Anti-Thymocyte Globulin

Thymoglobulin is available as sterile, lyophilized powder to be reconstituted with sterile Water for Injection, USP (SWFI). Each package contains a 10 mL vial of freeze-dried Thymoglobulin (25 mg) NDC# 58468-0080-1.

Storage

• Store in refrigerator at 2°C to 8°C (36°F to 46°F).
• Protect from light.
• Do not freeze.
• Do not use after the expiration date indicated on the label.
• Reconstituted Thymoglobulin is physically and chemically stable for up to 24 hours at room temperature; however, room temperature storage is not recommended. As Thymoglobulin contains no preservatives, reconstituted product should be used immediately.
• Infusion solutions of Thymoglobulin must be used immediately.
• Any unused drug remaining after infusion must be discarded.

REFERENCES

1. Bonnefoy-Bérard N, et al. Antibodies against functional leukocyte surface molecules in polyclonal antilymphocyte and antithymocyte globulins. Transplantation (1991)51:669-673.

2. Bonnefoy-Bérard N, et al. Inhibition of CD25 (IL-2Ra) expression and Tcell proliferation by polyclonal anti-thymocyte globulins. Immunology (1992)77:61-67.

3. Bonnefoy-Bérard N, et al. Antiproliferative effect of antilymphocyte globulins on B cells and B-cell lines. Blood (1992)79:2164-2170.

4. Bonnefoy-Bérard N, Revillard J-P. Mechanisms of immunosuppression induced by antilymphocyte globulins and OKT3. J Heart Lung Transplant (1996)15:435-442.

5. Bourdage J, et al. Comparative polyclonal antithymocyte globulin and antilymphocyte/antilymphoblast globulin anti-CD antigen analysis by flow cytometry. Transplantation (1995)59:1194- 1200.

6. Broyer M, et al. Triple therapy including cyclosporine A versus conventional regimen–a randomized prospective study in pediatric kidney transplantation. Transplant Proc (1987)19:3582-3585.

7. Clark KR, et al. Administration of ATG according to the absolute T lymphocyte count during therapy for steroid-resistant rejection. Transpl Int (1993)6:18-21.

8. Gaber AO, et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation (1998)66:29-37.

9. Guttmann RD, et al. Pharmacokinetics, foreign protein immune response, cytokine release, and lymphocyte subsets in patients receiving Thymoglobuline and immunosuppression. Transplant Proc (1997)29(suppl 7A):24S-26S.

10. Ippoliti G, et al. Prophylactic use of rabbit ATG vs horse ALG in heart transplanted patients under Sandimmun (CyA) therapy: clinical and immunological effects. Clin Transplantation (1989)3: 204-208.

Manufactured for: Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142 USA. By: Genzyme Polyclonals, S.A.S. Lyon, France, Revised: Sep 2015

Clinical Trials

Thymoglobulin adverse reactions are generally manageable or reversible. In the US Phase 3 randomized controlled clinical trial (n=163) comparing the efficacy and safety of Thymoglobulin and Atgam, adverse reactions occurring at least 5% more frequently in the Thymoglobulin group than in the Atgam comparison group are shown in Table 2. Malignancies were reported in 3 patients who received Thymoglobulin and in 3 patients who received Atgam during the one-year follow-up period. These included two post-transplant lymphoproliferative diseases (PTLDs) in the Thymoglobulin group and two PTLDs in the Atgam group.

Table 2: Adverse Reactions More Frequently Reported Following Thymoglobulin Infusion (incidence �5%) than following Atgam*

Treatment-emergent thrombocytopenia was reported in 30 (37%) of patients following Thymoglobulin infusion and in 36 (44%) of patients following Atgam infusion. Infections occurring more frequently in the Thymoglobulin group during the 3-month follow-up are summarized in Table 3. No significant differences were seen between the Thymoglobulin and Atgam groups for all types of infections, and the incidence of cytomegalovirus (CMV) infection was equivalent in both groups. (Viral prophylaxis was by the center's discretion during antibody treatment, but all centers used gancyclovir infusion during treatment.)

Table 3: Infections

Adverse reactions occurring during or shortly following Thymoglobulin infusion (infusion-associated adverse reactions) are generally manageable or reversible. Adverse reactions occurring during or within 24 hours of infusion in at least 5% of patients in the Thymoglobulin group are listed in Table 4.

Table 4: Infusion-Associated Adverse Reactions Occurring in at Least 5% of Thymoglobulin Subjects*

Treatment-emergent serum sickness was reported in 2 (2.4%) of patients following Thymoglobulin infusion and in no patients following Atgam infusion.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Thymoglobulin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infusion-Associated Adverse Reactions And Immune System Disorders

IARs may occur following the administration of Thymoglobulin and may occur as soon as the first or second infusion during a single course of Thymoglobulin treatment. Clinical manifestations of IARs have included any of the following signs and symptoms: fever, chills/rigors, dyspnea, nausea/vomiting, diarrhea, hypotension or hypertension, malaise, rash, urticaria, decreased oxygen saturation, and/or headache. IARs with Thymoglobulin are generally manageable with a reduction in infusion rates and/or with medications. (See PRECAUTIONS).

Transient reversible elevations in aminotransferases without any clinical signs or symptoms have also been reported during Thymoglobulin administration. Cases of hepatocellular injury, hepatotoxicity, or hepatic failure have been reported mainly in patients treated with thymoglobulin for hematologic disease. These reports included patients with hypoxic hepatitis, reactivation of hepatitis, or other underlying conditions, and who received concomitant medications with hepatotoxic potential. Serious and fatal anaphylactic reactions have been reported (See WARNINGS). The fatalities occurred in patients who did not receive epinephrine during the event. IARs consistent with cytokine release syndrome (CRS) have been reported. Severe and potentially life-threatening CRS cases have also been reported. Post-marketing reports of severe CRS have included cardiorespiratory dysfunction (including hypotension, acute respiratory distress syndrome, pulmonary edema, myocardial infarction, tachycardia, and/or death).

During post-marketing surveillance, reactions such as fever, rash, urticaria, arthralgia, lymphadenopathy, proteinuria, decreased oxygen saturation, and/or myalgia, indicating possible serum sickness, have been reported. Serum sickness tends to occur 5 to 15 days after onset of Thymoglobulin therapy. �Symptoms are manageable with corticosteroid treatment.

Adverse Events Due To Immunosuppression

Infections, reactivation of infection, febrile neutropenia and sepsis have been reported after Thymoglobulin administration in combination with multiple immunosuppressive agents, These infections can be fatal. (See WARNINGS and PRECAUTIONS). Malignancies including, but not limited to lymphoproliferative disorders (LPD) and other lymphomas (which may be virally mediated) as well as solid tumors have been reported. These events have been associated with fatal outcome. (See PRECAUTIONS). These adverse events were reported with use of a combination of multiple immunosuppressive agents.

Blood And Lymphatic System Disorders

Coagulopathy has been reported without clinical signs or symptoms related to bleeding, and generally resolves within a few days. Cases of disseminated intravascular coagulopathy have occurred secondary to anaphylaxis or infusion associated reaction.

Read the entire FDA prescribing information for Thymoglobulin (Anti-Thymocyte Globulin (Rabbit) Intravenous Administration)