Antithymocyte Globulin (Equine)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injectable, Intravenous [preservative free]:

Atgam: 50 mg/mL (5 mL) [thimerosal free]

Pharmacology

Mechanism of Action

Immunosuppressant involved in the elimination of antigen-reactive T lymphocytes (killer cells) in peripheral blood or alteration in the function of T-lymphocytes, which are involved in humoral immunity and partly in cell-mediated immunity; induces complete or partial hematologic response in aplastic anemia

Pharmacokinetics/Pharmacodynamics

Distribution

Poor into lymphoid tissues; binds to circulating lymphocytes, granulocytes, platelets, bone marrow cells

Excretion

Urine (~1%)

Half-Life Elimination

5.7 ± 3 days

Use: Labeled Indications

Aplastic anemia: Treatment of moderate-to-severe aplastic anemia in patients not considered suitable candidates for bone marrow transplantation

Limitations of use: The usefulness of antithymocyte globulin (equine) has not been demonstrated in patients with aplastic anemia who are suitable candidates for transplantation, or in aplastic anemia secondary to neoplastic disease, storage disease, myelofibrosis, Fanconi syndrome, or in patients with known prior treatment with myelotoxic agents or radiation therapy

Use: Off Label

Acute graft-versus-host disease (treatment)b

Data from a phase II/III study MacMillan 2007 and a retrospective analysis MacMillan 2002 support the use of antithymocyte globulin (equine) in the management of steroid-resistant acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant. Additional trials may be necessary to further define the role of antithymocyte globulin (equine) in the treatment of this condition.

Lung transplant (induction therapy)c

Data from a limited number of patients suggests that antithymocyte globulin (equine) may be beneficial as an induction agent to prevent acute rejection after lung transplantation Hachem 2005. Additional data may be necessary to further define the role of antithymocyte globulin (equine) in this condition.

Myelodysplastic syndromes, refractory, lower-risk diseaseb

Data from a single-treatment study supports the use of antithymocyte globulin (equine) in the treatment of myelodysplastic syndromes Molldrem 2002. Another study Sloand 2008 and a review Fenaoux 2013 have further defined the role of antithymocyte globulin (equine) as a second-line therapy for lower risk disease. Additional trials may be necessary to further define the role of antithymocyte globulin (equine) in the treatment of this condition.

Contraindications

History of systemic reaction (eg, anaphylactic reaction) to prior administration of antithymocyte globulin or any other equine gamma globulin preparation

Dosage and Administration

Dosing: Adult

Note: Test dose: While a skin test is recommended prior to administration of the initial dose, anaphylaxis may still occur in patients who display negative skin tests. Consider testing initially with an epicutaneous prick of undiluted antithymocyte globulin (ATG); if no wheal in 10 minutes, then use 0.02 mL intradermally of a 1:1000 dilution of ATG in normal saline along with a separate saline control of 0.02 mL; observe in 10 minutes. A positive skin reaction consists of a wheal with the initial prick test (undiluted) or ≥3 mm in diameter larger than the saline control with the diluted intradermal test. Alternatively, a 0.1 mL test dose (5 mg/mL concentration) may be administered intradermally along with a separate saline control; erythema larger than 5 mm in diameter (compared to the control) is considered a positive test (Molldrem 2002). A positive skin test is suggestive of an increased risk for systemic allergic reactions with an infusion. If ATG treatment is deemed appropriate following a positive skin test, the first infusion should be administered in a controlled environment with intensive life support immediately available. A systemic reaction precludes further administration.

Consider premedication with an antihistamine, corticosteroids, and/or an antipyretic. Concomitant immunosuppressants should also be administered.

Aplastic anemia: IV: 10 to 20 mg/kg once daily for 8 to 14 days, then if needed, may administer every other day for 7 more doses for a total of 21 doses in 28 days or

Off-label dosing: 40 mg/kg once daily for 4 days in combination with cyclosporine (Rosenfeld 1995; Scheinberg 2011)

Acute graft-versus-host disease (GVHD) treatment (off-label use): IV: 30 mg/kg every other day for 6 doses (MacMillan 2007) or 15 mg/kg twice daily for 10 doses (MacMillan 2002)

Lung transplant, induction therapy (off-label use): IV: 5 to 15 mg/kg daily for the first 3 days after transplant (Hachem 2005). Additional data may be necessary to further define the role of antithymocyte globulin (equine) in this condition.

Myelodysplastic syndromes, refractory, lower-risk disease (off-label use): IV: 40 mg/kg once daily for 4 days; an intradermal test dose was administered prior to treatment (Molldrem 2002)

Dosing: Geriatric

Refer to adult dosing. Begin at the lower end of dosing ranges.

Dosing: Pediatric

Test dose: While a skin test is recommended prior to administration of the initial dose, anaphylaxis may still occur in patients who display a negative skin test. Consider testing initially with an epicutaneous prick of undiluted antithymocyte globulin (ATG); if no wheal in 10 minutes, then use 0.02 mL intradermally of a 1 mg/mL dilution of ATG in normal saline along with a separate saline control of 0.02 mL; observe in 10 minutes. A positive skin reaction consists of a wheal with the initial prick test (undiluted) or ≥3 mm in diameter larger than the saline control with the diluted intradermal test. A positive skin test is suggestive of an increased risk for systemic allergic reactions with an infusion, although anaphylaxis may occur in patients who display negative skin tests. If ATG treatment is deemed appropriate following a positive skin test, the first infusion should be administered in a controlled environment with intensive life support immediately available. A systemic reaction precludes further administration of the drug. Note: Consider premedication with an antihistamine, corticosteroids, and/or an antipyretic.

Aplastic anemia, moderate to severe when no HLA-matched sibling donor:

Manufacturer's labeling: Children and Adolescents: IV: 10 to 20 mg/kg/dose once daily for 8 to 14 days; then if needed, may administer every other day up to a total of 21 doses in 28 days

Alternate dosing (in combination with cyclosporine): Limited data available: Children ≥2 years and Adolescents: IV: 40 mg/kg/dose once daily for 4 days (Afable 2011; Rosenfeld 1995; Scheinberg 2009; Scheinberg 2011)

Renal transplantation rejection, treatment: Children and Adolescents: IV: 10 to 15 mg/kg/dose once daily for 14 days, then if needed, may administer every other day up to a total of 21 doses in 28 days

Acute graft-versus-host disease, steroid-resistant, treatment: Limited data available: Children and Adolescents: IV: 30 mg/kg/dose every other day for 6 doses (MacMillan 2007) or 15 mg/kg/dose twice daily for 10 doses (MacMillan 2002)

Dosing: Adjustment for Toxicity

Anaphylaxis: Discontinue infusion immediately; administer epinephrine. May require corticosteroids, respiration assistance, and/or other resuscitative measures. Do not resume infusion.

Hemolysis (severe and unremitting): May require discontinuation of treatment.

Dosing: Obesity

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).

Reconstitution

Dilute into inverted container of sterile infusion solution to ensure that undiluted lymphocyte immune globulin does not contact air. Gently rotate or swirl to mix; do not shake (to avoid excessive foaming and/or denaturation of the protein). Final concentration should not exceed 4 mg/mL. May be diluted in NS, D5¹/₄NS, or D5¹/₂NS (do not use D5W; low salt concentrations may result in precipitation). Inspect for particulate matter or discoloration prior to administration (solution may be transparent to slightly opalescent, colorless to faintly pink or brown, and may develop a slight granular or flaky deposit during storage).

Administration

IV: For IV use only. Infuse over at least 4 hours through a 0.2 to 1 micron inline filter. Allow solution to reach room temperature prior to infusion. Infusion must be completed with 24 hours of preparation. Administration through a central line is recommended; high flow veins are preferred to reduce phlebitis (infuse into vascular shunt, arterial venous fistula, or high-flow central vein). May cause vein irritation (chemical phlebitis) if administered peripherally (peripheral administration is not recommended).

Monitor closely throughout the infusion for allergic reactions. Appropriate resuscitative equipment should be nearby during administration. May require premedication with an antipyretic, antihistamine, and/or a corticosteroid to prevent reactions. Discontinue infusion for anaphylaxis or respiratory distress. Administer epinephrine, corticosteroids, antihistamines, and/or antipyretics as indicated to manage reactions.

Due to possible infusion-related reactions, it may be preferable to avoid initiating treatment late in the day or on weekends; consider withholding beta-blockers prior to administration to avoid suppressing compensatory responses to anaphylaxis (Scheinberg, 2012).

Storage

Store ampules at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not shake. Solutions diluted for infusion NS, D5¹/₄NS, or D5¹/₂NS to a concentration of up to 4 mg/mL are stable for 24 hours (including infusion time) under refrigeration. Allow infusion solution to reach room temperature prior to administration.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belatacept: Antithymocyte Globulin (Equine) 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

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

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

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

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

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

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. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Vaccines (Live): Immune Globulins may diminish the therapeutic effect of Vaccines (Live). Management: Consult full interaction monograph for dose interval recommendations. This interaction does not apply to oral Ty21a typhoid vaccine or others listed as exceptions. Exceptions: Adenovirus (Types 4, 7) Vaccine; Cholera Vaccine; Influenza Virus Vaccine (Live/Attenuated); Poliovirus Vaccine (Live/Bivalent/Oral); Poliovirus Vaccine (Live/Trivalent/Oral); Rotavirus Vaccine; Yellow Fever Vaccine; Zoster Vaccine (Live/Attenuated). Consider therapy modification

Adverse Reactions

>10%:

Central nervous system: Chills, headache

Dermatologic: Dermatological reaction (wheal/flare), pruritus, skin rash, urticaria

Hematologic & oncologic: Leukopenia, thrombocytopenia

Neuromuscular & skeletal: Arthralgia

Miscellaneous: Fever

1% to 10%:

Cardiovascular: Bradycardia, cardiac disease, cardiac failure, chest pain, edema, hypertension, hypotension, myocarditis, phlebitis, thrombophlebitis

Central nervous system: Agitation, brain disease (viral), burning sensation (burning of soles and burning of palms), dizziness, encephalitis, generalized ache, lethargy, seizure

Dermatologic: Diaphoresis, night sweats

Gastrointestinal: Diarrhea, nausea, stomatitis, vomiting

Genitourinary: Proteinuria

Hematologic & oncologic: Lymphadenopathy

Hepatic: Abnormal hepatic function tests, hepatosplenomegaly

Hypersensitivity: Anaphylaxis, serum sickness

Infection: Viral infection

Local: Injection site reaction (pain, redness, swelling)

Neuromuscular & skeletal: Back pain, joint stiffness, myalgia

Ophthalmic: Periorbital edema

Renal: Renal function test abnormality

Respiratory: Dyspnea, pleural effusion, respiratory distress

<1%, postmarketing, and/or case reports: Abdominal pain, acute renal failure, anaphylactoid reaction, anemia, apnea, confusion, cough, deep vein thrombosis, disorientation, dizziness, eosinophilia, epigastric pain, epistaxis, erythema, flank pain, gastrointestinal hemorrhage, gastrointestinal perforation, granulocytopenia, hemolysis, hemolytic anemia, herpes simplex infection (reactivation), hiccups, hyperglycemia, infection, involuntary body movements, laryngospasm, malaise, muscle rigidity, neutropenia, pancytopenia, paresthesia, pulmonary edema, pure red cell aplasia, renal artery thrombosis, sore mouth, sore throat, tachycardia, thrombosis of vein (iliac), toxic epidermal necrolysis, tremor, vasculitis, viral hepatitis, weakness, wound dehiscence

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis: [US Boxed Warning]: Antithymocyte globulins may cause anaphylaxis when injected intravenously. Although antithymocyte globulin (equine) is processed to reduce the level of antibodies that will react to non-T cells, health care providers should be prepared for the potential risk of anaphylaxis and monitor for signs/symptoms during infusion. Hypersensitivity and anaphylactic reactions may occur; discontinue for symptoms of anaphylaxis; immediate treatment (including epinephrine 1 mg/mL) should be available. Systemic reaction (rash, dyspnea, hypotension, tachycardia, or anaphylaxis) precludes further administration of antithymocyte globulin (equine; ATG). Respiratory distress, hypotension, or pain (chest, flank, or back) may indicate an anaphylactoid/anaphylactic reaction. Serious immune-mediated reactions have been reported (rare), including anaphylaxis, infusion reactions, and serum sickness. Skin testing is recommended prior to administration of the initial ATG dose. A positive skin test is suggestive of an increased risk for systemic allergic reactions with an infusion, although anaphylaxis may occur in patients who display negative skin tests. If ATG treatment is deemed appropriate following a positive skin test, the first infusion should be administered in a controlled environment with intensive life support immediately available. Also observe for signs/symptoms of allergic reactions during repeat courses of administration. Skin testing is not predictive for later development of serum sickness.
• Hematologic toxicity: Thrombocytopenia may occur; may require platelets transfusion support. Discontinue if severe and unremitting leukopenia or thrombocytopenia occur in solid organ transplant patients.
• Hemolysis: Clinically significant hemolysis has been reported (rarely). Severe and unremitting hemolysis may require treatment discontinuation. Chest, flank or back pain may indicate hemolysis.
• Hepatic function: Abnormal hepatic function tests have been observed in patients with aplastic anemia and other hematologic disorders receiving ATG.
• Infection: ATG is an immunosuppressant; monitor closely for signs of infection. An increased incidence of cytomegalovirus (CMV) infection has been reported in studies.
• Renal function: Abnormal renal function tests have been observed in patients with aplastic anemia and other hematologic disorders receiving ATG.

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: Live viral vaccines may not replicate and antibody response may be reduced if administered during ATG treatment. Patients should not be immunized with attenuated live viral vaccines prior to planned ATG treatment, during, and after treatment.

Other warnings/precautions:

• Administration: Administer via central line due to chemical phlebitis that may occur with a peripheral vein. Dose must be administered over at least 4 hours; patient may need to be pretreated with an antipyretic, antihistamine, and/or corticosteroid. Should be administered with concomitant immunosuppressants.
• Disease transmission: Product of equine and human plasma; may have a risk of transmitting disease, including a theoretical risk of Creutzfeldt-Jakob disease (CJD).
• Potency: Product potency and activity may vary from lot to lot.

Monitoring Parameters

Complete blood count with differential and platelet count, monitor vital signs during administration; monitor for infusion reactions; monitor for signs/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).

Pregnancy

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

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.

Patient Education

• 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 headache or joint pain. Have patient report immediately to prescriber signs of infection, slow heartbeat, fast heartbeat, shortness of breath, severe dizziness, passing out, bruising, bleeding, muscle pain, edema, sweating a lot, diarrhea, or abdominal pain (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.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.