Antithymocyte globulin (ATG [equine]) is an immunoglobulin-containing immunosuppressive agent.1, 2, 7, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 51, 52, 53, 54, 55, 83
Antithymocyte globulin equine (ATG [equine]) is used for the treatment of acute rejection in renal allograft recipients, usually as an adjunct to other immunosuppressive therapy (e.g., azathioprine, corticosteroids, graft irradiation).1, 2, 17, 18, 21, 30, 31, 32, 33, 34, 35 Adjunctive therapy with ATG (equine) successfully reverses most initial episodes of acute rejection in renal allograft recipients,17, 21, 30, 31, 32, 33, 34, 35 including a high percentage of episodes severe enough to require hemodialysis.30, 31, 32 Adjunctive therapy with ATG (equine) may also be effective for recurrent episodes of acute rejection.33, 34 In addition, adjunctive therapy with ATG (equine) may be effective for the treatment of acute rejection unresponsive to high-dose corticosteroid therapy.31, 35
Immunosuppressive therapy that includes ATG (equine) generally appears to reverse initial episodes of acute rejection an average of 2-3 days earlier than immunosuppressive therapy that does not include ATG (equine).17, 30, 32 Adjunctive therapy with ATG (equine) for the treatment of initial episodes of acute rejection also appears to reduce the incidence of recurrent rejection17, 31, 32, 33 and is generally associated with a reduced cumulative corticosteroid dosage in the posttransplantation period,17, 32, 34, 35 possibly resulting in part from its apparent effect on recurrent rejections.34 Immunosuppressive therapy that includes ATG (equine) for the treatment of acute rejection also appears to increase long-term graft survival rates compared with immunosuppressive therapy that does not include ATG (equine).30, 33, 35
ATG (equine) is used for the prevention of acute renal allograft rejection, 1, 2, 7, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 109 usually as an adjunct to other immunosuppressive therapy.
ATG (equine) is used with other immunosuppressive therapy (e.g., azathioprine, corticosteroids, graft irradiation) to prevent or delay the onset of renal allograft rejection.1, 2, 7, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 109 The incidence of initial episodes of acute rejection appears to be decreased7, 17, 19, 22, 25, 27 and the onset of these episodes delayed in patients receiving combined therapy with ATG (equine), azathioprine, and corticosteroids compared with those receiving immunosuppressive therapy without ATG (equine).7, 17, 19, 20, 21, 23, 27 In addition, combined therapy with ATG (equine) may reduce the corticosteroid dosage necessary in the immediate posttransplantation period,7, 17, 20, 22, 23 and some data suggest that initial episodes of acute rejection may be substantially less severe in patients treated with ATG (equine).21, 26
Prophylactic immunosuppressive therapy that includes ATG (equine) may reduce the incidence and delay the onset of initial episodes of acute rejection, but improved renal allograft survival with such therapy has not been consistently demonstrated.1, 2, 7, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 109 Results of initial studies were generally inconclusive or conflicting,7, 17, 20, 23, 25, 26 but several recent studies that generally used higher dosages of ATG (equine) and more prolonged therapy (including the currently recommended dosage regimen) suggest that combined therapy with ATG (equine), azathioprine, and corticosteroids increases graft survival rates compared with immunosuppressive therapy without ATG (equine).17, 19, 20, 21, 22, 24, 27, 109 Further study is needed to determine the optimum dosage and duration of prophylactic ATG (equine) therapy.19, 20 Many factors, including variability among individual lots of ATG (equine), the number of patients studied and type of allograft received, and low dosage regimens used in early studies have made evaluation difficult, and the effect of prophylactic ATG (equine) on long-term graft survival remains to be clearly determined.7, 18, 19, 20, 21, 22, 23, 24, 25, 27 Data from a retrospective study suggest that the effect of ATG (equine) on renal allograft survival does not differ from that of ATG (rabbit).28 The relative effects of prophylactic immunosuppressive regimens containing cyclosporine and/or ATG (equine) on graft survival rates remain to be determined.29, 85 Results of several comparative studies indicate that the effects on graft survival rates of prophylactic immunosuppressive regimens containing equine antilymphocyte globulin (ALG) or cyclosporine are similar.110, 111, 112 Prophylactic immunosuppressive therapy that includes ATG (equine) does not appear to increase long-term patient survival rates compared with immunosuppressive therapy that does not include ATG (equine).7, 17, 21, 23, 27, 109
Despite the apparent beneficial effects of prophylactic ATG (equine) in preventing or delaying acute rejection episodes in some patients, many clinicians generally reserve ATG (equine) for the treatment of acute rejection since a beneficial effect on long-term graft survival with prophylactic ATG (equine) is not clearly established and the associated risks of the drug are thereby avoided in patients in whom rejection episodes would not occur.18, 30, 31, 32, 33, 34, 35 Prophylactic use of ATG (equine), however, is generally recommended in patients in whom complications (e.g., GI bleeding) necessitate rapid reduction of corticosteroid dosage or in those in whom oliguria secondary to rejection would be particularly detrimental to the allograft (e.g., patients with primary hyperoxaluria).33
ATG (equine) is used for the treatment of moderate to severe aplastic anemia in patients not considered suitable candidates for bone marrow transplantation.1, 36, 37, 38, 39, 40, 41, 42, 43, 91, 93, 94, 107, 108, 114 When combined with conventional supportive therapy in patients with aplastic anemia, ATG (equine) may induce a partial or complete hematologic remission.1, 40, 41, 43, 85, 107, 108 In a well-controlled study, ATG (equine) produced a substantially higher hematologic response rate (as determined by sustained increases in peripheral blood cell counts and decreased transfusion requirements) at 3 months when compared with conventional supportive therapy alone.1, 37 Results of this study37 and several uncontrolled studies36, 38, 39, 40, 41, 91, 93, 107, 108, 114 suggest that ATG (equine) produces a hematopoietic response of sufficient degree to obviate transfusions in about 40-50% of patients;36, 37, 38, 39, 40, 41, 91, 93, 107, 108, 114 many of these patients have an essentially complete hematologic recovery.40, 41, 43, 85, 107, 108 In patients who respond, improvement in peripheral blood cell counts usually is not evident for 1-3 months or longer after beginning treatment with ATG (equine).36, 37, 38, 39, 41, 91, 93, 107, 114 Patients with aplasia of longer than 9-months' duration may be less likely to respond to ATG (equine) than those with disease of shorter duration.37 It has not been clearly established whether ATG (equine) therapy prolongs survival in patients withaplastic anemia,37, 39, 41, 91 but patients treated with ATG (equine) and supportive therapy (sometimes combined with bone marrow infusion and/or androgens) generally have a 1-year survival rate of about 60-70%;1, 37, 38, 41, 91, 107, 108 historical data indicate that the 1-year survival rate is about 25% in patients receiving conventional supportive therapy alone.1 Combined ATG (equine) and androgen therapy does not appear to be more effective than ATG (equine) alone;85, 91, 94 results of one well-controlled study indicate that combined therapy does not increase response rate or improve survival compared with ATG (equine) alone.94 Combined therapy with ATG (equine), androgens, and HLA-haploidentical bone marrow infusion does not appear to be more effective than combined therapy with ATG (equine) and androgens.43
Further studies are needed to fully evaluate the role of ATG (equine) in the treatment of aplastic anemia.36, 37, 39, 41, 44, 85, 107, 108, 114 Most clinicians currently recommend that ATG (equine) therapy be administered to patients who lack an HLA-identical sibling donor for bone marrow transplantation37, 44, 85 and to patients older than 50 years of age in whom transplantation is generally not performed (even if an HLA-identical sibling donor is available).44, 85 In patients younger than 20 years of age with an HLA-identical sibling donor, bone marrow transplantation is the preferred therapy.44, 85, 107 There is considerable diversity of opinion regarding the relative value and roles of ATG (equine) therapy and bone marrow transplantation in patients 20-50 years of age, and management of these patients must be individualized;37, 44, 85, 107, 108 additional studies may clarify optimum therapy for subgroups of patients within this age group.37, 44, 85, 107 The safety and efficacy of ATG (equine) have not been fully evaluated in patients with aplastic anemia secondary to neoplastic disease, storage disease, myelofibrosis, Fanconi's syndrome, or exposure to myelotoxic agents or radiation.1
Bone Marrow Allotransplantation
The value and role, if any, of the commercially available ATG (equine) in the prevention of acute graft-vs-host disease following bone marrow transplantation† remain to be established.45, 46, 47, 85, 95 Results of studies to date suggest that prophylactic combination therapy with methotrexate and ATG (equine) is not more effective than methotrexate alone for the prevention or amelioration of acute graft-vs-host disease and does not improve survival compared with methotrexate alone;45, 46, 47 however, some clinicians have suggested that the inability to demonstrate additional benefit with ATG (equine) may have been related to several factors, including the dosage and schedule of administration of the drug.46, 96 ATG (equine) has been used with some success for the treatment of moderate to severe, acute graft-vs-host disease following bone marrow transplantation†.45, 50 ATG (equine) therapy ameliorates some of the manifestations of acute graft-vs-host disease, particularly those involving the skin, and appears to be as effective as corticosteroid therapy, although corticosteroid-treated patients may respond more rapidly.50 Corticosteroids are generally considered the initial therapy of choice for the treatment of acute graft-vs-host disease.50, 85, 97
ATG (equine) has been used in immunosuppressive combination regimens for the treatment of chronic graft-vs-host disease†, but its role and value, if any, for this condition have not been established95, 98
In the management of extensive, full-thickness burns, ATG (equine) is effective in preventing rejection of skin allografts† until replacement with autogenous skin grafts is feasible.51, 52, 53, 84 Although this use of ATG (equine) has been evaluated in only a limited number of patients (principally children), some clinicians consider ATG (equine) the immunosuppressive drug of choice.51, 52, 53 During ATG (equine) therapy, about 90-95% of skin allografts generally remain functional as effective skin until excised and replaced with autogenous grafts, although the extent of allograft survival varies depending on the anatomic area grafted.52, 53 Following discontinuance of ATG (equine) therapy, allograft rejection occurs routinely and generally becomes evident within 10-14 days.52, 53 Since the allografts are purposefully excised and replaced with autogenous grafts, the maximum duration of allograft survival with ATG (equine) therapy has not been determined.52, 53 In most patients, allograft survival is regularly maintained with ATG (equine) therapy for the 40-60 days necessary to achieve adequate coverage with autogenous grafts.52, 53, 84 In the management of a limited number of patients with extensive, full-thickness burns, use of ATG (equine) to extend skin allograft survival until adequate coverage with autogenous grafts is achieved has been associated with a patient survival rate of greater than 50%.52, 53
ATG (equine) has been used with some success as a component of immunosuppressive regimens for the prevention and/or management of rejection of cardiac allografts†, but its exact role has not been clearly established.54, 55, 99 Some clinicians use short courses of ATG (equine) in preventive regimens.55, 99 Other clinicians prefer ATG (rabbit) to ATG (equine) because of its apparent increased efficacy, and use ATG (equine) in cardiac transplantation only for the treatment of acute rejection episodes unresponsive to high-dose corticosteroids56, 100 and in the management of combined heart-lung transplantation†.101
ATG (equine) has produced partial responses of brief duration in several patients with refractory advanced non-Hodgkin's lymphomas†57, 58, 59 or cutaneous T-cell lymphomas†, 57, 60, 61 including Sézary syndrome57, 60 and mycosis fungoides.60, 61 Further studies are needed to evaluate the role of ATG (equine), if any, in the treatment of these tumors.57, 58, 59, 60
ATG (equine) was reportedly effective for the treatment of agranulocytosis† that was unresponsive to corticosteroids and other immunosuppressive therapy in a 15-year-old patient with a history of autoimmune disease.62 ATG (equine) therapy restored blood neutrophil counts to within normal limits in this patient, but prolonged therapy (almost 2 years) was required to maintain normal neutrophil counts, after which ATG (equine) was gradually discontinued and was no longer necessary (the patient received a total ATG (equine) dose of more than 100 g over a 30-month period).62 Because of this patient's response, some clinicians suggest that a trial of ATG (equine) therapy may be indicated in selected patients with severe neutropenia in whom autoimmune mechanisms may be involved.62 ATG (equine) was also reportedly effective for the treatment of pure red cell aplasia† characterized by erythropoietic maturation arrest, suggesting that the drug may be useful for the management of patients with pure red cell aplasia and evidence of an underlying immune disorder102
ATG (equine) may be potentially useful for the treatment of other conditions that have an immunologic basis† (e.g., multiple sclerosis),63, 64 but additional study is needed to determine the usefulness of the drug in these conditions.
Antithymocyte globulin (equine) (ATG [equine]) is administered by slow IV infusion.1, 2 Intradermal sensitivity testing is recommended in all individuals prior to administration of the initial dose of ATG (equine) .1, 2 (See Dosage and Administration: Intradermal Sensitivity Testing.)
ATG (equine) concentrate for injection must be diluted prior to IV infusion .1, 2 For IV infusion, the required dose of ATG (equine) should be diluted in 0.45 or 0.9% sodium chloride injection1, 2 (usually 250-1000 mL);7, 23, 27, 30, 34, 35, 37, 45, 46, 47, 50 the final concentration preferably should not exceed 4 mg of equine IgG per mL.1, 2 The use of dextrose injections or highly acidic infusion solutions is not recommended.1, 2 (See Chemistry and Stability: Stability.) The IV infusion solution container into which ATG (equine) concentrate is added should be inverted to prevent contact of undiluted ATG (equine) with air inside the container.1, 2 Following addition of ATG (equine) to the IV infusion solution, the container should be gently rotated or swirled to thoroughly mix the resultant solution; ATG (equine) concentrate for injection and diluted solutions of the drug should not be shaken since excessive foaming and/or denaturation of the protein may occur. The manufacturer recommends that diluted solutions of ATG (equine) be refrigerated at 2-8°C if administration is delayed and that the solutions not be used after a period of 24 hours (including actual infusion time), even if stored at 2-8°C.1, 2
Patients should be observed continuously throughout IV infusion of ATG (equine) for possible allergic reactions, during both the initial and any subsequent course(s) of therapy.1, 2 (See Cautions: Precautions and Contraindications.) To prevent or minimize febrile reactions, patients are usually pretreated with an antipyretic (e.g., 650 mg acetaminophen orally), antihistamine (e.g., 25-50 mg diphenhydramine hydrochloride orally), or corticosteroid (e.g., 25-50 mg hydrocortisone IV) or some combination of these agents.1, 23, 30, 33, 34, 35, 37, 43 ATG (equine) infusions may be administered via a high-flow central vein, a vascular shunt, or an arteriovenous fistula (e.g., Brescia-Cimino fistula); administration via high-flow veins is recommended to minimize the risk of phlebitis and thrombosis.1, 2, 23 Inline filters should be used with all IV infusions of ATG (equine) to prevent inadvertent administration of any insoluble material that may develop during stora 1, 2 filters with a pore size of 0.2-1 µm have generally been used,1, 2 but 5-µm filters have also been employed.85 The required dose of ATG (equine) should be infused over at least 4 hours1, 2 (usually 4-8 hours).23, 27, 30, 34, 45, 46, 47, 50 ATG (equine) concentrate for injection and the diluted solution for infusion should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1, 2
Dosage of ATG (equine) is expressed in terms of equine IgG.1, 2
Monitoring peripheral blood levels of rosette-forming cells (RFCs) during ATG (equine) therapy in allograft recipients has been used by some clinicians to determine the degree of immunosuppression attained and to guide dosage adjustment, with ATG (equine) dosage adjusted to maintain the level of RFCs at about 10% of the pretreatment level;22, 23, 32, 77 however, other clinicians have questioned the reliability and value of this method.71, 78 The availability of monoclonal antibodies has allowed monitoring of specific T-cell subsets,79, 80 and some clinicians currently monitor peripheral blood levels of OKT3-reactive cells as a method for guiding dosage adjustment, with ATG (equine) dosage adjusted to maintain the level of OKT3-reactive cells at about 10% of the pretreatment value.80
For the prevention and/or treatment of renal allograft rejection, ATG (equine) is usually administered concomitantly with other immunosuppressive therapy (e.g., azathioprine, corticosteroids, graft irradiation).1, 2, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 30, 31, 32, 33, 34, 35 Dosages of ATG (equine) have ranged from 10-30 mg/kg daily in adults and 5-25 mg/kg daily in a limited number of children.1, 2
For the prevention of renal allograft rejection in adults and children, it is recommended that ATG (equine) be given in a fixed dosage of 15 mg/kg daily for 14 days, followed by alternate-day therapy with the same dosage for another 14 days (a total of 21 doses in 28 days).1, 2 The first dose of ATG (equine) should be administered within 24 hours before or after transplantation.1, 2
For the treatment of acute renal allograft rejection in adults and children, the recommended dosage of ATG (equine) is 10-15 mg/kg daily for 14 days; if necessary, this may be followed by alternate-day therapy with the same dosage for up to another 14 days (i.e., up to a total of 21 doses in 28 days).1, 2 Therapy with ATG (equine) should be initiated when the initial episode of acute rejection is diagnosed.1, 2
The manufacturer states that the total number of ATG (equine) doses (10-20 mg/kg per dose) that can be administered safely to an individual patient has not been determined to date.1, 2 Some renal allograft recipients have received up to 50 doses in 4 months and others have received up to four 28-day courses of 21 doses each for the management of acute rejection, without an increased incidence of adverse effects.1, 2
For the treatment of aplastic anemia, the usual dosage of ATG (equine) is 10-20 mg/kg daily for 8-14 consecutive days,1, 36, 37, 41, 91, 103, 104, 107 followed by alternate-day therapy with the same dosage for up to another 14 days if necessary (i.e., up to a total of 21 doses in 28 days).1, 41, 91 These dosages also have been used safely in children with aplastic anemia.1 Because thrombocytopenia occurs in many patients receiving ATG (equine) for the treatment of aplastic anemia, prophylactic platelet transfusions may be necessary to maintain platelet counts at clinically acceptable levels during therapy with the drug.1
Bone Marrow Allotransplantation
Although its value has not been established, ATG (equine) has been given in a dosage of 7 or 10 mg/kg every other day for 6 doses for the prevention of acute graft-vs-host disease following bone marrow transplantation†.45, 46, 47
For the treatment of moderate to severe, acute graft-vs-host disease following bone marrow transplantation†, ATG (equine) has been given in a dosage of 7 mg/kg every other day for 6 doses.45, 50
When used in the management of extensive, full-thickness burns to extend skin allograft survival† until adequate coverage with autogenous grafts is achieved, ATG (equine) has been given in an initial dose of 10 mg/kg 24 hours before the first allograft is performed; subsequently, the dose and frequency of administration were adjusted to maintain the level of RFCs at about 10% of the pretreatment level.51, 52, 84 The usual maintenance dosage is 10-15 mg/kg every other day,84 but dosage is extremely variable and dosages ranging from 5 mg/kg every other day to up to 40 mg/kg daily have been used.51, 52, 84 ATG (equine) therapy is discontinued when allografts cover less than 20% of the total body surface area, which usually requires 40-60 days of treatment.52, 53, 84
Intradermal Sensitivity Testing
Because of the risk of a severe systemic reaction (e.g., anaphylaxis), an intradermal skin test is strongly recommended by the manufacturer prior to administration of the initial dose of ATG (equine).1, 2 The skin test procedure consists of intradermal injection of 0.1 mL of a 1:1000 dilution of ATG (equine) concentrate for injection in 0.9% sodium chloride injection (5 mcg of equine IgG); only freshly diluted ATG (equine) should be used.1, 2 A control test using 0.9% sodium chloride injection should be administered contralaterally to facilitate interpretation of the results.1, 2 The patient and the skin test site should be observed every 15-20 minutes during the first hour following intradermal injection of the drug for the appearance of a positive reaction,1, 85, 86 and patients should be questioned about the occurrence of any systemic manifestations.85 A positive skin test reaction consists of a wheal and/or area of erythema 10 mm or more in diameter, with or without pseudopod formation, and itching or marked local swelling.1, 2 If the intradermal skin test is positive, serious consideration should be given to alternative forms of therapy, and the risk of administering ATG (equine) must be weighed against the risk of withholding the drug.1 If therapy with ATG (equine) is considered appropriate following a positive reaction to the skin test, the drug should be administered only in a setting in which facilities for intensive life support are immediately available and in which a clinician familiar with the management of potentially life-threatening allergic reactions is in attendance.1 A systemic reaction to the skin test such as generalized rash, tachycardia, dyspnea, hypotension, or anaphylaxis usually precludes further administration of the drug .1, 2, 85 (See Cautions: Precautions and Contraindications.) The predictive value of the ATG (equine) skin test has not been clearly established, and the absence of a reaction to a properly performed skin test does not preclude the possibility of an immediate sensitivity reaction.1, 2 Allergic reactions including anaphylaxis have been reported in patients with negative skin test results.1 Precautions must always be taken to treat a severe systemic reaction if it occurs.1, 2 (See Cautions: Precautions and Contraindications.)
Although many adverse effects have been reported during therapy with ATG (equine), it should be considered that patients receiving ATG (equine) for the prevention and/or treatment of renal allograft rejection usually are receiving other immunosuppressive therapy (e.g., azathioprine, corticosteroids) concomitantly and those receiving ATG (equine) for the treatment of aplastic anemia usually are receiving conventional supportive therapy (e.g., transfusions, corticosteroids, anti-infective agents, antihistamines) concomitantly.1, 2
Fever, which is frequently accompanied by chills and which may be marked, is the most common adverse effect of ATG (equine).1, 2, 7, 19, 22, 23, 33, 35, 37, 38, 39, 45, 46, 50, 52 The manufacturer states that fever and chills occur in 51 and 16% of patients, respectively,1 but many reports suggest that these reactions occur in a majority of patients receiving the drug.35, 37, 39, 46, 50, 114 The exact mechanism of the febrile reaction is not known, but ATG (equine) may cause the release of endogenous leukocyte pyrogens.1, 2 Febrile reactions tend to decrease in severity after the first few doses of the drug.19, 45, 46, 52 Febrile reactions are generally readily controlled with antipyretics, antihistamines, or corticosteroids or combinations of these agents.1, 2, 23, 30, 33, 34, 35, 37, 43 To prevent or minimize febrile reactions, patients are usually pretreated with antipyretics and/or antihistamines1, 30, 33, 35, 37, 43 and, in some cases, also with corticosteroids;1, 33, 34, 37 corticosteroids are sometimes reserved for the treatment of severe reactions37, 43 and then subsequently used in pretreatment regimens.37
Leukopenia1, 2, 7, 19, 32, 35 and thrombocytopenia1, 2, 7, 17, 19, 23, 33, 35 generally occur in about 14 and 30% of patients receiving ATG (equine), respectively,1, 2, 7, 17, 19, 23 although these adverse hematologic effects have been reported to occur more frequently in some studies.33, 35 Leukopenia and particularly thrombocytopenia appear to occur more frequently in patients with aplastic anemia treated with ATG (equine).37, 39, 43, 85 ATG (equine) decreases the number of circulating lymphocytes in renal allograft recipients,1, 2, 7 but severe lymphopenia generally does not occur;1, 2 in patients with aplastic anemia, ATG (equine) often produces alymphocytosis within 24 hours after administration.85 In renal allograft recipients, thrombocytopenia induced by ATG (equine) is usually transient1, 2, 23 and platelet count generally returns to adequate levels without discontinuing ATG (equine) and without platelet transfusions;1, 2, 7, 23, 33 however, dosage reduction may occasionally be required.33 In patients with aplastic anemia, platelet transfusions are frequently required during administration of ATG (equine).37, 39, 43, 85, 107, 114 Severe and unremitting leukopenia and/or thrombocytopenia in renal allograft recipients requires discontinuance of ATG (equine);1, 2 in patients with aplastic anemia, severe leukopenia and/or thrombocytopenia are managed with blood component transfusions37, 39, 43, 85, 107, 114 and ATG (equine) is usually not discontinued.85
Anemia has occurred in humans10 and animals receiving ATG (equine).1, 2 (See Pharmacology: Hematologic Effects.) Clinically important hemolysis and resultant hemolytic anemia induced by ATG (equine) have occurred rarely in humans.1, 2 ATG (equine)-induced hemolysis may be indicated by pain in the chest, flank, or back, but is usually detected only by laboratory monitoring.1, 2 Appropriate therapy of ATG (equine)-induced hemolysis may include red blood cell transfusions and, if necessary, administration of IV mannitol, furosemide, sodium bicarbonate, and fluids.1, 2 Severe and unremitting hemolysis may require discontinuance of ATG (equine) therapy.1, 2
Other adverse hematologic effects that have occurred in patients receiving ATG (equine) therapy include aplasia, pancytopenia, neutropenia, granulocytopenia, eosinophilia, and epistaxis.1
Sensitivity and Serum Sickness Reactions
Anaphylaxis occurs in less than 1% of patients receiving ATG (equine).1, 2, 30 Anaphylaxis may occur at any time during ATG (equine) therapy and may be indicated by hypotension, respiratory distress, or pain in the chest, flank, or back.1, 2 If anaphylaxis or any of these other symptoms occurs, IV infusion of ATG (equine) should be discontinued immediately and the patient given appropriate therapy.1, 2 The manufacturer recommends that anaphylaxis be managed with epinephrine, corticosteroids, assisted respiration, and other supportive measures.1, 2 If respiratory distress persists after discontinuance of an ATG (equine) infusion, an antihistamine, epinephrine, or a corticosteroid or some combination of these agents should be administered.1, 2 If hypotension occurs, vasopressor therapy may be necessary to stabilize blood pressure.1, 2
Serum sickness reactions have occurred in patients receiving ATG (equine).1, 17, 35, 37, 38, 42, 47, 65, 66, 103, 104, 115 The manufacturer states that serum sickness reactions have been reported in 5-10% of renal allograft recipients receiving ATG (equine);1 however, the actual incidence of serum sickness reactions in these patients is not known, in part because of the difficulty in diagnosing the reaction in these patients.17, 35, 65 Serum sickness reactions have occurred in a high percentage (up to 85-100%)37, 103, 104, 115 of patients receiving the drug for the treatment of aplastic anemia.37, 38, 42, 103, 104, 115 Serum sickness reactions may occur during ATG (equine) therapy or following discontinuance of the drug,17, 37, 65 but generally develop within 6-18 days after initiation of therapy.37, 65, 103, 104, 115 The diagnosis of serum sickness associated with ATG (equine) is usually made on a clinical basis,17, 23, 35, 37, 42, 65, 103, 115 with the patient manifesting signs and symptoms such as fever, malaise, arthralgia, nausea and vomiting, lymphadenopathy, and cutaneous eruptions.103, 115 The adverse dermatologic effects may be particularly useful for diagnosing ATG (equine)-induced serum sickness reactions.103, 115 The most common type of rash appears to be a morbilliform eruption that tends to begin on the trunk and then spreads to the extremities; the rash may become generalized and may be accompanied by urticarial lesions.103, 115 The morbilliform eruption appears initially in the periumbilical region, groin, and axillae, with the lesions beginning as asymptomatic faint pink macules.115 The lesions rapidly become erythematous and often become confluent, resulting in an almost complete erythroderma of the trunk; in patients with low platelet counts, erythema may be rapidly replaced by purpura in the same physical distribution.115 The lesions occur predominantly along the spine; when the extremities are involved, the legs are usually more severely affected than the arms.115 In some patients, erythema of the palms and soles may be evident.115 Urticarial lesions may be widespread, with large plaques involving the trunk and extremities115 Urticarial eruptions usually subside within several hours after administration of an antihistamine and/or after infusion of ATG (equine) is completed; however, these lesions often recur during subsequent infusions of the drug.115 In addition, many patients with ATG (equine)-induced serum sickness may initially develop a serpiginous band of progressing erythema along the sides of the hands, fingers, feet, and toes at the margin of the palmar or plantar skin; in many of these patients, particularly those with low platelet counts (e.g., patients with aplastic anemia), the erythema may be replaced by petechiae or purpura in the same physical distribution.103, 115 Although the efficacy is not clearly established,85, 103, 104 corticosteroids are commonly administered prophylactically and for the treatment of ATG (equine)-induced serum sickness reactions.1, 37, 38, 42, 65, 85, 103, 104, 114, 115 The manufacturer states that serum sickness reactions in patients with aplastic anemia generally resolve promptly following oral or IV corticosteroid therapy; long-term sequelae in such patients have not been reported to date.1
When ATG (equine) is administered with other immunosuppressive therapy, the formation of anti-ATG antibody is generally believed to be minimal;1, 2, 17, 23, 32 however, substantial titers of anti-ATG antibody have been documented with the use of sensitive assays in some patients receiving the drug.65, 66 In some patients, serum sickness reactions have been temporally associated with anti-ATG antibody titers,65 increased levels of circulating immune complexes,103 and decreased levels of complement,103 and confirmed by detection of equine immunoglobulin deposits in kidney and lung tissues65 and immune deposits in the blood vessels of skin lesions.103, 115 Serologic testing using sensitive assays may be potentially useful for diagnosing ATG (equine)-induced serum sickness reactions and as a screening method to avoid possible reactions, but further study is needed.65
Because ATG (equine) has immunosuppressive effects, local and systemic infections or infectious complications may occur in patients receiving the drug.1, 2, 22, 23, 24, 25, 26, 33, 35, 46, 47, 50, 67, 68, 69, 70 Generally, immunosuppressive therapy that includes ATG (equine) does not appear to be associated with an increased incidence of bacterial, fungal, or viral infections compared with immunosuppressive therapy that does not include ATG (equine);1, 22, 25, 26, 46, 47, 50, 69 however, a tendency for immunosuppressive therapy that includes ATG (equine) to be associated with increased susceptibility to viral infections and complications has been noted.22, 23, 67, 68, 70 ATG (equine) therapy may result in reactivation of or infection with cytomegalovirus,1, 67, 68, 69 herpes simplex virus33, 35, 67 (particularly labial infections),33 or Epstein-Barr virus (EBV).70 An increased incidence of cytomegalovirus viremia and clinical syndromes has been associated with immunosuppressive therapy that included ATG (equine);1, 67, 68 this may have been related to the degree of immunosuppression attained,1, 68, 69 since an increased incidence of these effects in renal allograft recipients reportedly does not occur when ATG (equine) is combined with reduced dosages of azathioprine and corticosteroids.69 Immunosuppressive therapy that included ATG (equine) has also been associated with increased shedding of EBV in the oropharynx and with increases in antibody titers (4-fold or greater) to some EBV-related antigens;70 like the effects on cytomegalovirus, the effects of ATG (equine) on EBV may be related to the degree of immunosuppression attained with combined therapy.70 Viral hepatitis also has been reported in patients receiving ATG (equine).1
Dermatologic and Local Effects
Adverse dermatologic effects occur in 10-27% of patients receiving ATG (equine) and may include rash1, 2, 7, 37 (e.g., morbilliform),103, 115 pruritus,1, 2, 7, 17, 23, 35 erythema,17, 23, 35, 37, 39 urticaria,1, 2, 7, 23, 37, 39 and/or wheal and flare.1, 2, 7 Patients with ATG (equine)-induced serum sickness reactions may exhibit characteristic adverse dermatologic effects.103, 115 (See Cautions: Sensitivity and Serum Sickness Reactions.) Pruritus and erythema are generally relieved by antihistamine therapy.1, 2, 17, 23 Toxic epidermal necrosis1, 2, 22 and wound dehiscence1, 2 have occurred in less than 1% of patients.1, 2
In addition to adverse local dermatologic effects (e.g., urticaria, erythema, wheal and flare), pain, swelling, or erythema at the injection site;1, 2, 7 local thrombophlebitis1, 2, 7, 17, 23, 35 (particularly with the use of small peripheral veins);23 and clotted fistulas or shunts1, 2, 7 have occurred in about 2-5% of patients receiving ATG (equine).1, 2, 7, 17, 23, 35 In monkeys, thrombus formation occurred frequently along the route of ATG (equine) infusion (e.g., saphenous and femoral veins); however, the occurrence of disseminated intravascular coagulation was not observed in these animals, and the frequency of thrombus formation was decreased when ATG (equine) was infused via inline filters.1, 2 In humans, administration of ATG (equine) via high-flow veins is recommended to minimize the risk of phlebitis and thrombosis.1, 2, 23
Other adverse effects of ATG (equine) have been reported infrequently.1, 2 Adverse cardiovascular effects have included hypotension1, 2, 7, 37, 39, 47, 107 (which may be transient37, 107 or occasionally may require vasopressor therapy1, 2 ), hypertension,1, 2 tachycardia,1, 2, 7 congestive heart failure,1 edema,1, 2 pulmonary edema,1, 2 iliac vein obstruction,1, 2 and renal artery thrombosis.1, 2 Bradycardia,1 myocarditis,1 and cardiac irregularity1 also have occurred in patients receiving the drug.
Adverse GI effects may include diarrhea,1, 2 nausea and/or vomiting,1, 2, 7, 46, 50, 103 stomatitis,1, 2 sore mouth and/or throat, GI bleeding or perforation,1 hiccups,1, 2 abdominal distention,39 and epigastric, gastric, or abdominal pain.1, 2 Adverse musculoskeletal effects associated with ATG (equine) therapy include arthralgia,1, 2, 7, 22, 32, 39, 114 joint stiffness, myalgia,1, 2, 7 aches,1 leg pain,1 and chest, back, and/or flank pain.1, 2 Adverse nervous system effects reported in patients receiving the drug include malaise,1, 2, 32 headache,1, 2 dizziness,1, 2 lightheadedness, weakness or faintness,1, 2 listlessness, lethargy, agitation,1 and confusion or disorientation.1 Abnormal involuntary movements or tremor,1 rigidity,1 paresthesia,1, 2 burning soles or palms,1 foot sole pain,1 seizures,1, 2, 93, 107 and possible encephalitis or postviral encephalopathy1 also have occurred. Lymphadenopathy, including postcervical lymphadenopathy and tender lymph nodes,1, 2, 74, 75, 103 also has been reported. (See Cautions: Mutagenicity and Carcinogenicity.) Some of these adverse effects (e.g., nausea, vomiting, arthralgia, malaise, lymphadenopathy) may be associated with ATG (equine)-induced serum sickness reactions.85, 103, 114, 115
Adverse renal effects reported in patients receiving ATG (equine) include abnormal renal function test results (including elevated serum creatinine concentration), enlarged or ruptured kidney,1 proteinuria,1 and acute renal failure.1 Abnormal liver function test results (including elevations in serum hepatic enzyme concentrations), hepatosplenomegaly,1 viral hepatitis,1 periorbital edema,1 vasculitis,1 and deep-vein thrombosis1 also have occurred in patients receiving the drug. Other adverse effects reportedly include apnea or dyspnea,1, 2 respiratory distress,1 cough,1 bilateral pleural effusion,1 laryngospasm or laryngeal edema,1, 2 diaphoresis (including night sweats),1, 2 and hyperglycemia.1, 2
Precautions and Contraindications
When used for the prevention and/or treatment of allograft rejection (e.g., renal allografts), ATG (equine) should be used only under the supervision of a clinician experienced in immunosuppressive therapy and the management of transplant patients.1, 2, 85 When used for the treatment of aplastic anemia, ATG (equine) should be used only under the supervision of a clinician experienced in immunosuppressive therapy and the management of this condition,1, 37 preferably in a closely supervised setting.37 Management of patients during therapy with ATG (equine) should be performed in facilities equipped with adequate laboratory and supportive medical equipment and staffed with adequate medical personnel.1, 2
Immunosuppression with ATG (equine), which may be combined with other immunosuppressive therapy (e.g., corticosteroids, azathioprine), may result in increased susceptibility to infection (e.g., with cytomegalovirus).1, 2 (See Drug Interactions: Immunosuppressive Agents.) Patients receiving ATG (equine) should be closely observed for signs of leukopenia, thrombocytopenia, and/or concurrent infection.1, 2 If severe and unremitting leukopenia and/or thrombocytopenia occurs in renal allograft recipients, therapy with ATG (equine) should be discontinued.1, 2 If infection occurs, appropriate therapy should be initiated promptly, and the clinician responsible for monitoring ATG (equine) therapy should decide whether to discontinue the drug.1, 2
As with other preparations derived from, or purified with, human blood components, the possibility of transmission of infectious agents, including viruses and theoretically Creutzfeldt-Jakob disease (CJD) exists with use of ATG (equine).1
Because of the risk of a severe systemic reaction (e.g., anaphylaxis), an intradermal skin test is strongly recommended by the manufacturer prior to administration of the initial dose of ATG (equine).1, 2 (See Dosage and Administration: Intradermal Sensitivity Testing.) A systemic reaction to the skin test such as generalized rash, tachycardia, dyspnea, hypotension, or anaphylaxis usually precludes further administration of the drug .1, 2, 85 Some clinicians suggest that patients with a systemic reaction to the skin test might receive ATG (equine) for life-threatening situations or severe disease for which other drugs cannot be used or are ineffective; however, use of ATG (equine) in these patients should be attempted with extreme caution and only after successful desensitization under the guidance of an allergist, immunologist, and/or other experts.85 The predictive value of the ATG (equine) skin test has not been clearly established, and an allergic reaction can still occur despite a negative skin test.1, 2 Appropriate equipment for maintenance of an adequate airway and other supportive measures and agents (e.g., epinephrine, oxygen) for the treatment of anaphylaxis or other severe systemic reactions should be readily available whenever ATG (equine) is administered.1, 2 If anaphylaxis or other signs or symptoms suggesting potential anaphylaxis (e.g., hypotension, respiratory distress, or pain in the chest, flank, or back) occur, IV infusion of ATG (equine) should be discontinued immediately and the patient given appropriate therapy as indicated.1, 2 ATG (equine) therapy should not be resumed in patients who have anaphylactic reactions to the drug.1, 2 ATG (equine) is contraindicated in patients who have had a severe systemic reaction during therapy with the drug or other equine immunoglobulin G preparation.1, 2
Clinical experience with ATG (equine) in children is limited.1, 2, 51, 52, 71, 72, 73, 84 The drug has been used for the prevention of rejection without unusual adverse effects in a limited number of renal allograft recipients 3 months to 19 years of age71, 72, 73 at dosages comparable to those used in adults;1, 2, 71, 72, 73 however, further study is needed to fully determine the efficacy of ATG (equine) in children with renal allografts.71, 72 ATG (equine) also has been used safely for the management of aplastic anemia in a limited number of pediatric patients at dosages comparable to those used in adults. The drug has been used effectively in a limited number of children to extend skin allograft survival in the management of extensive, full-thickness burns†.51, 52, 84 (See Uses: Skin Allotransplantation.)
Mutagenicity and Carcinogenicity
Studies to determine the mutagenic potential of ATG (equine) have not been performed to date.86
Lymphadenopathy, which histologically appeared to be diffuse histiocytic lymphoma but which was benign and transient in nature, was reported in several renal allograft recipients following treatment with ATG (equine).74, 75 ATG (equine)-induced lymphadenopathy in these patients appeared to be related to the lot and dosage of ATG (equine) administered, suggesting that it was a severe immunoblastic response to a potent lot of the drug;75 however, one of the patients subsequently developed a diffuse, poorly differentiated lymphocytic lymphoma 2 years after resolution of the initial lymphadenopathy.76 Lymphomas and lymphoproliferative disorders, apparently associated with Epstein-Barr virus infections,105 have also been observed in transplant patients receiving immunosuppressive therapy with or without ATG preparations.105, 106 Although a causal relationship was not established, other malignancies (e.g., squamous cell carcinoma of the skin, Hodgkin's disease) have developed 2 or more years after transplantation in some renal allograft recipients who received immunosuppressive therapy that included ATG (equine).26 As with other immunosuppressive agents, the carcinogenic potential of ATG (equine) cannot be excluded.26, 76 The nature and optimum management of posttransplant lymphomas and lymphoproliferative disorders in allograft recipients remain to be clearly established,74, 105, 106 and clinicians should consult specialized references for current methods of evaluation and management. If lymphadenopathy occurs in patients treated with ATG (equine), some clinicians recommend that the drug be discontinued and the patient carefully monitored with serial lymph node biopsies;74 specific antineoplastic therapy is not indicated unless the lymphoproliferative disorder does not resolve within a few months and/or other organ involvement becomes apparent.74
Pregnancy, Fertility, and Lactation
Animal reproduction studies have not been performed with ATG (equine), and it is not known whether ATG (equine) can cause fetal harm when administered to pregnant women.1, 2 The manufacturer states that use of ATG (equine) during pregnancy is not recommended and should be considered only under exceptional circumstances.1, 2
It is not known if ATG (equine) affects fertility.1, 2 In vitro, ATG (equine) has been shown to distribute into testicular tissue, including Leydig cells.87
Information on the distribution of ATG (equine) into milk is not available.1, 2 ATG (equine) may be distributed into milk, since immunoglobulins (e.g., IgA, IgM, IgG) are present in the colostrum.16 ATG (equine) should be used with caution in nursing women.1
When antithymocyte globulin (equine) (ATG [equine]) is administered with other immunosuppressive therapy (e.g., azathioprine, corticosteroids, graft irradiation), the degree of immunosuppression may be increased, and this effect is used to therapeutic advanta 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 30, 31, 32, 33, 34, 35 however, susceptibility to infection,1, 2, 22, 23, 67, 68, 70 including cytomegalovirus (CMV) infection,1 and possibly the risk of lymphoma or lymphoproliferative disorders74, 75, 76, 105, 106 may be increased. Patients must be closely monitored for signs of infection during ATG (equine) therapy.1, 2 (See Cautions: Precautions and Contraindications.) There is some evidence that the risks of leukopenia and infection, may be minimized by decreasing the dosage of concomitantly administered immunosuppressive agents.1, 33, 69 Some clinicians recommend that azathioprine and corticosteroid dosages be reduced by 50% when ATG (equine) is used concomitantly with these drugs for the prevention and/or treatment of renal allograft rejection.33, 69 Careful observation of patients receiving ATG (equine) and other immunosuppressive agent(s) (e.g., azathioprine, corticosteroids) is recommended when dosage of the other immunosuppressant(s) is reduced, since such dosage adjustment may result in reduced immunosuppression and the development of previously masked reactions to ATG (equine).1, 2
Limited information is available on the acute toxicity of antithymocyte globulin (equine) (ATG [equine]).1, 2 Because of ATG (equine)'s mechanism of action and its biologic nature, the maximum tolerated dose of the drug can be expected to vary on an individual basis.1, 2 Administration of a single dose of 7 g of ATG (equine) in an infusion solution containing approximately 10 mg/mL (about 7 times the recommended total dose and infusion concentration) in one patient was not associated with any signs of acute intoxication.1, 2
Antithymocyte globulin (equine) (ATG [equine]) mainly exhibits immunosuppressive activity1, 2, 7, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 51, 52, 53, 54, 55, 83 The immunosuppressive action of ATG (equine) is generally similar to that of antilymphocyte serum (ALS) and antilymphocyte globulin (ALG), but the various antilymphocyte preparations may differ qualitatively and/or quantitatively in the extent to which they produce specific effects, in part because of factors such as the source of antigenic material used, the type of animal used to produce the antiserum, and the method of production.3, 4, 5, 6, 10, 14, 83 In vivo studies in animals and in humans have shown that antilymphocyte preparations, including ATG (equine), principally inhibit cell-mediated immune responses such as allograft rejection3, 5, 6, 8, 13, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 51, 52, 53, 54, 55, 83 and delayed hypersensitivity reactions.6, 14 Antilymphocyte preparations may also inhibit humoral immune responses to some extent.3, 6, 14 Increased survival of allogeneic (homologous) transplants involving skin, bone marrow, liver, and kidneys has been shown in animals receiving antilymphocyte preparations5, 6, 8, 13, 51, 83
The exact mechanism(s) of immunosuppressive action of ATG (equine) has not been fully elucidated but may involve elimination of antigen-reactive T cells (T-lymphocytes) in peripheral blood and/or alteration of T-cell function.1, 2, 3, 4, 5, 6, 8, 9, 14 The effects of antilymphocyte preparations, including ATG (equine), on T cells are variable and complex,3, 4, 5, 6, 8, 9, 14, 49, 82, 87, 90 and may depend on the condition being treated (e.g., allograft rejection, aplastic anemia).14, 82, 87, 89, 90 Whether the effects of ATG (equine) are mediated through a specific subset of T cells has not been determined.58, 87, 88 In vitro studies indicate that binding of ATG (equine) to cells is generally nonspecific; the drug binds to visceral tissues, including thymus and testis cell membranes and nuclear and cytoplasmic components of tissues such as tonsil, kidney, and liver,87 and is extensively bound to bone marrow cells87 and to other peripheral blood cells besides lymphocytes.58, 87 (See Pharmacology: Hematologic Effects.) The apparent lymphocyte-selective action of ATG (equine) in allograft recipients is evidenced in part by its ability to reduce the number of circulating T cells that form rosettes with sheep erythrocytes (E rosettes) in vitro.1, 2, 9 ATG (equine) may inhibit rosette formation by coating T-cell antigenic receptors.9 In vitro studies indicate that ATG (equine) inhibits bone marrow precursors of E rosette-forming cells and that these precursors are less sensitive to ATG (equine) inhibition than mature E rosette-forming cells in bone marrow and those in peripheral blood.48 In vitro studies also indicate that unsensitized or undifferentiated T cells may be more sensitive to ATG (equine)-mediated immunosuppression than sensitized or differentiated T cells.49 In monkeys, ATG (equine) decreases the number of lymphocytes in thymus-dependent areas of the spleen and lymph nodes and decreases thymus size with involution and/or atrophy of the gland.1, 2
Studies in animals suggest that the immunosuppressive effects of antilymphocyte preparations may also result in part from inhibitory effects on the reticuloendothelial system.11, 12
In addition to its antilymphocytic activity, commercially available ATG (equine) contains antibodies to other formed elements of blood1, 2, 10, 58, 87 and may produce leukopenia,1, 2, 7, 19, 32, 35 thrombocytopenia,1, 2, 7, 17, 19, 23, 33, 35 and/or hemolysis in some patients.1, 2 (See Cautions: Hematologic Effects.) In monkeys receiving high dosages of ATG (equine), packed cell volume, total erythrocyte count, and hemoglobin concentration decreased and reticulocytes and nucleated erythrocytes increased sufficiently to be classified as anemia; in some cases, ATG (equine)-induced anemia apparently resulted in death.1, 2 In vitro studies indicate that ATG (equine) binds to essentially all circulating lymphocytes (both T and B cells),58, 87 granulocytes,87 and platelets.87 In vitro studies also indicate that ATG (equine) can cause lysis of normal lymphocytes (both T and B cells),58, 60, 87 platelets,87 and granulocytes87 in the presence of complement; lymphocytes and platelets appear to be more susceptible to ATG (equine)-induced lysis than granulocytes.87 Since binding of ATG (equine) to these blood elements does not correlate with cytotoxicity in vitro, it has been suggested that decreases in platelet and granulocyte counts observed in patients receiving ATG (equine) may result from antibody binding to these elements with subsequent removal from circulation by tissue macrophages.87 The effects of ATG (equine) on bone marrow cells are variable and complex and remain to be fully elucidated.48, 49, 89, 90 In vitro studies indicate that ATG (equine) binds to bone marrow cells (including erythroid and myeloid precursors)87 and may be cytotoxic to committed macrophage progenitor cells in the presence of complement.49
ATG (equine) produces a hematopoietic response in some patients with aplastic anemia.36, 37, 38, 39, 40, 41, 42, 91, 107, 108 The mechanism(s) of action of ATG (equine) in restoring hematopoiesis has not been fully elucidated,37, 38, 40, 41, 42, 43, 44, 81, 89, 90, 91 in part because the etiology of aplastic anemia is complex.81 In at least some patients, ATG (equine) may act by inhibiting or altering the function of myelosuppressive activated suppressor T cells,42, 82 possibly in part by reducing excessive interferon production by these cells in bone marrow.82, 91 In vitro studies with peripheral blood lymphocytes from patients with aplastic anemia indicate that ATG (equine) is mitogenic, stimulating lymphocyte proliferation and production of hematopoietic growth factors and lymphokines such as interleukin-2 (T-cell growth factor).89, 90, 91 While the exact relationships among these factors and their target cells are not clear, ATG (equine) may act in some patients with aplastic anemia by stimulating lymphocytes to increase local concentrations of growth factors in bone marrow that initiate normal hematopoiesis.89, 90, 91 Other mechanisms of action not related to immune modulation may also be involved.37, 40, 81
ATG (equine) appears to have some antineoplastic activity against malignant lymphomas.57, 58, 59, 60 The exact mechanism(s) of antineoplastic action of ATG (equine) is not known.58, 59, 60 ATG (equine) causes lysis of neoplastic T cells in the presence of complement in vitro, but only minimally at concentrations attainable in vivo, suggesting that another mechanism(s) is principally responsible for the drug's antineoplastic activity.58, 60 Other suggested mechanisms include antibody-induced cellular cytotoxicity58, 59 and coating of neoplastic cells to facilitate their removal by the reticuloendothelial system.60
Peak plasma levels of equine IgG following IV administration of antithymocyte globulin (equine) (ATG [equine]) vary, depending on the patient's ability to catabolize foreign IgG.2 After IV infusion of ATG 10 mg/kg daily for 5 days in one study, mean peak plasma levels of equine IgG averaged 727 ± 310 mcg/mL.2 Following IV administration of ATG (equine), there is an immediate reduction in the levels of rosette-forming cells (RFCs) in peripheral blood;2 the time for RFCs to recover to normal levels after discontinuance of ATG (equine) therapy depends on the patient's catabolic rate and, in some patients, on the duration of ATG (equine) therapy.2
Distribution of ATG (equine) into body fluids and tissues has not been fully characterized.1, 2, 87 Since antilymphocyte serum reportedly is poorly distributed into lymphoid tissues (e.g., spleen, lymph nodes),3, 6, 9 it is likely that ATG (equine) is also poorly distributed into these tissues. In vitro studies indicate that ATG (equine) binds to essentially all circulating lymphocytes, granulocytes, and platelets; to bone marrow cells; and to visceral tissues, including thymus and testis cell membranes and to nuclear and cytoplasmic components of tonsil, kidney, breast, liver, lung, intestine, and testes (including Leydig cells).87
Although information on the distribution of ATG (equine) across the placenta is not available, it is likely that ATG (equine) crosses the placenta since other immunoglobulins cross the placenta.15 Virtually all transplacental passage of immunoglobulins occurs during the last 4 weeks of pregnancy.15 Information on the distribution of ATG (equine) into milk is not available.1, 2 ATG (equine) may be distributed into milk, since immunoglobulins (e.g., IgA, IgM, IgG) are present in the colostrum.16
The plasma half-life of equine IgG reportedly averages about 6 days (range: 1.5-12 days).2 Approximately 1% of a dose of ATG (equine) is excreted in urine, principally as unchanged equine IgG.2 Following administration of approximately 21 doses of ATG (equine) over 28 days in one study, mean urinary concentration of equine IgG was approximately 4 mcg/mL.2
Antithymocyte globulin (equine) (ATG [equine]) is an immunoglobulin-containing immunosuppressive agent.1, 2, 7, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 51, 52, 53, 54, 55, 83 ATG (equine) is a sterile, concentrated, nonpyrogenic solution of immunoglobulin G (gamma globulin, IgG), principally monomeric IgG, prepared from plasma or serum of healthy horses hyperimmunized with human thymus lymphocytes.1, 2, 10 Commercially available ATG (equine) concentrate for injection contains 50 mg of equine IgG per mL.1, 2, 10 The concentrate for injection occurs as a transparent to slightly opalescent, colorless to faintly pink or brown, almost odorless solution and has a pH of approximately 6.8.1, 2, 10 ATG (equine) concentrate for injection contains glycine as a stabilizing agent,1, 2, 10 and air in the commercially available ampuls of the drug is replaced with nitrogen.86
Each lot of commercially available ATG (equine) concentrate for injection is tested to ensure its ability to inhibit rosette formation between human peripheral lymphocytes and sheep erythrocytes in vitro, but precise methods for determining the potency of ATG (equine) have not been established and activity may vary from lot to lot.1, 2, 10 During manufacture, ATG (equine) is adsorbed with human erythrocyte stroma to reduce the hemagglutinin titer and with insolubilized human plasma to remove antibodies to circulating plasma proteins.10 Antibody activity against human erythrocytes and platelets is measured and determined to be within acceptable limits.1, 2, 10 Commercially available ATG (equine) concentrate for injection does not show serologic evidence of antihuman serum protein antibody, antiglomerular basement membrane antibody, or pyrogens.1, 2, 10
ATG (equine) concentrate for injection should be refrigerated at 2-8°C; freezing should be avoided.1, 2 Slight granular or flaky deposits may develop in ATG (equine) concentrate for injection during storage, and ATG (equine) solutions should be filtered through an inline filter during administration;1, 2 filters with a pore size of 0.2-1 µm have generally been used,1, 2 but 5-µm filters have also been employed.85 When refrigerated at 2-8°C, ATG (equine) concentrate for injection is stable for 2 years from the date of manufacture.2 Following storage of ATG (equine) concentrate for injection at 25°C, substantial decreases in rosette-inhibiting activity occur after 6 months.2 When the concentrate for injection is stored at 40°C, an insoluble precipitate forms.2
Following dilution in 0.45 or 0.9% sodium chloride injection, ATG (equine) solutions containing 1 mg/mL are reportedly physically stable for at least 24 hours at 4 or 25°C at a pH of 5-7.3.2, 86 However, the manufacturer recommends that diluted solutions of ATG (equine) be refrigerated at 2-8°C if administration is delayed and that the solutions not be used after a period of 12 hours from the time of dilution (including actual infusion time), even if stored at 2-8°C.1, 2 Contact of undiluted ATG (equine) with air may result in denaturation of the protein.86 Because of potential instability of undiluted ATG (equine) in the presence of air,86 the manufacturer recommends that contact of undiluted ATG (equine) with air be minimized by inverting the IV infusion solution container into which the drug is added.1 It is recommended that ATG (equine) concentrate for injection not be diluted in dextrose injections, since precipitation can occur in solutions with a low salt concentration.1, 2 Dilution of ATG (equine) concentrate for injection in highly acidic IV solutions should also be avoided because of potential physical instability over time.1, 2
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Pharmacia. Atgam® prescribing information. Kalamazoo, MI; 2000 Jun.
2. The Upjohn Company. Drug reference: Atgam®. Kalamazoo, MI; 1981 Nov.
3. Lance EM. Mode of action of antilymphocyte serum. Fed Proc . 1970; 29:209-11. [PubMed 4904625]
4. Martin WJ, Miller JFAP. Site of action of antilymphocyte globulin. Lancet . 1967; 2:1285-7. [PubMed 4168616]
5. Levey RH, Medawar PB. Nature and mode of action of antilymphocytic antiserum. Proc Natl Acad Sci USA . 1966; 56:1130-7. [PubMed 5339289][PubMedCentral]
6. Wohlman MH, Toledo-Pereyra LH, Zeichner WD. The immunosuppressive properties of antilymphocyte serum preparations: a current review. Dial Transplant . 1981; 10:19-28.
7. Wechter WJ, Brodie JA, Morrell RM et al. Antithymocyte globulin (Atgam) in renal allograft recipients. Transplantation . 1979; 28:294-302. [PubMed 388762]
8. Zimmerman B, Tsui F. Immunosuppressive antilymphocyte serum: different subpopulations of T lymphocytes are influenced at different doses of antilymphocyte serum. Transplantation . 1979; 28:323-8. [PubMed 315628]
9. Bach JF. Mechanism and significance of rosette inhibition by antilymphocyte serum. In: Bach JF, Dormont J, Eyquem A et al., eds. International symposium on antilymphocyte serum; symposium series on immunobiology standardization, vol 16; New York: S Karger; 1970:189-98.
10. Wechter WJ, Nelson JW, Perper RJ et al. Manufacture of antithymocyte globulin (Atgam) for clinical trials. Transplantation . 1979; 28:303-7. [PubMed 116400]
11. Harris NS, Merino GE, Najarian JS. Mode of action of antilymphocyte sera (ALS). Transplant Proc . 1971; 3:797-9. [PubMed 4398511]
12. Sheagren JN, Barth RF, Edelin JB et al. Reticuloendothelial blockade produced by antilymphocyte serum. Lancet . 1969; 2:297-8. [PubMed 4184214]
13. Starzl TE, Marchioro TL, Porter KA et al. The use of heterologous antilymphoid agents in canine renal and liver homotransplantation and in human renal homotransplantation. Surg Gynecol Obstet . 1967; 124:301-18. [PubMed 4163340][PubMedCentral]
14. Pirofsky B, Beaulieu R, Bardana EJ et al. Antithymocyte antiserum effects in man. Am J Med . 1974; 56:290-6. [PubMed 4130597]
15. Vaughan VC III. Developmental pediatrics—the newborn infant. In: Behrman RE, Vaughan VC III, eds. Nelson textbook of pediatrics. 12th ed. Philadelphia: WB Saunders Company; 1983:13-4.
16. Hong R. Immunity, allergy, and related diseases—the immunologic system. In: Behrman RE, Vaughan VC III, eds. Nelson textbook of pediatrics. 12th ed. Philadelphia: WB Saunders Company; 1983:498.
17. Cosimi AB. The clinical value of antilymphocyte antibodies. Transplant Proc . 1981; 13:462-8. [PubMed 7022874]
18. Cosimi AB. The clinical usefulness of antilymphocyte antibodies. Transplant Proc . 1983; 15:583-9.
19. Wechter WJ, Morrell RM, Bergan J et al. Extended treatment with antithymocyte globulin (Atgam) in renal allograft recipients. Transplantation . 1979; 28:365-7. [PubMed 392832]
20. Kountz SL, Butt KHM, Rao TKS et al. Antithymocyte globulin (ATG) dosage and graft survival in renal transplantation. Transplant Proc . 1977; 9:1023-5. [PubMed 325728]
21. Cho SI, Bradley JW, Carpenter CB et al. Antithymocyte globulin, pretransplant blood transfusion, and tissue typing in cadaver kidney transplantation. Am J Surg . 1983; 145:464-71. [PubMed 6340551]
22. Kreis H, Mansouri R, Descamps JM et al. Antithymocyte globulin in cadaver kidney transplantation: a randomized trial based on T-cell monitoring. Kidney Int . 1981; 19:438-44. [PubMed 7017244]
23. Cosimi AB, Wortis HH, Delmonico FL et al. Randomized clinical trial of antithymocyte globulin in cadaver renal allograft recipients: importance of T cell monitoring. Surgery . 1976; 80:155-63. [PubMed 781887]
24. Kerman RH, Floyd M, Van Buren CT et al. Improved allograft survival of strong immune responder-high risk recipients with adjuvant antithymocyte globulin therapy. Transplantation . 1980; 30:450-4. [PubMed 7008294]
25. Turcotte JG, Feduska NJ, Haines RF et al. Antithymocyte globulin in renal transplant recipients: a clinical trial. Arch Surg . 1973; 106:484-8. [PubMed 4572345]
26. Diethelm AG, Aldrete JS, Shaw JF et al. Clinical evaluation of equine antithymocyte globulin in recipients of renal allografts: analysis of survival, renal function, rejection, histocompatibility, and complications. Ann Surg . 1974; 180:20-8. [PubMed 4599406][PubMedCentral]
27. Butt KMH, Zielinski CM, Parsa I et al. Trends in immunosuppression for kidney transplantation. Kidney Int . 1978; 13(Suppl 8):S95-8.
28. Cho SI, Cosimi AB, Monaco AP. Low-dose rabbit ATG versus high-dose equine ATG in clinical kidney transplantation. Surg Forum . 1981; 32:370-2.
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