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Antithymocyte Globulin (Equine)

Pronunciation

(an te THY moe site GLOB yu lin, E kwine)

Index Terms

  • Anti-Thymocyte Globulin (Equine)
  • Antithymocyte Immunoglobulin
  • ATG
  • Horse Antihuman Thymocyte Gamma Globulin
  • Lymphocyte Immune Globulin

Dosage Forms

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

Injectable, Intravenous:

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

Brand Names: U.S.

  • Atgam

Pharmacologic Category

  • Immune Globulin
  • Immunosuppressant Agent
  • Polyclonal Antibody

Pharmacology

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

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 be 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

Renal transplantation: Management of allograft rejection in renal transplantation (increases the frequency of resolution of acute rejection episode when administered with conventional therapy at the time of rejection)

Use: Unlabeled

Prevention and treatment of rejection in heart and lung transplantation; treatment of acute graft-versus-host disease (GVHD) following allogeneic stem cell transplantation; treatment of myelodysplastic syndromes (MDS)

Contraindications

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

Dosing: Adult

Note: Test dose: A skin test is recommended prior to administration of the initial dose. Test 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, 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.

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)

Renal transplantation rejection (treatment): IV: 10 to 15 mg/kg once daily for 14 days, then if needed, may administer every other day for 7 more doses for a total of 21 doses in 28 days

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)

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

Note: Test dose: A skin test is recommended prior to administration of the initial dose. Test 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. 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.

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

Aplastic anemia, moderate to severe when no HLA-matched sibling donor: 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 up to a total of 21 doses in 28 days or

Off-label dosing (in combination with cyclosporine): Children ≥2 years and Adolescents: IV: 40 mg/kg/day 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 once daily for 14 days, then if needed, may administer every other day for 7 more doses for up to a total of 21 doses in 28 days

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

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

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.

Leukopenia (severe and unremitting) in renal transplant patients: Discontinue treatment.

Thrombocytopenia (severe and unremitting) in renal transplant patients: Discontinue 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

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. May cause vein irritation (chemical phlebitis) if administered peripherally; high flow veins are preferred to reduce phlebitis (infuse into vascular shunt, arterial venous fistula, or high-flow central vein).

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

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

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

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. Avoid combination

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

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% (Limited to important or life-threatening: Abdominal pain, acute renal failure, anaphylactoid reaction, anemia, aplasia, apnea, confusion, cough, deep vein thrombosis, disorientation, dizziness, enlarged kidney (and ruptured kidney), eosinophilia, epigastric pain, epistaxis, erythema, flank pain, gastrointestinal hemorrhage, gastrointestinal perforation, granulocytopenia, hemolysis, hemolytic anemia, herpes simplex infection (reactivation), hiccups, hyperglycemia, iliac vein obstruction, infection, involuntary body movements, laryngospasm, malaise, muscle rigidity, neutropenia, pancytopenia, paresthesia, pulmonary edema, renal artery thrombosis, sore mouth, sore throat, tachycardia, toxic epidermal necrolysis, tremor, vasculitis, viral hepatitis, weakness, wound dehiscence

ALERT: U.S. Boxed Warning

Anaphylaxis

Antithymocyte globulins can 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 patients for signs and symptoms during infusion.

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

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

The National Transplantation Pregnancy Registry (NTPR) is a registry which follows pregnancies which occur in maternal transplant recipients or those fathered by male transplant recipients. The NTPR encourages reporting of pregnancies following solid organ transplant by contacting them at 877-955-6877 or NTPR@giftoflifeinstitute.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, muscle pain, or joint pain. Have patient report immediately to prescriber signs of infection, angina, tachycardia, signs of breathing problems (shortness of breath, wheezing, coughing, or breathing gets worse), severe dizziness, passing out, bruising, bleeding, severe back pain, loss of strength and energy, confusion, severe skin irritation, seizures, or injection site irritation (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 healthcare 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.

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