensive life support are immediately available and where a clinician familiar with management of potentially life-threatening allergic reactions is in attendance.

    A systemic reaction to the skin test (e.g., generalized rash, tachycardia, dyspnea, hypotension, anaphylaxis) usually precludes further ATG (equine) administration. (See Contraindications under Cautions.)

  • Predictive value of skin test procedure not proven clinically; allergic reactions, including anaphylaxis, have occurred in patients whose skin test was negative. Always take precautions to treat severe systemic reactions.

    • Premedication

  • To minimize or prevent infusion-related adverse effects (including fever and chills), the manufacturer and some clinicians recommend premedication with an antipyretic (e.g., acetaminophen), antihistamine (e.g., diphenhydramine), or corticosteroids or some combination of these agents prior to ATG (equine) infusion.

    • Prophylactic Antiviral Therapy

  • Although not specifically recommended by manufacturer, some clinicians administer prophylactic antiviral therapy (e.g., acyclovir, ganciclovir, valganciclovir) during ATG (equine) therapy. (See Immunosuppressive-related Infectious Complications and Hematologic Effects under Cautions.)

    • Administration

    IV Administration

    For solution compatibility information, see Stability.

    Administer ATG (equine) by slow IV infusion. Allow to reach room temperature prior to administration.

    Because slight granular or flaky deposits may develop in ATG (equine) concentrate for injection during storage, the manufacturer states that ATG (equine) solutions should be infused through an inline 0.2- to 1-µm filter.

    Administer into a high-flow central vein, vascular shunt, or arteriovenous fistula (e.g., Brescia-Cimino fistula) to minimize risk of phlebitis and thrombosis.

    Dilution

    ATG (equine) concentrate for injection must be diluted prior to IV infusion.

    Dilute appropriate dose of ATG (equine) concentrate for injection in 0.9% sodium chloride injection, 5% dextrose and 0.225% sodium chloride injection, or 5% dextrose and 0.45% sodium chloride injection (usually 250–1000 mL); final concentration preferably should not provide >4 mg of equine IgG per mL.

    Invert IV infusion solution container into which ATG (equine) is added to prevent contact of undiluted ATG (equine) with air inside container. Mix diluted solution by gently rotating or swirling container; do not shake.

    Rate of Administration

    Infuse the appropriate dose over at least 4 hours (usually 4–8 hours).

    Dosage

    Dosage of ATG (equine) is expressed in terms of equine IgG.

    Some clinicians have monitored peripheral blood levels of rosette-forming cells (RFCs) during ATG (equine) therapy in allograft recipients to determine the degree of immunosuppression attained and guide dosage adjustment, with ATG (equine) dosage adjusted to maintain RFC level at about 10% of the pretreatment level, while other clinicians have questioned the reliability and value of this method. The availability of monoclonal antibodies has allowed monitoring of specific T-cell subsets, and some clinicians previously have monitored peripheral blood levels of OKT3-reactive cells as a method for guiding dosage adjustment, with ATG (equine) dosage adjusted to maintain the level of OKT3-reactive cells at about 10% of the pretreatment value. Monitoring of CD3 T cells currently is used by some clinicians to guide ATG (equine) dosage adjustment and reduce risk of immunosuppression and treatment costs.

    Pediatric Patients

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

    15 mg/kg daily for 14 days followed by 15 mg/kg every other day for an additional 14 days (total of 21 doses in 28 days). Usually continue other immunosuppressive therapies used for prevention and/or treatment of renal transplant rejection (e.g., azathioprine, corticosteroids, graft irradiation). (See Interactions.)

    First dose given within 24 hours before or after transplantation.

    Treatment of Acute Renal Allograft Rejection IV Infusion

    10–15 mg/kg daily for 14 days; if necessary, may be followed by 10–15 mg/kg every other day for an additional 14 days (total of 21 doses in 28 days). Usually continue other immunosuppressive therapies used for prevention and/or treatment of renal transplant rejection (e.g., azathioprine, corticosteroids, graft irradiation). (See Interactions.)

    First dose given when initial episode of acute rejection is diagnosed.

    Aplastic Anemia Treatment of Aplastic Anemia IV Infusion

    10–20 mg/kg daily for 8–14 consecutive days, followed by 10–20 mg/kg every other day for up to an additional 14 days if necessary (up to a total of 21 doses in 28 days).

    Prophylactic platelet transfusions may be necessary to maintain platelet counts at clinically acceptable levels because thrombocytopenia may occur in aplastic anemia patients receiving ATG (equine) therapy.

    Graft-versus-host Disease† Treatment of Acute GVHD† IV Infusion

    Optimum dosage not established; various dosage regimens including 5–15 mg/kg daily, 15–30 mg/kg every other day, and 15 mg/kg twice daily have been given for at least 1–10 doses in adult and pediatric patients.

    Adults

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

    15 mg/kg daily for 14 days followed by 15 mg/kg every other day for an additional 14 days (total of 21 doses in 28 days). Usually continue other immunosuppressive therapies used for prevention and/or treatment of renal transplant rejection (e.g., azathioprine, corticosteroids, graft irradiation). (See Interactions.)

    First dose given within 24 hours before or after transplantation.

    Treatment of Acute Renal Allograft Rejection IV Infusion

    10–15 mg/kg daily for 14 days; may be followed by 10–15 mg/kg every other day for another 14 days (total of 21 doses in 28 days). Usually continue other immunosuppressive therapies used for prevention and/or treatment of renal transplant rejection (e.g., azathioprine, corticosteroids, graft irradiation). (See Interactions.)

    First dose given when initial acute rejection episode diagnosed.

    Aplastic Anemia Treatment of Aplastic Anemia IV Infusion

    10–20 mg/kg daily for 8–14 consecutive days, followed by 10–20 mg/kg every other day for up to an additional 14 days if necessary (up to a total of 21 doses in 28 days).

    Prophylactic platelet transfusions may be necessary to maintain platelet counts at clinically acceptable levels because thrombocytopenia may occur in aplastic anemia patients receiving ATG (equine) therapy.

    GVHD† Treatment of Acute GVHD† IV Infusion

    Optimum dosage not established; various dosage regimens including 5–15 mg/kg daily, 15–30 mg/kg every other day, and 15 mg/kg twice daily have been given for at least 1–10 doses in adult and pediatric patients.

    Prevention of Acute GVHD† IV Infusion

    Optimum dosage not established; 7 or 10 mg/kg every other day for 6 doses has been given.

    Prescribing Limits

    Adults

    Renal Allotransplantation Prevention and Treatment of Renal Allograft Rejection IV infusion

    Not determined; manufacturer states that some patients have received up to 50 doses of ATG (equine) (10–20 mg/kg per dose) in 4 months and others have received 28-day courses of 21 doses followed by up to 3 additional courses.

    Special Populations

    No special population dosage recommendations at this time.

    Warnings

    Contraindications

  • Severe systemic reaction during prior ATG (equine) administration or to any other equine immunoglobulin G preparation.

    • Warnings/Precautions

    Warnings

    For information regarding supervising clinicians and treatment facilities, see Boxed Warning.

    Lot Variability in Activity

    Precise methods for determining the potency of ATG (equine) not established; activity may vary from lot to lot.

    Discontinuance of Therapy for Severe Adverse Reactions

    Immediately discontinue ATG (equine) and give appropriate therapy if anaphylaxis or signs or symptoms suggesting potential anaphylaxis (e.g., hypotension, respiratory distress, or pain in the chest, flank, or back) occur. (See Intradermal Sensitivity Testing under Dosage and Administration and see Anaphylaxis under Cautions.)

    Discontinue ATG (equine) if severe and unremitting thrombocytopenia and/or leukopenia occurs in renal transplant patients.

    Risk of Infectious Agent Transmission

    Because ATG (equine) is made using equine and human blood components, possible risk of transmitting infectious agents (e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease [CJD] agent).

    Sensitivity Reactions

    Anaphylaxis

    Anaphylaxis (which may be manifested as hypotension, respiratory distress, or pain in the chest, flank, or back) reported in <1% of patients.

    Because of the risk of severe systemic reaction (including anaphylaxis) to ATG (equine), intradermal sensitivity testing is recommended in all individuals prior to administration of initial ATG (equine) dose. (See Intradermal Sensitivity Testing under Dosage and Administration.)

    If anaphylaxis or any of these other symptoms occurs, immediately discontinue the ATG (equine) infusion and initiate appropriate therapy (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen, IV fluids, antihistamines, maintenance of BP).

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

    General Precautions

    Intradermal sensitivity testing strongly recommended prior to IV infusion of ATG (equine). (See Intradermal Sensitivity Testing under Dosage and Administration and see Anaphylaxis under Cautions.)

    Manufacturer states that safety and efficacy of ATG (equine) demonstrated only in renal transplant patients who received concomitant immunosuppressive therapy and in patients with aplastic anemia.

    Immunosuppressive-related Infectious Complications and Hematologic Effects

    Because ATG (equine) is an immunosuppressive agent and ordinarily is combined with other immunosuppressive therapy (e.g., corticosteroids, azathioprine), carefully observe patients for signs of leukopenia, thrombocytopenia, and/or concurrent infection during therapy.

    An increased incidence of cytomegalovirus (CMV) infection has been reported in several studies; results of 1 study suggest possible reduced risk if lower dosages of other immunosuppressive agents are concurrently administered with ATG (equine). (See Prophylactic Antiviral Therapy under Dosage and Administration and see Specific Drugs under Interactions.) If infection occurs, promptly initiate appropriate therapy; clinician should decide based on clinical circumstances whether to discontinue ATG (equine) therapy.

    Specific Populations

    Pregnancy

    Category C. National Transplantation Pregnancy Registry at 877-955-6877.

    Lactation

    Not known whether ATG (equine) is distributed into milk, but may be distributed into milk since immunoglobulins (e.g., IgA, IgM, IgG) are present in colostrum. Use with caution.

    Pediatric Use

    The manufacturer states that experience in children is limited. However, ATG (equine) has been administered safely to some pediatric renal allograft recipients and aplastic anemia patients without unusual adverse effects. ATG (equine) has also been used in the treatment of acute GVHD in pediatric patients following allogeneic hematopoietic stem cell transplantation or bone marrow allotransplantation. (See Graft-versus-host Disease under Uses.)

    Common Adverse Effects

    Renal allotransplantation: Fever, chills, leukopenia, thrombocytopenia, dermatologic reactions (rash, pruritus, urticaria, wheal and flare).

    Aplastic anemia: Fever, chills, skin reactions, arthralgia, headache, myalgia, nausea, chest pain, phlebitis, serum sickness.

    What other drugs will affect Antithymocyte Globulin (Equine)

    Specific Drugs

    Drug

    Interaction

    Comments

    Basiliximab

    No increase in adverse effects

    Immunosuppressive agents

    Risk of oversuppression of the immune system and associated susceptibility to infection and malignancies, including lymphoma and lymphoproliferative disorders

    Consider decreasing maintenance immunosuppressive therapy during concurrent administration

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