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Horse Gamma Globulin Stabilized in 0.3 Molar Glycine to a Ph of Approximately 6.8

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Horse Gamma Globulin Stabilized in 0.3 Molar Glycine to a Ph of Approximately 6.8 LPD Reference: ATG-SIN-0414/1 Date of Last Revision: 08 September 2014 Country: Singapore Reference document: CDS Version 3.0, effective date: 17-Mar-2014 Reason for change: LPD update in accordance with CDS 3.0 ; 2014-09-08 IR: 1. Remove entire proposed subsection <Renal Transplant Prophylaxis> under ‘Pharmacodynamic Properties - Clinical Studies’ & 2. Relocate paragraph “Clinical trials […] standard supportive care alone” from <Therapeutic Indications> to < Pharmacodynamic Properties - Clinical Studies>, subsection <Aplastic Anemia>. Atgam® lymphocyte immune globulin, anti-thymocyte globulin [equine] sterile solution For Intravenous Use only DESCRIPTION ATGAM Sterile Solution contains lymphocyte immune globulin, anti-thymocyte globulin [equine]. It is the purified, concentrated, and sterile gamma globulin, primarily monomeric IgG, from hyperimmune serum of horses immunized with human thymus lymphocytes. Anti-thymocyte globulin (equine) is a transparent to slightly opalescent aqueous protein solution. It may appear colorless to faintly pink or brown and is nearly odorless. It may develop a slight granular or flaky deposit during storage. (For information about in-line filters, see Infusion Instructions in the POSOLOGY AND METHOD OF ADMINISTRATION.) Before release for clinical use, each lot of anti-thymocyte globulin (equine) is tested to assure its ability to inhibit rosette formation between human peripheral lymphocytes and sheep red blood cells in vitro. In each lot, antibody activity against human red blood cells and platelets is also measured and determined to be within acceptable limits. Only lots that test negative for antihuman serum protein antibody, antiglomerular basement membrane antibody and pyrogens are released. Each milliliter of anti-thymocyte globulin (equine) contains 50 mg of horse gamma globulin stabilized in 0.3 molar glycine to a pH of approximately 6.8. PHARMACOLOGICAL PROPERTIES Pharmacodynamic Properties ATGAM Sterile Solution is a lymphocyte-selective immunosuppressant as is demonstrated by its ability to reduce the number of circulating, thymus-dependent lymphocytes that form rosettes with sheep erythrocytes. This antilymphocytic effect is believed to reflect an alteration of the function of the T lymphocytes, which are responsible in part for cell-mediated immunity and are involved in humoral immunity. In addition to its antilymphocytic activity, ATGAM contains low concentrations of antibodies against other formed elements of the blood. In rhesus and cynomolgus monkeys, ATGAM reduces lymphocytes in the thymus-dependent areas of the spleen and lymph nodes. It also decreases the circulating sheep-erythrocyte-rosetting lymphocytes that can be detected, but ordinarily ATGAM does not cause severe lymphopenia. The mechanism of anti-thymocyte globulin (equine)-induced immunosuppression has not been determined. Published data indicate that the primary mechanism is the depletion of circulating lymphocytes, with greatest effect on T lymphocytes. Lymphocyte depletion may be caused by complement dependent lysis and/or activation-induced apoptosis. In addition, immunosuppression may be mediated by ATG-SIN-0414/1 Date of Last Revision: September 2014 Page 1 of 13 LPD Reference: ATG-SIN-0414/1 Date of Last Revision: 08 September 2014 Country: Singapore Reference document: CDS Version 3.0, effective date: 17-Mar-2014 Reason for change: LPD update in accordance with CDS 3.0 ; 2014-09-08 IR: 1. Remove entire proposed subsection <Renal Transplant Prophylaxis> under ‘Pharmacodynamic Properties - Clinical Studies’ & 2. Relocate paragraph “Clinical trials […] standard supportive care alone” from <Therapeutic Indications> to < Pharmacodynamic Properties - Clinical Studies>, subsection <Aplastic Anemia>. the binding of antibodies to lymphocytes which results in partial activation and induction of T lymphocyte anergy. The mechanism of anti-thymocyte globulin (equine) therapy for aplastic anemia is attributed to its immunosuppressive actions. In addition, anti-thymocyte globulin (equine) directly stimulates the growth of hematopoietic stem cells and release of hematopoietic growth factors such as interleukin-3 and granulocyte/macrophage colony stimulating factor . In general, when ATGAM is given with other immunosuppressive therapy, such as antimetabolites and corticosteroids, the patient's own antibody response to horse gamma globulin is minimal. Clinical Studies Renal Transplant Rejection The use of anti-thymocyte globulin (equine) for acute allograft rejection was evaluated in three different treatment applications: 1. In one randomized controlled trial, anti-thymocyte globulin (equine) treatment was substituted for standard therapy (i.e., bolus doses of intravenous steroids) in living related transplant recipients experiencing their first rejection episode and was proven effective in reversing the rejection episodes in all treated subjects. 2. Results from randomized controlled trials in the United States in patients with steroid resistant rejection episodes showed that anti-thymocyte globulin (equine), when administered in conjunction with standard therapy, yielded efficacy results superior to those of standard therapy alone. 3. The effect of anti-thymocyte globulin (equine) when administered in conjunction with standard therapy at the time of diagnosis of the first rejection episode was studied under two different protocols with living donors and cadaveric transplants. The results from these studies showed a statistically significant improvement in rejection resolution and functional graft survival associated with anti-thymocyte globulin (equine) therapy. The effectiveness of anti-thymocyte globulin (equine) in acute renal allograft rejection was also demonstrated in other controlled and non-controlled studies performed in various medical centers. In these studies, anti-thymocyte globulin (equine) was administered at time of diagnosis of the first rejection episode at a range of 10 to 15 mg/kg per day for 14 days, followed by alternate day therapy for a total of 21 doses in 28 days. Aplastic Anemia Anti-thymocyte globulin (equine) was administered with standard supportive care and/or various other conventional therapies. Anti-thymocyte globulin (equine)-treated patients showed a statistically significantly higher improvement rate compared with standard supportive care at 3 months. Anti-thymocyte globulin (equine) administered at a dose range of 10 to 20 mg/kg/day for 8 to 14 days has been beneficial, with the ATG-SIN-0414/1 Date of Last Revision: September 2014 Page 2 of 13 LPD Reference: ATG-SIN-0414/1 Date of Last Revision: 08 September 2014 Country: Singapore Reference document: CDS Version 3.0, effective date: 17-Mar-2014 Reason for change: LPD update in accordance with CDS 3.0 ; 2014-09-08 IR: 1. Remove entire proposed subsection <Renal Transplant Prophylaxis> under ‘Pharmacodynamic Properties - Clinical Studies’ & 2. Relocate paragraph “Clinical trials […] standard supportive care alone” from <Therapeutic Indications> to < Pharmacodynamic Properties - Clinical Studies>, subsection <Aplastic Anemia>. majority of clinical studies employing 15-20 mg/kg/day. Additional alternate day therapy for another 14 days may also be given for a total of up to 21 doses. A variety of published studies reported the use of anti-thymocyte globulin (equine) at doses 15 to 20 mg/kg/day for 4 to 10 days or for 14 days of daily therapy and another 14 days of alternate-day therapy for a total of up to 21 doses. Clinical trials conducted at two centers evaluated the 1-year survival rate for patients with severe and moderate to severe aplastic anemia. Seventy-four of the 83 patients enrolled were evaluable based on response to treatment. The treatment groups studied consisted of 1) anti-thymocyte globulin (equine) and supportive care, 2) anti thymocyte globulin (equine) administered following 3 months of supportive care alone, 3) anti-thymocyte globulin (equine), mismatched marrow infusion, androgens, and supportive care, or 4) anti-thymocyte globulin (equine), androgens, and supportive care. There were no statistically significant differences between the treatment groups. The 1-year survival rate for the pooled treatment groups was 69%. These survival results can be compared with a historical survival rate of about 25% for patients receiving standard supportive care alone. Pharmacokinetic Properties Distribution During infusion of 10-15 mg/kg/day, the mean peak value (n = 27 renal transplant patients) was found to be 727 ± 310 μg/mL. Metabolism and elimination The half-life of equine immunoglobulin after anti-thymocyte globulin (equine) infusion was found to be 5.7 ± 3.0 days in one group of recipients. The range for half-life was 1.5 to 13 days. THERAPEUTIC INDICATIONS Renal Transplantation Anti-thymocyte globulin (equine) Sterile Solution is indicated for the management of allograft rejection in renal transplant patients. When administered with conventional therapy at the time of rejection, it increases the frequency of resolution of the acute rejection episode. The drug has also been administered as an adjunct to other immunosuppressive therapy to delay the onset of the first rejection episode. Data accumulated to date have not consistently demonstrated improvement in functional graft survival associated with therapy to delay the onset of the first rejection episode. Aplastic Anemia Anti-thymocyte globulin (equine) is indicated for the treatment of moderate to severe aplastic anemia in patients who are unsuitable for bone marrow
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