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Antithymocyte Globulin (Rabbit)

Pronunciation

(an te THY moe site GLOB yu lin RAB bit)

Index Terms

  • Antithymocyte Immunoglobulin
  • rATG

Dosage Forms

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

Solution Reconstituted, Intravenous:

Thymoglobulin: 25 mg (1 ea) [contains glycine, mannitol, sodium chloride]

Brand Names: U.S.

  • Thymoglobulin

Pharmacologic Category

  • Immune Globulin
  • Immunosuppressant Agent
  • Polyclonal Antibody

Pharmacology

Polyclonal antibody which appears to cause immunosuppression by acting on T-cell surface antigens and depleting CD4 lymphocytes

Onset of Action

T-cell depletion: Within 24 hours (Hardinger 2006)

Duration of Action

Lymphopenia may persist for up to 1 year (Hardinger 2006)

Half-Life Elimination

2 to 3 days

Use: Labeled Indications

Renal transplant rejection: Treatment of acute renal transplant rejection (in conjunction with concomitant immunosuppression)

Use: Unlabeled

Induction therapy in renal transplant; treatment of myelodysplastic syndrome (MDS)

Contraindications

Hypersensitivity (allergy or anaphylaxis) to antithymocyte globulin, rabbit proteins, or any component of the formulation; active acute or chronic infection

Documentation of allergenic cross-reactivity for drugs in this class is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Note: Premedicate with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to infusion to reduce the incidence and severity of infusion-related reactions. Antiviral prophylaxis is recommended.

Acute renal transplant rejection, treatment: IV: 1.5 mg/kg/day for 7 to 14 days

Cardiac transplant, acute cellular rejection (ACR) treatment (off-label use): IV: 0.75 to 1.5 mg/kg/day for 5 to 14 days (ISHLT [Costanzo 2010])

Cardiac transplant, antibody-mediated rejection treatment (off-label use): IV: 0.75 to 1.5 mg/kg/day for 5 to 7 days (AHA [Colvin 2015])

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Refer to adult dosing.

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

WBC count 2,000 to 3,000 cells/mm3 or platelet count 50,000 to 75,000 cells/mm3: Reduce dose by 50%.

WBC count <2,000 cells/mm3 or platelet count <50,000 cells/mm3: Consider discontinuing 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

Allow vials to reach room temperature, then reconstitute each vial with SWFI 5 mL to a concentration of 5 mg/mL. Rotate vial gently until completely dissolved. Prior to administration, further dilute for infusion, each 25 mg vial should be diluted in 50 mL saline or dextrose (total volume is usually 50 to 500 mL depending on total number of vials needed per dose). Mix by gently inverting infusion bag once or twice.

Administration

IV: The first dose should be infused over at least 6 hours through a high-flow vein. Subsequent doses should be administered over at least 4 hours. Administer through an in-line 0.22 micron filter. Premedication with corticosteroids, acetaminophen, and/or an antihistamine may reduce infusion-related reactions. Reducing the infusion rate may minimize infusion reactions.

Compatibility

Stable in D5W, NS.

Storage

Store powder under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Reconstituted product is stable for up to 24 hours at room temperature; however, the product contains no preservative and room temperature storage is not recommended; the manufacturer recommends use immediately after reconstitution and preparation for infusion in D5W or NS.

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

Test Interactions

Potential interference with rabbit antibody-based immunoassays

Adverse Reactions

>10%:

Cardiovascular: Hypertension (27% to 37%), tachycardia (23%), peripheral edema (20%), hypotension (10% to 16%)

Central nervous system: Chills (55% to 57%), headache (27% to 40%), pain (26%), insomnia (12% to 20%), malaise (9% to 13%), acne vulgaris (12%)

Dermatologic: Skin rash (7% to 13%), diaphoresis (6% to 13%), acne vulgaris (12%)

Endocrine & metabolic: Hyperkalemia (17% to 27%), hypokalemia (12%)

Gastrointestinal: Abdominal pain (17% to 38%), nausea (29% to 37%), diarrhea (20%), vomiting (20%), constipation (15%)

Hematologic & oncologic: Leukopenia (49% to 57%; including lymphopenia and neutropenia), thrombocytopenia (29% to 37%), leukocytosis (13%), anemia (12%)

Infection: Infection (31%), cytomegalovirus disease (13%), sepsis (12%)

Neuromuscular & skeletal: Myalgia (11% to 20%), arthralgia (15%), weakness (13%), back pain (12%)

Respiratory: Dyspnea (15% to 28%), pulmonary disease (12%)

Miscellaneous: Fever (46%)

1% to 10%:

Cardiovascular: Chest pain (9%), edema (6%)

Central nervous system: Anxiety (7%)

Dermatologic: Pruritus (6%)

Endocrine & metabolic: Acidosis (9%), hypophosphatemia (6%)

Gastrointestinal: Dyspepsia (10%), anorexia (6%), intestinal candidiasis (5%), gastritis (1%)

Hematologic & oncologic: Malignant neoplasm (2%)

Hypersensitivity: Serum sickness (2%)

Infection: Herpes simplex infection (5%)

Respiratory: Increased cough (7%)

Miscellaneous: Drug overdose (6%)

<1% (Limited to important or life-threatening): Anaphylaxis, blood coagulation disorder, cytokine release syndrome, decreased oxygen saturation, increased liver enzymes, infusion related reaction, lymphadenopathy, lymphoproliferative disorder (post-transplant), malignant lymphoma, proteinuria, solid tumor

ALERT: U.S. Boxed Warning

Experienced physician:

Anti-thymocyte globulin should only be used by physicians experienced in immunosuppressive therapy for the management of renal transplant patients.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis: Hypersensitivity and fatal anaphylactic reactions have been reported. Stop infusion if anaphylactic reaction occurs; further administration in patients with a history of anaphylaxis to antithymocyte globulin (rabbit) is not recommended. Immediate treatment (including epinephrine 1 mg/mL) should be available during infusion for management of hypersensitivity.

• Cytokine release syndrome (CRS): Release of cytokines by activated monocytes and lymphocytes may cause CRS during administration of antithymocyte globulin (rabbit); may cause serious cardiopulmonary arrest (sometimes fatal). Rapid infusion rates of have been associated with CRS (case reports). Symptoms range from a mild, self-limiting "flu-like reaction" to severe, life-threatening reactions. Severe or life-threatening symptoms include hypotension, acute respiratory distress syndrome, pulmonary edema, myocardial infarction, and tachycardia.

• Infection: Severe infections (bacterial, fungal, viral and/or protozoal) may develop following concomitant use of immunosuppressants with antithymocyte globulin. Reactivation of infections and sepsis have been reported. Appropriate antiviral, antibacterial, antiprotozoal, and/or antifungal prophylaxis is recommended. Monitor closely for infection.

• Local: Infusion site reactions (pain, swelling, erythema) may occur.

• Malignancy: Immunosuppressants, including antithymocyte globulins may increase the incidence of malignancies, including lymphoma, post-transplant lymphoproliferative disease (PTLD) or other malignancies; may be fatal.

• Hematologic toxicity: Reversible neutropenia and thrombocytopenia may result from the development of cross-reactive antibodies. Dose adjustment may be necessary.

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: Patients should not be immunized with attenuated live viral vaccines during or shortly after treatment; safety of immunization following therapy has not been studied.

Other warnings/precautions:

• Administration: Dosing of antithymocyte globulin (rabbit) differs from dosing of other antithymocyte globulin products; protein compositions and concentrations are different; use caution to assure dose prescribed is intended for product being administered. Initial dose must be administered over at least 6 hours into a high flow vein. Reducing the infusion rate (and prolonging the administration time) may minimize infusion reactions. May pretreat with an antipyretic, antihistamine, and/or corticosteroid.

• Experienced physician: [US Boxed Warning]: Should only be used by physicians experienced in immunosuppressive therapy for the treatment of renal transplant patients. Medical surveillance is required during the infusion. Should be administered in combination with other immunosuppressants.

Monitoring Parameters

Lymphocyte count (total lymphocyte and/or T-cell subset), CBC with differential and platelet count; vital signs during administration; signs and symptoms of infection

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted.

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 nausea, vomiting, abdominal pain, acne, muscle pain, joint pain, insomnia, sweating a lot, constipation, back pain, injection site pain or irritation, or diarrhea. Have patient report immediately to prescriber signs of infection, signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, numbness or tingling feeling), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), angina, tachycardia, bruising, bleeding, severe headache, severe dizziness, passing out, vision changes, severe loss of strength and energy, swelling of arm or leg, shortness of breath, or signs of cytokine release syndrome (chills, dizziness, loss of strength and energy, fever, headache, passing out, rash, angioedema, difficulty breathing, nausea, vomiting, or wheezing) 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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