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    Other Immunosuppressants

    BOXED WARNING

    Fungal infection, herpes infection, infection, lymphoma, neoplastic disease, requires an experienced clinician, varicella, viral infection

    Antithymocyte globulin (ATG) therapy requires an experienced clinician. Only clinicians experienced in immunosuppressant therapy and organ transplantation should use ATG. Increased susceptibility to infection and possible development of neoplastic disease, especially lymphoma, may result from combination immunosuppression. ATG (equine) therapy requires a specialized care setting. Patients receiving ATG should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services. Bacterial, viral, protozoal, or fungal infection occurs commonly during immunosuppressive therapy and can be fatal. Thymoglobulin is contraindicated in patients who have active acute or chronic infections that contraindicate any additional immunosuppression. Prophylactic antiviral therapy is recommended. One study has suggested an increased incidence of cytomegalovirus in patients receiving equine ATG. It may be possible to decrease this risk by decreasing the dose of other immunosuppressive agents administered concomitantly. Reactivation of a latent viral infection, especially herpes infection or varicella, can occur with immunosuppressive therapy. As with other products derived from or purified with human blood components, the possibility of transmission of infection exists in patients receiving ATG. Patients should be instructed to promptly report signs of infection.

    DEA CLASS

    Rx

    DESCRIPTION

    Immunosuppressant, polyclonal IgG against human T-lymphocytes derived from horses (Atgam) or rabbits (Thymoglobulin)
    Used for kidney organ transplant rejection, organ transplant rejection prophylaxis, and moderate to severe aplastic anemia
    Risk of serious hypersensitivity reactions, including anaphylaxis or cytokine release syndrome (CRS)

    COMMON BRAND NAMES

    Atgam, Thymoglobulin

    HOW SUPPLIED

    Atgam Intravenous Inj Sol: 1mL, 50mg
    Thymoglobulin Intravenous Inj Pwd F/Sol: 25mg

    DOSAGE & INDICATIONS

    For the treatment of acute kidney transplant rejection.
    Intravenous infusion dosage (Atgam)
    Adults

    10 to 15 mg/kg/day IV for 14 days in conjunction with concomitant immunosuppression. Administration may continue every other day, up to a total of 21 doses. Clinical practice guidelines suggest a lymphocyte-depleting agent such as antithymocyte globulin for severe, steroid-refractory or recurrent acute rejection cases.

    Children and Adolescents

    Data are limited. Doses comparable to adults have been used. In a study evaluating the use of anti-lymphocyte medications to treat acute rejection, 4 patients aged 10 to 16 years received 10 to 15 mg/kg/dose IV for 8 to 14 days for corticosteroid-resistant, biopsy-proven acute rejection that occurred 5 to 96 months after transplantation. Of 4 patients, 3 had reversal of acute rejection, and 1 patient had no further acute rejection episodes and stable renal function. Clinical practice guidelines suggest a lymphocyte-depleting agent such as antithymocyte globulin for severe, steroid-refractory or recurrent acute rejection cases.

    Intravenous infusion dosage (Thymoglobulin)
    Adults

    1.5 mg/kg/day IV for 7 to 14 days in conjunction with concomitant immunosuppression. Monitor T-cell counts (absolute or subsets) to assess T-cell depletion. Monitor white blood cell (WBC) and platelet counts to adjust dosage. For WBC count 2,000 to 3,000 cells/mm3 or platelet count 50,000 to 75,000 cells/mm3, reduce dosage by 50%. Consider discontinuing therapy if WBC count is less than 2,000 cells/mm3 or platelet count is less than 50,000 cells/mm3. Clinical practice guidelines suggest a lymphocyte-depleting agent such as antithymocyte globulin for severe, steroid-refractory or recurrent acute rejection cases.

    For kidney transplant rejection prophylaxis.
    Intravenous infusion dosage (Atgam)†
    Adults

    15 mg/kg/day IV given within 24 hours of the transplant, then once daily for 14 days. Then continue with every other day for a total of 21 doses in 28 days. Adult renal allograft patients have received 10 to 30 mg/kg/day. Usually, ATG is administered in combination with other immunosuppressive agents such as azathioprine and corticosteroids. In a study designed to reduce cost and total use of ATG, renal transplant patients were randomized to receive a fixed daily dose of ATG vs. a dose adjusted to keep the T-cell count less than 50 cells/microliter. The mean daily dose of ATG was substantially less, leading to cost savings and a reduction in thrombocytopenia and leukopenia in the study group. There was no significant difference in patient or graft survival at 6 months, 1 year, or 2 years between the 2 groups. Clinical practice guidelines suggest induction therapy with a lymphocyte-depleting agent such as antithymocyte globulin as part of the initial immunosuppressive regimen for those at high immunologic risk. However, lymphocyte-depleting agents do not prolong graft survival and are associated with a higher incidence of serious adverse effects.

    Children and Adolescents

    15 mg/kg/dose IV for 14 doses. In a retrospective, comparative study of data from 220 patients younger than 19 years of age, significantly more patients who received Atgam (mean 12.5 doses, range 1 to 21) had acute rejection (50%) as compared with patients who received Thymoglobulin (33%) 1.5 mg/kg/dose for 10 doses (mean 10 doses, range 6 to 15); all patients received prednisone, cyclosporine, and azathioprine or mycophenolate mofetil. The incidence of patient survival, graft survival, delayed graft function, or chronic rejection over the 3 years after transplantation did not differ significantly between the groups. Clinical practice guidelines suggest induction therapy with a lymphocyte-depleting agent such as antithymocyte globulin as part of the initial immunosuppressive regimen for those at high immunologic risk. However, lymphocyte-depleting agents do not prolong graft survival and are associated with a higher incidence of serious adverse effects.

    Intravenous infusion dosage (Thymoglobulin)
    Adults

    1.5 mg/kg/day IV with the first dose initiated prior to reperfusion of the donor kidney. The usual duration of administration is 4 to 7 days. Clinical practice guidelines suggest induction therapy with a lymphocyte-depleting agent such as antithymocyte globulin as part of the initial immunosuppressive regimen for those at high immunologic risk. However, lymphocyte-depleting agents do not prolong graft survival and are associated with a higher incidence of serious adverse effects.

    Children† and Adolescents†

    2.5 mg/kg/day IV up to 30 kg; 0.5 to 1 mg/kg/day IV after 30 kg (Max: 150 mg/day) IV until cyclosporine concentrations are therapeutic, at least 7 to 14 doses, in combination with corticosteroids, azathioprine and cyclosporine. The dosing interval was extended to 36 to 48 hours if prolonged graft dysfunction was noted. Doses were decreased by 50% for platelets less than 50,000/mm3 and held for platelets less than 25,000/mm3. In a retrospective, comparative study of data from 220 patients younger than 19 years of age, significantly more patients who received Atgam 15 mg/kg/dose for 14 doses (mean 12.5 doses, range 1 to 21) had acute rejection (50%) as compared with patients who received Thymoglobulin (33%) 1.5 mg/kg/dose for 10 doses (mean 10 doses, range 6 to 15); all patients received prednisone, cyclosporine, and azathioprine or mycophenolate mofetil. The incidence of patient survival, graft survival, delayed graft function, or chronic rejection over the 3 years after transplantation did not differ significantly between the groups. Clinical practice guidelines suggest induction therapy with a lymphocyte-depleting agent such as antithymocyte globulin as part of the initial immunosuppressive regimen for those at high immunologic risk. However, lymphocyte-depleting agents do not prolong graft survival and are associated with a higher incidence of serious adverse effects.

    For the treatment of patients with moderate to severe aplastic anemia who are not candidates for hematopoietic stem cell transplantation.
    NOTE: The usefulness of Atgam has not been demonstrated in patients who are suitable candidates for bone marrow transplantation or in patients with aplastic anemia secondary to neoplastic disease, storage disease, myelofibrosis, Fanconi's syndrome, or in patients known to have been exposed to myelotoxic agents or radiation.
    NOTE: Patients may need prophylactic platelet transfusions to maintain platelets at clinically acceptable concentrations.
    Intravenous infusion dosage (Atgam)
    Adults, Adolescents, and Children

    10 to 20 mg/kg/day IV infusion for 8 to 14 days, continuing with every-other-day dosing up to a total of 21 doses, if needed. When given in combination with cyclosporine and/or high-dose corticosteroids, ATG is given at doses of 10 to 15 mg/kg/day for 10 to 14 days. A high-dose ATG regimen (40 mg/kg/day for 4 days) in combination with cyclosporine resulted in a 78% response rate among patients who had not received previous therapy with ATG or cyclosporine. The majority of patients who relapsed responded to additional courses of immunosuppressive therapy. Actual survival at 1 and 2 years was 86% and 72%, respectively.

    Intravenous infusion dosage (Thymoglobulin)†
    Adults, Adolescents and Children

    In one study, patients not responding to horse-derived ATG were treated with rabbit-derived ATG 3.5 mg/kg/day IV infusion for 5 days, cyclosporine and G-CSF. The overall response was 77% (23 of 30 patients) after a median time of 95 days (range: 58 to 361 days). The overall survival rate was 93% with a median follow-up of 2.5 years.

    For the treatment of heart transplant rejection†.
    Intravenous dosage (Atgam)
    Adults

    10 mg/kg/day IV for 5 to 14 days along with corticosteroid, antihistamine, and antipyretic premedication.

    Intravenous dosage (Thymoglobulin)
    Adults

    0.75 to 1.5 mg/kg/day IV for 5 to 14 days along with corticosteroid, antihistamine, and antipyretic premedication.

    For heart transplant rejection prophylaxis†.
    Intravenous infusion dosage (Atgam)
    Adults

    In a prospective randomized study, OKT-3 was compared to horse-derived ATG, which was titrated between 2.5 to 15 mg/kg/day IV to achieve a daily CD2 lymphocyte count of approximately 100 cells/mm3. Following an initial ATG dose of 500 mg IV given prior to surgery, the average daily dose of ATG was 5.8 mg/kg/day. There was no difference in rejection rates, and adverse effects were more common with OKT-3. A retrospective review of prophylactic regimens in cardiac transplant patients reports the benefits to patients treated with ATG 10 mg/kg/day for 4 days followed by cyclosporine versus OKT-3 or Minnesota antilymphocyte globulin (ALG) based protocols. Induction with ATG may be beneficial for patients at high risk for acute rejection, but routine use of induction in all patients has not been shown to be superior to regimens without such therapy.

    Intravenous infusion dosage (Thymoglobulin)
    Adults

    125 mg IV over 8 hours once daily for 3 days following surgery in combination with azathioprine, corticosteroids and cyclosporine. This regimen was successful in suppressing T-lymphocytes in patients and the median actuarial survival was 85% one year after transplant. Induction with ATG may be beneficial for patients at high risk for acute rejection, but routine use of induction in all patients has not been shown to be superior to regimens without such therapy.

    For stem cell transplant preparation† prior to allogeneic stem hematopoietic stem cell transplantation (SCT).
    Intravenous infusion dosage (Atgam)
    Adults, Adolescents and Children

    90 mg/kg IV divided over 3 days (i.e., 30 mg/kg/day IV) in combination with cyclophosphamide followed by methotrexate and cyclosporine for graft-versus-host disease prophylaxis has shown to be well tolerated and effective. In 39 aplastic anemia patients treated with this regimen, the actuarial survival at 3 years was 92%. Acute graft-versus-host disease occurred in 15% and chronic graft-versus-host disease occurred in 34% of patients. Lower doses of ATG have been used (15 mg/kg/day IV for 4 days) in combination with cyclophosphamide with durable engraftment at 7 to 41 months of follow-up without significant graft-versus-host disease.

    Intravenous infusion dosage (Thymoglobulin)
    Adults

    The dose of rabbit ATG has not been determined. Studies have used 2 to 5 mg/kg/day IV for 4 to 5 days prior to matched-unrelated or T-cell depleted BMT with good survival and a decreased incidence of graft-versus-host disease. In general, GVHD is suppressed with low-dose rabbit ATG 2 to 2.5 mg/kg/day IV.

    Children

    Pediatric experience supports the use of conditioning regimens with up to 5 mg/kg/day IV for 5 days prior to BMT in patients with at least one antigen mismatch.

    For the treatment of myelodysplastic syndrome (MDS)†.
    Intravenous infusion dosage (Atgam)
    Adults

    Several small studies have been published reporting success in some patients with myelodysplastic syndromes. In one study, 25 patients were treated with ATG 40 mg/kg/day IV over 4 hours for 4 days in combination with prednisone. The overall survival at 38 months was 84% and 11 patients became independent of red cell transfusions. The median duration of response was 10 months with 64% of the responses maintained between 8 to 38 months. Responses were categorized as CR in 3, PR in 6, and a minimal response in 2. Most of the responders had refractory anemia.

    Intravenous infusion dosage (Thymoglobulin)
    Adults

    Of 20 patients with either refractory anemia or with refractory anemia with excess blasts, 6 had at least a partial response; 3 of the 6 had a complete response after rabbit ATG and cyclosporine started on day 4 to achieve a target serum concentration of 200 ng/mL. Only 1 of 9 patients had a response to ATG 10 mg/kg/day IV for 4 days whereas 5 of 11 patients had a response to ATG 20 mg/kg/day IV for 3 days. All 3 of the patients with a complete response were young (43 to 58 years) and had normal karyotypes, and 2 patients maintained complete remission; one at 42 months and one at 58 months.

    For the treatment of acute graft-versus-host disease (GVHD)† and graft-versus-host disease (GVHD) prophylaxis†.
    Intravenous infusion dosage (Atgam)
    Adults

    In a trial comparing induction therapy with ATG then maintenance treatment of cyclosporine with or without methylprednisolone as prophylaxis of graft-versus-host disease, patients were treated with ATG 15 mg/kg/day IV on days 1, 3, and 5 and cyclosporine was started on day 3 following the second dose of ATG. The ATG and cyclosporine combination provided effective therapy for acute graft-versus-host disease with long-term survival in 66% of patients with fewer side effects than those patients treated with methylprednisolone as well. These results are superior to the use of ATG, cyclosporine, or methylprednisolone alone. ATG (15 mg/kg IV twice a day for 5 days) in combination with corticosteroids was not associated with a significant improvement in response rate as compared to monotherapy with corticosteroids or anti-T cell immunotoxin. ATG is a common treatment of graft-versus-host disease that has failed to respond to initial therapy. Studies have not shown a benefit of monotherapy with ATG versus corticosteroids in delaying the onset or decreasing the severity of graft-versus-host disease.

    Intravenous infusion dosage (Thymoglobulin)
    Adults

    15 mg/kg given as 3.75 mg/kg IV on days -5, -4, -3, and -2 with cyclosporine and methotrexate before bone marrow transplantation from an unmatched donor led to significantly less grade 3 or 4 acute GVHD as compared with only receipt of cyclosporine and methotrexate. The incidence of acute GVHD among recipients of ATG 7.5 mg/kg did not differ significantly from patients who did not get ATG. Patients who got ATG 15 mg/kg had more fatal infections, but the transplant-related mortality and actuarial 1-year survival rates were similar as compared with patients who got no ATG. The impact of ATG on survival, transplant related mortality, and long-term risk of chronic GVHD and chronic lung dysfunction was determined from 75 patients who survived 100 days after transplantation. As compared with no ATG receipt, ATG recipients had significantly less chronic GVHD (60% versus 37%) and chronic lung disease (51% versus 19%). Further, actuarial 6-year survival was 31% and 44%, respectively.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    1.5 mg/kg/day IV for Thymoglobulin; 30 mg/kg/day IV for Atgam.

    Elderly

    1.5 mg/kg/day IV for Thymoglobulin; 30 mg/kg/day IV for Atgam.

    Adolescents

    Safe and effective use has not been established for Thymoglobulin; 25 mg/kg/day IV for Atgam.

    Children

    Safe and effective use has not been established for Thymoglobulin; 25 mg/kg/day IV for Atgam.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    Skin Test (Atgam)
    Skin testing is recommended to identify patients at greatest risk for anaphylaxis.
    A conservative, conventional approach is to use an epicutaneous (prick) test with undiluted Atgam. If the subject does not show a wheal 10 minutes after pricking, proceed to intradermal testing.
    Use an intradermal injection of 0.02 mL of a 1:1,000 dilution of Atgam in 0.9% Sodium Chloride Injection. A control of 0.9% Sodium Chloride Injection should be placed as well.
    Read the result at 10 minutes. A wheal at the Atgam site of 3 mm or more in diameter than that at the saline control site (or a positive prick test) suggests clinical sensitivity and an increased possibility of a systemic allergic reaction with intravenous administration. If the test is positive, consider alternative treatments. A risk to benefit ratio should be considered. If ATG is deemed appropriate to administer to a patient with a locally positive skin test, the presence of a physician who is familiar with the treatment of potentially life threatening allergic reactions is advised. Also, administer in a setting where intensive life support facilities are immediately available.
    Desensitization protocol: A 4 year-old, with an immediate 14 mm wheal and flare acute hypersensitivity reaction without wheezing or difficulty breathing after the skin test, successfully received 40 mg/kg/day IV of equine ATG for 4 days by gradual dose escalation. After treatment with diphenhydramine 1 mg/kg IV and methylprednisolone sodium succinate 2 mg/kg IV, he received equine ATG 0.1 mcg, 1 mcg, 10 mcg, and 100 mcg IV at 15 minute intervals; vital signs were checked before the first dose and every 5 minutes. An infusion of equine ATG 0.16 mg/minute IV over 10 minutes was administered; vital signs were continuously monitored. Over the next 4 days, he received 40 mg/kg IV equine ATG at a concentration of 1 mg/mL plus methylprednisolone sodium succinate 55 mg. Thirty minutes before each full dose, he was given acetaminophen 15 mg/kg and diphenhydramine 1 mg/kg. Infusion rate reduction from 69 mL/hour and diphenhydramine and acetaminophen administration resolved hypersensitivity reactions of shivering, wheals, and hives that occurred on days 1 and 2. The methylprednisolone dose was tapered over 2 weeks.

    Injectable Administration

    Only administer under the supervision of a physician experienced with immunosuppressive therapy. Patients receiving antithymocyte globulin (ATG) should be treated in facilities equipped and staffed with adequate medical and life-support equipment.
    Do not shake diluted or undiluted ATG because excessive foaming and/or denaturing of the protein may occur.
    Visually inspect the dilution for particulate matter and discoloration before administration. Atgam can be transparent to slightly opalescent, colorless to faintly pink or brown, and may develop a slight granular or flaky deposit during storage.

    Intravenous Administration

    Dilution (Atgam)
    Dilute Atgam in an inverted glass bottle of 0.9% Sodium Chloride Injection, 5% Dextrose and 0.225% Sodium Chloride Injection, or 5% Dextrose and 0.45% Sodium Chloride Injection so the undiluted solution does not contact the air inside. Add the total daily dose to the sterile vehicle. Gently rotate or swirl to mix; do not shake. The final concentration should not exceed 4 mg/mL.
    It is not recommended to use dextrose solutions to dilute Atgam, as the low salt concentration can cause precipitation.
    Store diluted solutions in the refrigerator. The total time in dilution should not exceed 24 hours including infusion time.
     
    Intravenous infusion (Atgam)
    Allow the infusion to come to room temperature prior to infusing.
    Infuse the first dose after negative skin test results obtained.
    Administer through a vascular shunt, arterial-venous fistula, or a high-flow central vein using an in-line 0.22- to 1-micron filter. Infuse over at least 4 hours.
    Closely observe the patient for any signs of an allergic reaction. Keep appropriate resuscitation equipment at the patient's bedside during the infusion.
     
    Reconstitution and Dilution (Thymoglobulin)
    Allow Thymoglobulin and diluent to come to room temperature prior to reconstituting the powder.
    Reconstitute each vial with 5 mL of Sterile Water for Injection. Gently rotate the vial until powder is dissolved; final concentration is 5 mg/mL. If particulate matter persists, discard the vial.
    Thymoglobulin may be diluted in 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
    Transfer the contents of the calculated number of Thymoglobulin vials into a bag of infusion solution. The recommended volume of infusion solution is 50 mL of infusion solution per each vial of drug. Final total volume of the diluted solution is typically 50 to 500 mL with a final concentration of 0.5 mg/mL. Mix the solution by inverting the bag gently once or twice. Do not shake.
    Infusion solutions should be used immediately; no preservatives are in the vials. Discard any unused drug.
     
    Intravenous infusion (Thymoglobulin)
    Skin testing is not recommended for Thymoglobulin.
    Premedication with corticosteroids, acetaminophen, and antihistamines 1 hour prior to each infusion is recommended and may reduce the incidence of infusion-related adverse reactions.
    Infuse the first dose over at least 6 hours into a high-flow vein using an in-line 0.22-micron filter. Subsequent doses should be infused over at least 4 hours.
    Closely observe the patient for any signs of an allergic reaction. Keep appropriate resuscitation equipment at the patient's bedside during the infusion.

    STORAGE

    Atgam:
    - Do not freeze
    - Refrigerate (between 36 and 46 degrees F)
    - Store diluted product in accordance with package insert instructions
    Thymoglobulin:
    - Discard unused portion. Do not store for later use.
    - Protect from freezing
    - Protect from light
    - Reconstituted product may be stored at room temperature for up to 24 hours but is not recommended
    - Reconstituted product should be used immediately. Discard unused portion
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Antithymocyte globulin (ATG) does not interfere with laboratory tests that do not use immunoglobulins. However, ATG may interfere with rabbit or equine antibody-based immunoassays and with crossmatch or panel-reactive antibody cytotoxic assays.

    Fungal infection, herpes infection, infection, lymphoma, neoplastic disease, requires an experienced clinician, varicella, viral infection

    Antithymocyte globulin (ATG) therapy requires an experienced clinician. Only clinicians experienced in immunosuppressant therapy and organ transplantation should use ATG. Increased susceptibility to infection and possible development of neoplastic disease, especially lymphoma, may result from combination immunosuppression. ATG (equine) therapy requires a specialized care setting. Patients receiving ATG should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services. Bacterial, viral, protozoal, or fungal infection occurs commonly during immunosuppressive therapy and can be fatal. Thymoglobulin is contraindicated in patients who have active acute or chronic infections that contraindicate any additional immunosuppression. Prophylactic antiviral therapy is recommended. One study has suggested an increased incidence of cytomegalovirus in patients receiving equine ATG. It may be possible to decrease this risk by decreasing the dose of other immunosuppressive agents administered concomitantly. Reactivation of a latent viral infection, especially herpes infection or varicella, can occur with immunosuppressive therapy. As with other products derived from or purified with human blood components, the possibility of transmission of infection exists in patients receiving ATG. Patients should be instructed to promptly report signs of infection.

    Acute bronchospasm, equine protein hypersensitivity, hypotension, leporine protein hypersensitivity, serious hypersensitivity reactions or anaphylaxis

    Due to the presence of animal proteins, there is a risk of serious hypersensitivity reactions or anaphylaxis, including cytokine release syndrome (CRS), with antithymocyte globulin (ATG). A skin test is recommended prior to therapy with Atgam but not Thymoglobulin. The predictive value of this test has not been determined and severe hypersensitivity reactions, including anaphylaxis, have occurred after a negative skin test. Patients should be monitored closely during ATG infusions and appropriate life-support equipment should be readily available. Monitor for signs of acute bronchospasm and hypotension, which may be signs of an anaphylactic reaction. Slowing the infusion rate may minimize infusion-associated reactions. Thymoglobulin is contraindicated in patients with previous leporine protein hypersensitivity (allergic reaction to rabbit proteins) or to any product excipients. Atgam is contraindicated in patients with a previous severe systemic reaction to the product or to any other equine gamma globulin preparation (equine protein hypersensitivity).

    Leukopenia, thrombocytopenia

    Antithymocyte globulin (ATG) may cause thrombocytopenia and/or leukopenia. Dosage adjustments are recommended for Thymoglobulin for platelet count less than 75,000/mm3 or white blood cell count less than 3,000/mm3. In renal transplant patients, discontinue Atgam for severe and unremitting leukopenia or thrombocytopenia.

    Vaccination

    When possible, administer any needed immunizations prior to transplantation. Live vaccines (e.g., intranasal influenza, MMR, varicella) should not be administered prior to, during, or after recently finished antithymocyte globulin therapy. Clinicians should consult the most recent Advisory Committee on Immunization Practices (ACIP) guidance on best practices for vaccination in patients with altered immunocompetence.

    Pregnancy

    Administer antithymocyte globulin (ATG) during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well controlled studies of ATG in pregnant women. It is not known if ATG can cause fetal harm if administered to a pregnant woman or if ATG affects reproductive capacity. At a dose up to 20 mg/kg, Atgam was not teratogenic in rats or monkeys; however, Atgam 20 mg/kg/day for 16 days during organogenesis was fetotoxic in monkeys. No maternal or fetal toxicity was observed with Atgam 10 mg/kg/day for 16 days during organogenesis.

    Breast-feeding

    It is not known if antithymocyte globulin (ATG) is excreted in breast milk. Because other immunoglobulins and many drugs are excreted into human breast milk and because of the potential for serious adverse reactions in the breast-feeding infant from ATG, discontinue breast-feeding or discontinue ATG taking into consideration the importance of the drug to the mother.

    Contraception requirements, reproductive risk

    It is not known if Thymoglobulin is associated with reproductive risk. Due to the lack of information on the risks associated with Thymoglobulin use during pregnancy, effective contraception is recommended during and for a minimum of 3 months after treatment. Discuss contraception requirements with the patient.

    Thromboembolic disease

    Coadministration (at the same time or nearly the same time) of belatacept and antithymocyte immune globulin in patients with thromboembolic disease or other predisposing risk factors for venous thrombosis of the renal allograft may pose a risk for venous thrombosis of the renal allograft. In postmarketing experience, venous thrombosis of the renal allograft has occurred in patients with other predisposing risk factors for venous thrombosis of the renal allograft when the initial doses of antithymocyte immune globulin and belatacept were coadministered as immunosuppressive induction.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 27.0-57.0
    serum sickness / Delayed / 0.6-2.0
    bradycardia / Rapid / 1.5-1.5
    anaphylactic shock / Rapid / 0-1.0
    seizures / Delayed / 0.8-0.8
    pleural effusion / Delayed / 0.8-0.8
    toxic epidermal necrolysis / Delayed / 0.2-0.2
    anaphylactoid reactions / Rapid / 0.2-0.2
    laryngospasm / Rapid / 0.2-0.2
    pulmonary edema / Early / 0.2-0.2
    serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    cytokine release syndrome / Rapid / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    post-transplant lymphoproliferative disorder (PTLD) / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    apnea / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    coagulopathy / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 68.0-78.0
    leukopenia / Delayed / 17.9-63.0
    thrombocytopenia / Delayed / 16.0-37.0
    hypertension / Early / 2.9-37.0
    constipation / Delayed / 15.0-33.0
    dyspnea / Early / 1.1-28.0
    anemia / Delayed / 12.0-25.0
    sinus tachycardia / Rapid / 1.1-23.0
    peripheral edema / Delayed / 20.0-20.0
    hypotension / Rapid / 2.9-16.0
    hyperlipidemia / Delayed / 15.0-15.0
    hypokalemia / Delayed / 6.0-12.0
    chest pain (unspecified) / Early / 2.7-9.0
    hyperphosphatemia / Delayed / 7.0-7.0
    candidiasis / Delayed / 6.0-6.0
    hypophosphatemia / Delayed / 6.0-6.0
    phlebitis / Rapid / 3.2-3.2
    lymphadenopathy / Delayed / 1.3-1.3
    elevated hepatic enzymes / Delayed / 1.0-1.0
    stomatitis / Delayed / 0.6-0.6
    hyperglycemia / Delayed / 0.6-0.6
    proteinuria / Delayed / 0.4-0.4
    dyskinesia / Delayed / Incidence not known
    flank pain / Delayed / Incidence not known
    hemolysis / Early / Incidence not known
    eosinophilia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    infusion-related reactions / Rapid / Incidence not known

    Mild

    infection / Delayed / 0-76.0
    chills / Rapid / 9.0-57.0
    fever / Early / 13.0-46.0
    headache / Early / 5.3-40.0
    abdominal pain / Early / 2.7-38.0
    nausea / Early / 4.2-37.0
    rash / Early / 13.0-25.6
    insomnia / Early / 12.0-20.0
    diarrhea / Early / 2.9-20.0
    vomiting / Early / 3.4-20.0
    arthralgia / Delayed / 14.0-17.2
    anxiety / Delayed / 7.0-14.0
    diaphoresis / Early / 6.0-13.0
    leukocytosis / Delayed / 13.0-13.0
    asthenia / Delayed / 0.4-13.0
    malaise / Early / 4.0-13.0
    acne vulgaris / Delayed / 12.0-12.0
    myalgia / Early / 11.0-11.0
    dyspepsia / Early / 10.0-10.0
    urticaria / Rapid / 9.2-9.2
    cough / Delayed / 7.0-7.0
    pruritus / Rapid / 4.6-6.0
    anorexia / Delayed / 6.0-6.0
    back pain / Delayed / 1.5-1.5
    dizziness / Early / 1.1-1.1
    night sweats / Early / 0.8-0.8
    agitation / Early / 0.4-0.4
    hiccups / Early / 0.4-0.4
    paresthesias / Delayed / 0.2-0.2
    tremor / Early / Incidence not known
    syncope / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    lethargy / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    epistaxis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abatacept: (Moderate) Concomitant use of immunosuppressives may potentially increase the risk of serious infection in abatacept treated patients. Advise patients taking abatacept to seek immediate medical advice if they develop signs and symptoms suggestive of infection.
    Adalimumab: (Moderate) The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with adalimumab may be at a greater risk of developing an infection. Many of the serious infections occurred in patients on immunosuppressive therapy that received adalimumab.
    Aldesleukin, IL-2: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Alefacept: (Contraindicated) Patients receiving other immunosuppressives should not receive concurrent therapy with alefacept; there is the possibility of excessive immunosuppression and subsequent risks of infection and other serious side effects. In clinical efficacy trials, concurrent treatment of alefacept with these types of agents did not occur. The duration of the period following treatment with alefacept that is appropriate before starting other immunosuppressive therapy has not been evaluated.
    Azelastine; Fluticasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Beclomethasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Belatacept: (Moderate) Coadministration at the same time or nearly the same time of belatacept and anti-thymocyte immune globulin in patients with other predisposing risk factors for venous thrombosis of the renal allograft may pose a risk for venous thrombosis of the renal allograft.
    Betamethasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Bortezomib: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive effects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects. Some protocols recommend decreasing the dosage of the standard immunosuppressive agents during treatment with antithymocyte globulin. Carefully observe patients for new adverse effects if the dose of immunosuppressants is reduced, as adverse effects of antithymocyte globulin may have been masked.
    Budesonide: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide; Formoterol: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Certolizumab pegol: (Moderate) The safety and efficacy of certolizumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with certolizumab may be at a greater risk of developing an infection. Many of the serious infections occurred in patients on immunosuppressive therapy who received certolizumab.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Ciclesonide: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Corticosteroids: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cortisone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Deflazacort: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Dexamethasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Fludrocortisone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flunisolide: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Salmeterol: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Vilanterol: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Formoterol; Mometasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Golimumab: (Moderate) The safety and efficacy of golimumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with golimumab may be at a greater risk of developing an infection.
    Hydrocortisone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Infliximab: (Moderate) Many serious infections during infliximab therapy have occurred in patients receiving concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposes patients to infections.
    Interferon Gamma-1b: (Moderate) Caution is advised with the concomitant use of antithymocyte globulin and interferon gamma-1b as an additive risk of bleeding may occur. Interferon gamma-1b can cause severe, reversible neutropenia and thrombocytopenia that may be dose-related.
    Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Methylprednisolone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Mometasone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Penicillamine: (Major) Agents such as immunosuppressives have adverse reactions similar to those of penicillamine. Concomitant use of penicillamine with these agents is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
    Platelet Inhibitors: (Moderate) An increased risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia, such as antithymocyte globulin. Platelet inhibitors should be used cautiously in patients with thrombocytopenia following the administration of antithymocyte globulin or other drugs that cause significant thrombocytopenia due to the increased risk of bleeding.
    Prednisolone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Prednisone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Rilonacept: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and immunosuppressives should be avoided. Concurrent administration of immunosuppressives with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving immunosuppressives may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of immunosuppressives prior to initiating therapy with sipuleucel-T.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Triamcinolone: (Moderate) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Upadacitinib: (Major) Do not use upadacitinib in combination with potent immunosuppressants such as anti-thymocyte immune globulin. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied.
    Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Administer antithymocyte globulin (ATG) during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well controlled studies of ATG in pregnant women. It is not known if ATG can cause fetal harm if administered to a pregnant woman or if ATG affects reproductive capacity. At a dose up to 20 mg/kg, Atgam was not teratogenic in rats or monkeys; however, Atgam 20 mg/kg/day for 16 days during organogenesis was fetotoxic in monkeys. No maternal or fetal toxicity was observed with Atgam 10 mg/kg/day for 16 days during organogenesis.

    It is not known if antithymocyte globulin (ATG) is excreted in breast milk. Because other immunoglobulins and many drugs are excreted into human breast milk and because of the potential for serious adverse reactions in the breast-feeding infant from ATG, discontinue breast-feeding or discontinue ATG taking into consideration the importance of the drug to the mother.

    MECHANISM OF ACTION

    Antithymocyte globulin (ATG) is a potent immunosuppressant. Although T-lymphocyte depletion is the primary means, the full mechanism by which ATG suppresses immune responses is not completely understood. ATG induces lymphocyte depletion in the periphery by complement-dependent cell lysis. Lymphocyte depletion may also result from antibody-mediated cytotoxicity and activation-induced apoptosis. T-cells are also depleted in secondary lymphoid tissues. Dose dependent depletion of CD2, CD3, CD4, CD8, CD20, and CD56 lymphocyte subsets has occurred. T-cell depletion is usually observed within a day following initiation. At certain concentrations, ATG may activate T-cells resulting in the synthesis of pro-inflammatory cytokines such as interleukin-2, interferon-gamma, and tumor necrosis factor-alpha. There appears to be a balance between the activating, co-activating, and inhibitory antibody specificities in ATG. Apoptosis in B-cell lineages, interference with dendritic cell function, and induction of regulatory T and natural killer cells has been observed. Additionally, equine ATG directly stimulates the growth of hematopoietic stem cells and the release of hematopoietic growth factors such as interleukin-3 and granulocyte/macrophage colony stimulating factor.

    PHARMACOKINETICS

    Antithymocyte globulin (ATG) is administered intravenously. Following administration, there is a short distribution phase that lasts approximately 8 hours. Reported mean elimination half-lives for rabbit IgG are 2 to 3 days after first dose and 35.5 days after a 10-day course. The elimination half-life for equine IgG is 5.7 +/- 3 days (range 1.5 to 13 days). Pharmacokinetic activity of the subset of IgG with relevant antilymphocyte activity within the antithymocyte globulin dose may exhibit different pharmacokinetic properties, perhaps partially arising from rapid elimination associated with antigen binding. Reductions in lymphocyte count begin within 24 hours after administration of rabbit antithymocyte globulin and absolute lymphocyte reductions have been demonstrated to persist for up to 1-year in renal transplant patients.

    Intravenous Route

    During treatment of acute renal allograft rejection, peak plasma concentrations of rabbit IgG of 87 mcg/mL (23 to 170 mcg/mL) after the last dose have been reported. Following doses of 10 to 15 mg/day, mean peak plasma equine IgG concentrations were 727 +/- 310 mcg/mL and weakly correlated to the total ATG dose.