ATGAM 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.

ATGAM is indicated for the treatment of moderate to severe aplastic anemia in patients who are unsuitable for bone marrow transplantation.

When administered with a regimen of supportive care, ATGAM may induce partial or complete hematologic remission. In a controlled trial, patients receiving ATGAM showed a statistically significantly higher improvement rate compared with standard supportive care at 3 months. Improvement was defined in terms of sustained increase in peripheral blood counts and reduced transfusion needs.

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) ATGAM and supportive care, 2) ATGAM administered following 3 months of supportive care alone, 3) ATGAM, mismatched marrow infusion, androgens, and supportive care, or 4) ATGAM, 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.

The usefulness of ATGAM has not been demonstrated in patients with aplastic anemia 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.

To date, safety and efficacy have not been established in circumstances other than renal transplantation and aplastic anemia.

Before the first infusion of ATGAM, Pharmacia & Upjohn Company strongly recommends that patients be tested with an intradermal injection of 0.1 mL of a 1:1,000 dilution (5 mg horse IgG) of ATGAM in sodium chloride injection, USP and a contralateral sodium chloride injection control. Use only freshly diluted ATGAM for skin testing. The patient, and specifically the skin test, should be observed every 15 to 20 minutes over the first hour after intradermal injection. A local reaction of 10 mm or greater with a wheal or erythema, or both, with or without pseudopod formation and itching or a marked local swelling should be considered a positive test. Note: The predictive value of this test has not been proved clinically. Allergic reactions such as anaphylaxis have occurred in patients whose skin test is negative. In the presence of a locally positive skin test to ATGAM, serious consideration to alternative forms of therapy should be given. The risk to benefit ratio must be carefully weighed. If therapy with ATGAM is deemed appropriate following a locally positive skin test, treatment should be administered in a setting where intensive life support facilities are immediately available and with a physician familiar with the treatment of potentially life threatening allergic reactions in attendance.

SEE WARNINGS, PRECAUTIONS, AND ADVERSE REACTIONS.

Renal Allograft Recipients

Adult renal allograft patients have received ATGAM Sterile Solution at the dosage of 10 to 30 mg/kg of body weight daily. The few children studied received 5 to 25 mg/kg daily. ATGAM has been used to delay the onset of the first rejection episode^(2-5) and at the time of the first rejection episode.^(6-10) Most patients who received ATGAM for the treatment of acute rejection had not received it starting at the time of transplantation.

Usually, ATGAM is used concomitantly with azathioprine and corticosteroids, which are commonly used to suppress the immune response. Exercise caution during repeat courses of ATGAM; carefully observe patients for signs of allergic reactions.

Delaying the Onset of Allograft Rejection: Give a fixed dose of 15 mg/kg daily for 14 days, then every other day for 14 days for a total of 21 doses in 28 days. Administer the first dose within 24 hours before or after the transplant.

Treatment of Rejection: The first dose of ATGAM can be delayed until the diagnosis of the first rejection episode. The recommended dose is 10 to 15 mg/kg daily for 14 days. Additional alternate-day therapy up to a total of 21 doses can be given.

Aplastic Anemia

The recommended dosage regimen is 10 to 20 mg/kg daily for 8 to 14 days. Additional alternate-day therapy up to a total of 21 doses can be administered.^(11-13) Because thrombocytopenia can be associated with the administration of ATGAM, patients receiving it for the treatment of aplastic anemia may need prophylactic platelet transfusions to maintain platelets at clinically acceptable levels.

Preparation of Solution

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. However, because ATGAM is a gamma globulin product, it can be transparent to slightly opalescent, colorless to faintly pink or brown, and may develop a slight granular or flaky deposit during storage. ATGAM (diluted or undiluted) should not be shaken because excessive foaming and/or denaturation of the protein may occur.

Dilute ATGAM for intravenous infusion in an inverted bottle of sterile vehicle so the undiluted ATGAM does not contact the air inside. Add the total daily dose of ATGAM to the sterile vehicle (see Compatibility and Stability). The concentration should not exceed 4 mg of ATGAM per mL. The diluted solution should be gently rotated or swirled to effect thorough mixing.

Administration

The diluted ATGAM should be allowed to reach room temperature before infusion. ATGAM is appropriately administered into a vascular shunt, arterial venous fistula, or a high-flow central vein through an in-line filter with a pore size of 0.2 to 1.0 micron. The in-line filter should be used with all infusions of ATGAM to prevent the administration of any insoluble material that may develop in the product during storage. The use of high-flow veins will minimize the occurrence of phlebitis and thrombosis. Do not infuse a dose of ATGAM in less than 4 hours. Always keep appropriate resuscitation equipment at the patient's bedside while ATGAM is being administered. Observe the patient continuously for possible allergic reactions throughout the infusions (See ADVERSE REACTIONS).

Compatibility and Stability

ATGAM, once diluted, has been shown to be physically and chemically stable for up to 24 hours at concentrations of up to 4 mg per mL in the following diluents: 0.9% sodium chloride injection, 5% dextrose and 0.225% sodium chloride injection, and 5% dextrose and 0.45% sodium chloride injection.

Adding ATGAM to dextrose injection is not recommended, as low salt concentrations can cause precipitation. Highly acidic infusion solutions can also contribute to physical instability over time. It is recommended that diluted ATGAM be stored in a refrigerator if it is prepared prior to the time of infusion. Even if it is stored in a refrigerator, the total time in dilution should not exceed 24 hours (including infusion time).

ATGAM Sterile Solution, containing 50 mg of horse gamma globulin/mL, is supplied as follows:

5 - 5 mL ampoules NDC 0009-7224-02

STORAGE

Store in a refrigerator at 2° to 8°C (36° to 46°F). DO NOT FREEZE.

ANIMAL TOXICOLOGY

During the development of ATGAM Sterile Solution, aliquots of the various clinical lots were infused intravenously in either Macaca mulatta or Macaca irus monkeys. The dosage used was 100 mg/kg on day 0, 200 mg/kg on day 2, and 400 mg/kg on day 4. A 3-week observation period followed.

Many of the changes observed could have been anticipated on the basis of the antilymphocytic activity of ATGAM. They are decreased peripheral blood lymphocytes and increased total leukocyte and neutrophil counts occurring within 24 hours after infusion, decreased thymus size with involution or atrophy, or both, and decreased lymphocyte populations in the thymus-dependent areas of the spleen and lymph nodes. The atrophy was particularly common in the animals receiving the higher doses. In animals receiving either dosage regimen, packed cell volume, total ery-throcyte counts, and hemoglobin concentrations have decreased and reticulocytes and nucleated erythrocytes have increased enough to be classified as anemia. An occasional animal death believed to have resulted from anemia has occurred. Transient decreases in blood platelet counts have also occurred. Thrombus formation occurred frequently along the routes of infusion, ie, the saphenous and femoral veins. However, the incidence of thrombi has dropped since in-line filters have been used during infusion. In these animals, definitive evidence of DIC (disseminated intravascular coagulation) has not been observed.

REFERENCES

1. Rubin RH, Cosimi AB, Hirsch MS, Herrin JT: Effects of antithymocyte globulin on cytomegalovirus infection in renal transplant recipients. Transplantation. 1981; 31(2):143-145.

2. Cosimi AB, Wortis HH, Delmonico FL, Russell PS: Randomized clinical trial of antithymocyte globulin in cadaver renal allograft recipients: importance of T cell monitoring. Surgery. 1976; 80: 155-163.

3. Wechter WJ, Brodie JA, Morrell RM, Rafi M, Schultz JR: Antithymocyte globulin (ATGAM) in renal allograft recipients. Transplantation. 1979; 28(4):294-302.

4. Kountz SL, Butt KHM, Rao TKS, Zielinski CM, Rafi M, Schultz JR: Antithymocyte globulin (ATG) dosage and graft survival in renal transplantation. Transplant. Proc. 1977; 9:1023-1025.

5. Butt KMH, Zielinski CM, Parsa I, Elberg AJ, Wechter WJ, Kountz SL: Trends in immunosuppres-sion for kidney transplantation. Kidney Int. 1978; 13(Suppl 8): S95-S98.

6. Filo RS, Smith EJ, Leapman SB: Reversal of acute renal allograft rejection with adjunctive ATG therapy. Transplant. Proc. 1981; 13(1): 482-490.

7. Nowygrod R, Appel G, Hardy M: Use of ATG for reversal of acute allograft rejection. Transplant. Proc. 1981; 13(1): 469-472.

8. Hardy MA, Nowygrod R, Elberg A, Appel G: Use of ATG in treatment of steroid-resistant rejection. Transplantation. 1980; 29:162-164.

9. Shield CH, Cosimi AB, Tolkoff-Rubin N, Rubin R, Herrin J, Russell PS: Use of antithymocyte globulin for reversal of acute allograft rejection. Transplantation. 1979; 28(6): 461-464.

10. Cosimi AB: The clinical value of antilymphocyte antibodies. Transplant. Proc. 1981; 13(1): 462-468.

11. Cosimi AB, Peters C, Harmon D, Ellman L: Treatment of severe aplastic anemia with a prolonged course of antithymocyte globulin. Transplant. Proc. 1982; 14:761-764.

12. Champlin R, Ho W, Gale R: Antithymocyte globulin treatment in patients with aplastic anemia. N Engl J Med. 1983; 308(3):113-118.

13. Doney K, Dahlberg S, Monroe D et al: Therapy of severe aplastic anemia with anti-human thy-mocyte globulin and androgens: The effect of HLA-haploidentical marrow infusion. Blood. 1984; 63(2):342-348.

Pharmacia & Upjohn Company Kalamazoo, Michigan 49001, USA, Revised June 2000

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