Thymoglobulin

1 INDICATIONS AND USAGE THYMOGLOBULIN is indicated for the prophylaxis and treatment of acute rejection in adult and pediatric patients receiving a kidney transplant in conjunction with concomitant immunosuppression. THYMOGLOBULIN is an immunoglobulin G indicated for the prophylaxis and treatment of acute rejection in adult and pediatric patients receiving a kidney transplant in conjunction with concomitant immunosuppression. ( 1 )

2 DOSAGE AND ADMINISTRATION The first dose should be infused over at least 6 hours; doses on subsequent days should be infused over at least 4 hours. ( 2.2 ) Premedication with corticosteroids, acetaminophen, and/or an antihistamine prior to each infusion is recommended. ( 2.2 ) The THYMOGLOBULIN dose should be reduced by one-half if the white blood cell (WBC) count is between 2,000 and 3,000 cells/mm 3 or if the platelet count is between 50,000 and 75,000 cells/mm 3 . Stopping THYMOGLOBULIN treatment should be considered if the WBC count falls below 2,000 cells/mm 3 or if the platelet count falls below 50,000 cells/mm 3 . ( 2.3 ) Indication Dose Prophylaxis of acute rejection 1.5 mg/kg of body weight administered daily for 4 to 7 days Treatment of acute rejection 1.5 mg/kg of body weight administered daily for 7 to 14 days For complete dosing instructions, see full prescribing information. ( 2 ) 2.1 Dosing Information For intravenous use only Prophylaxis of Acute Rejection The recommended dosage of THYMOGLOBULIN for prophylaxis of acute rejection in patients receiving a kidney transplant is 1.5 mg/kg of body weight administered daily with the first dose initiated prior to reperfusion of the donor kidney. The usual duration of administration is 4 to 7 days. Treatment of Acute Rejection The recommended dosage of THYMOGLOBULIN for treatment of acute rejection in patients receiving a kidney transplant is 1.5 mg/kg of body weight administered daily for 7 to 14 days. Dosing for THYMOGLOBULIN is different from dosing for other anti-thymocyte globulin (ATG) products, because protein composition and concentrations vary depending on the source of ATG. The prescribing physician must ensure that the dose prescribed is appropriate for the ATG product being administered. 2.2 Recommended Dosing Regimen Administer the first dose of THYMOGLOBULIN over a minimum of 6 hours; administer doses on subsequent days over at least 4 hours [see Warnings and Precautions (5.2) ] . Premedicate with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to each infusion of THYMOGLOBULIN to reduce the incidence and intensity of infusion-related reactions [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] . 2.3 Dose Modifications Monitor patients for adverse reactions during and after infusion. Monitor total white blood cell and platelet counts during and after THYMOGLOBULIN therapy. Reduce the THYMOGLOBULIN dose by one-half if the white blood cell (WBC) count is between 2,000 and 3,000 cells/mm 3 or if the platelet count is between 50,000 and 75,000 cells/mm 3 . Consider stopping THYMOGLOBULIN treatment if the WBC count falls below 2,000 cells/mm 3 or if the platelet count falls below 50,000 cells/mm 3 . 2.4 Recommended Concomitant Medication THYMOGLOBULIN is used with concomitant immunosuppressants. Administer prophylactic antifungal and antibacterial therapy if clinically indicated [see Warnings and Precautions (5.4) ] . Antiviral prophylactic therapy is recommended for patients who are seropositive for cytomegalovirus (CMV) at the time of transplant and for CMV-seronegative patients scheduled to receive a kidney from a CMV-seropositive donor [see Warnings and Precautions (5.4) ]. 2.5 Instructions for Dilution and Administration Reconstitution After calculating the number of vials needed, using aseptic technique, reconstitute each vial of THYMOGLOBULIN with 5 mL of Sterile Water for Injection, USP (SWFI). Allow THYMOGLOBULIN vials to reach room temperature before reconstituting the lyophilized product. Aseptically remove caps to expose rubber stoppers. Clean stoppers with germicidal or alcohol swab. Aseptically reconstitute each vial of THYMOGLOBULIN lyophilized powder with the 5 mL of SWFI. Rotate vial gently until powder is completely dissolved. Each reconstituted vial contains 25 mg or 5 mg/mL of THYMOGLOBULIN. Inspect solution for particulate matter after reconstitution. Should some particulate matter remain, continue to g…

5 WARNINGS AND PRECAUTIONS THYMOGLOBULIN should only be used by physicians experienced in immunosuppressant therapy in transplantation. ( 5.1 ) Hypersensitivity and infusion-related reactions: THYMOGLOBULIN infusion could result in an anaphylactic reaction. Close compliance with the recommended infusion time may reduce the incidence and severity of infusion-related reactions. ( 5.2 ) Cytopenias including anemia, neutropenia, and thrombocytopenia have occurred with THYMOGLOBULIN administration ( 6 ) and require monitoring of blood counts. Adjust dose accordingly to reverse cytopenias. ( 5.3 ) Infection: Infections and reactivation of infections have been reported. Monitor patients and administer anti-infective prophylaxis. ( 5.4 ) Malignancy: Incidence of malignancies may increase. ( 5.5 ) Immunization with attenuated live vaccines is not recommended for patients who have recently received THYMOGLOBULIN. ( 5.6 ) THYMOGLOBULIN may interfere with rabbit antibody–based immunoassays and with cross-match or panel-reactive antibody cytotoxicity assays. ( 5.7 ) 5.1 Management of Immunosuppression To prevent over-immunosuppression, physicians may wish to decrease the dose of the maintenance immunosuppression regimen during the period of THYMOGLOBULIN use. 5.2 Hypersensitivity and Infusion-Related Reactions Severe hypersensitivity and infusion-related reactions, including fatal anaphylaxis and severe cytokine release syndrome (CRS), have been reported with the use of THYMOGLOBULIN [see Adverse Reactions (6) ] . Severe acute CRS can cause serious cardiorespiratory events and/or death. Close compliance with the recommended dosage and infusion time may reduce the incidence and severity of infusion-related reactions. Slowing the infusion rate may minimize the risk of infusion-related reactions. If a hypersensitivity or infusion-related reaction occurs, terminate the infusion immediately and provide supportive treatment according to clinical practice. 5.3 Cytopenias Cytopenias including anemia, neutropenia, and thrombocytopenia have occurred with THYMOGLOBULIN administration [see Adverse Reactions (6) ] . Monitors blood counts after THYMOGLOBULIN administration. Adjust dose accordingly to reverse cytopenias [see Dosage and Administration (2.3) ] . 5.4 Infection THYMOGLOBULIN is routinely used in combination with other immunosuppressive agents. Infections (bacterial, fungal, viral and protozoal), reactivation of infection (particularly cytomegalovirus [CMV]) and sepsis have been reported after THYMOGLOBULIN administration in combination with multiple immunosuppressive agents [see Adverse Reactions (6) ] . These infections can be fatal. Monitor patients carefully and administer appropriate anti-infective treatment when indicated [see Dosage and Administration (2.4) ] . 5.5 Malignancy Malignancies with fatal outcomes have been reported in patients treated with THYMOGLOBULIN [see Adverse Reactions (6) ]. Use of immunosuppressive agents, including THYMOGLOBULIN, may increase the risk of malignancies, including lymphoma or lymphoproliferative disorders. 5.6 Immunizations The safety of immunization with attenuated live vaccines following THYMOGLOBULIN therapy has not been studied; therefore, immunization with attenuated live vaccines is not recommended for patients who have recently received THYMOGLOBULIN. 5.7 Laboratory Tests THYMOGLOBULIN may interfere with rabbit antibody–based immunoassays and with cross-match or panel-reactive antibody cytotoxicity assays. THYMOGLOBULIN has not been shown to interfere with any routine clinical laboratory tests that do not use immunoglobulins.

4 CONTRAINDICATIONS THYMOGLOBULIN is contraindicated in patients with history of allergy or anaphylactic reaction to rabbit proteins or to any product excipients, or who have active acute or chronic infections that contraindicate any additional immunosuppression [see Warnings and Precautions (5.2 , 5.4) and Adverse Reactions (6.2) ] . Allergy or anaphylactic reaction to rabbit proteins or to any product excipients, or active acute or chronic infections which contraindicate any additional immunosuppression ( 4 )

7 DRUG INTERACTIONS No drug interaction studies have been performed. THYMOGLOBULIN can stimulate the production of antibodies that cross-react with rabbit immune globulins [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary Animal reproduction studies have not been conducted with THYMOGLOBULIN. It is also not known whether THYMOGLOBULIN can cause fetal harm. THYMOGLOBULIN should be given to a pregnant woman only if the benefit outweighs the risk.

6 ADVERSE REACTIONS The most common adverse reactions and laboratory abnormalities (incidence >5% higher than comparator) are urinary tract infection, abdominal pain, hypertension, nausea, shortness of breath, fever, headache, anxiety, chills, increased potassium levels in the blood, low counts of platelets and white blood cells. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions and laboratory abnormalities (incidence >5% higher than comparator) are urinary tract infection, abdominal pain, hypertension, nausea, shortness of breath, fever, headache, anxiety, chills, increased potassium levels in the blood, and low counts of platelets and white blood cells. Prophylaxis of Acute Rejection The safety of THYMOGLOBULIN compared to Active Comparator for the prophylaxis of acute rejection in patients receiving a kidney transplant were evaluated in a randomized, open-label, international, multicenter trial in patients receiving solitary kidneys from deceased donors (n=278; Study 1). Table 1: Adverse Reactions Adverse reactions are treatment emergent adverse events (TEAE) reported as related to the study agent in at least 1 patient. and Laboratory Abnormalities Reported More Frequently (incidence Number (percentage) is shown regardless of causal relationship. >5%) Following THYMOGLOBULIN versus Active Comparator basiliximab Adverse Reaction [n (%) ] THYMOGLOBULIN (N=141) Active Comparator (N=137) Urinary tract infection 55 (39%) 36 (26%) Pyrexia 39 (28%) 25 (18%) Headache 26 (18%) 17 (12%) Hyperlipidemia 21 (15%) 9 (7%) Anxiety 20 (14%) 12 (9%) Chills 13 (9%) 5 (4%) Laboratory Abnormalities Hyperkalemia: blood potassium ≥5.5 mmol/L; Leukopenia: WBC <3000 cells/mm 3 . Thrombocytopenia: platelet count <75,000 cells/mm 3 . Hyperkalemia 81 (57%) 70 (51%) Leukopenia 89 (63%) 20 (15%) Thrombocytopenia 23 (16%) 7 (5%) Malignancies Six patients in the THYMOGLOBULIN group developed malignancies (Epstein-Barr virus-induced lymphoma of the cavum, Epstein-Barr virus-positive large B-cell lung lymphoma, Epstein-Barr virus-induced lymphoma of the brain, squamous cell carcinoma, renal cancer, and recurrent basal cell carcinoma). In the Active Comparator group, 1 patient developed renal cancer. Infections Infections occurred in 76% of THYMOGLOBULIN-treated patients (severe in 23%), and in 63% of Active Comparator-treated patients (severe in 15%). Infections occurring in ≥5% of the patients in either treatment group during the 12-month follow-up are summarized in Table 2. Urinary tract infection was the most frequent type of infection, and was reported as severe in 9% of THYMOGLOBULIN-treated patients and in 2% of Active Comparator-treated patients. CMV infections were reported more frequently in the Active Comparator group, with an incidence of 6% (severe in 1%) in THYMOGLOBULIN-treated patients and of 18% (severe in 7%) in Active Comparator-treated patients. Patients who were CMV-positive at the time of transplant, as well as CMV-negative recipients of transplants from CMV-positive donors, were required to receive antiviral prophylaxis for 3 months after transplant. Table 2: Infections Reported in ≥5% of Study Patients Infection THYMOGLOBULIN (N=141) Active Comparator basiliximab (N=137) All Severe/Unknown All Severe/Unknown Urinary tract infections Urinary tract infection group includes: Urinary tract infections, Urinary tract infection fungal, Urinary tract infection bacterial, Bacterial pyelonephritis, Urosepsis. 59 (42%) 12 (9%) 39 (29%) 3 (2%) Sepsis Sepsis group includes: Sepsis, Escherichia sepsis, Staphylococcal bacteremia. 9 (6%) …