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 gently rotate the vial until no particulate matter is visible. If particulate matter persists, discard this vial. Dilution Transfer the contents of the calculated number of THYMOGLOBULIN vials into the bag of infusion solution (saline or dextrose). Recommended volume: per one vial of THYMOGLOBULIN use 50 mL of infusion solution (total volume usually between 50 to 500 mL). Discard unused portion. Mix the solution by inverting the bag gently only once or twice. Infusion Administer THYMOGLOBULIN under strict medical supervision in a hospital setting, and carefully monitor patients during the infusion. THYMOGLOBULIN is less likely to produce side effects when administered at the recommended flow rate [see Warnings and Precautions (5.2) ] . Follow the manufacturer's instructions for the infusion administration set. Infuse through a 0.22 micrometer filter into a high-flow vein. Set the flow rate to deliver the dose over a minimum of 6 hours for the first dose and over at least 4 hours for subsequent doses.

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 )

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.

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) ] .

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%) 5 (4%) 1 (1%) 1 (1%) Lower respiratory tract and lung infections Lower respiratory tract and lung infections group includes: Lower respiratory tract and lung infections, and Pneumonia pseudomonal. 18 (13%) 2 (1%) 16 (12%) 4 (3%) Upper respiratory tract infection 15 (11%) 0 15 (11%) 1 (1%) Nasopharyngitis 7 (5%) 0 9 (7%) 0 Cytomegaloviral infections The collective term "cytomegaloviral infections" includes CMV duodenitis, CMV gastritis, CMV hepatitis, CMV infection, and CMV viremia. 8 (6%) 2 (1%) 21 (18%) 7 (7%) Herpes zoster 7 (5%) 0 2 (2%) 1 (1%) Oral candidiasis 8 (6%) 0 11 (8%) 0 Adverse Drug Reactions Occurring within 24 Hours and Infusion-Related Reactions Adverse reactions occurring during or within 24 hours of infusion in >5% of patients in the THYMOGLOBULIN group are summarized in Table 3. Table 3: Adverse Drug Reactions Adverse reactions that occurred during or within 24 hours of an infusion, and where the incidence was higher in the THYMOGLOBULIN group. Occurring within 24 Hours of Infusion and with >5% Incidence in Patients who Received THYMOGLOBULIN Primary System Organ Class n (%) THYMOGLOBULIN (N=141) Active Comparator basiliximab (N=137) Constipation 47 (33%) 23 (17%) Anemia 35 (25%) 19 (14%) Hyperkalemia 33 (23%) 18 (13%) Hypertension 25 (18%) 19 (14%) Leukopenia and White blood cell count decreased 29 (21%) 0 Pyrexia 18 (13%) 3 (2%) Vomiting 17 (12%) 14 (10%) Thrombocytopenia 13 (9%) 1 (1%) Abdominal pain 11 (8%) 6 (4%) Anxiety 10 (7%) 2 (2%) Hyperphosphatemia 10 (7%) 2 (2%) Tachycardia 10 (7%) 5 (4%) Acidosis 9 (6%) 8 (6%) Diarrhea 9 (6%) 1 (1%) Hypokalemia 9 (6%) 4 (3%) Infusion-related reactions Adverse reactions that occurred within 24 hours after the completion of the THYMOGLOBULIN administration and are considered as possible infusion related reactions (IARs) include the following: anxiety, confusional state, agitation, restlessness, headache, lethargy, dizziness, decreased sensitivity, fast heart rate, myocardial infarction, elevated blood pressure, decreased blood pressure, cough, throat irritation, reduced oxygen supply to tissues, shortness of breath, pulmonary edema, pain in mouth and throat, diarrhea, upper abdominal pain, abdominal tenderness, abdominal discomfort, nausea, pruritus, rash, joint pain, fever, chills, lack of energy, localized edema, malaise, and chest pain. Serum sickness was reported in 6 of 405 patients enrolled across completed studies where patients had been treated with THYMOGLOBULIN for the prophylaxis of acute rejection in patients receiving a kidney transplant. Anaphylactic shock was reported in 2 of 405 patients enrolled across completed studies. Treatment of acute rejection In the US Phase 3 randomized controlled clinical trial (n=163; Study 3) comparing the efficacy and safety of THYMOGLOBULIN and Active Comparator in the treatment of acute rejection in kidney transplant patients, adverse reactions occurring at least 5% more frequently in the THYMOGLOBULIN group than in the Active Comparator group are shown in Table 4. Malignancies were reported in 3 patients who received THYMOGLOBULIN and in 3 patients who received Active Comparator during the one-year follow-up period. These included two cases of post-transplant lymphoproliferative disease (PTLD) in the THYMOGLOBULIN group and two cases of PTLD in the Active Comparator group. Table 4: Adverse Reactions Treatment-emergent adverse events/reactions (TEAE) are summarized. Reported More Frequently (incidence ≥5%) Following THYMOGLOBULIN versus Active Comparator Anti-thymocyte globulin equine (ATG-E) Frequently Reported Events THYMOGLOBULIN n=82 Active Comparator n=81 Chills 47 (57%) 35 (43%) Leukopenia 47 (57%) 24 (30%) Headache 33 (40%) 28 (35%) Abdominal pain 31 (38%) 22 (27%) Hypertension 30 (37%) 23 (28%) Nausea 30 (37%) 23 (28%) Dyspnea 23 (28%) 16 (20%) Hyperkalemia 22 (27%) 15 (19%) Myalgia 16 (20%) 10 (12%) Insomnia 16 (20%) 10 (12%) Hypotension 13 (16%) 6 (7%) Rash 11 (13%) 6 (7%) Sweating 11 (13%) 4 (5%) Malaise 11 (13%) 3 (4%) Acne 10 (12%) 4 (5%) Overdose 5 (6%) 0 Treatment-emergent thrombocytopenia was reported in 30 (37%) of patients following THYMOGLOBULIN infusion and in 36 (44%) of patients following Active Comparator infusion. Infections occurring more frequently in the THYMOGLOBULIN group during the 3-month follow-up are summarized in Table 5. No significant differences were seen between the THYMOGLOBULIN and Active Comparator groups for all types of infections. The incidence of CMV infection was the same in both groups. Viral prophylaxis was by the center's discretion during antibody treatment, but all centers used ganciclovir infusion during treatment. Table 5: Infections THYMOGLOBULIN n=82 Active Comparator ATG-E n=81 Body System No. of Patients (%) Total Reports No. of Patients (%) Total Reports Body as a Whole 30 (37) 36 22 (27) 29 Infection 25 (31) 26 19 (24) 21 Other 14 (17) 15 11 (14) 12 CMV 11 (13) 11 9 (11) 9 Sepsis 10 (12) 10 7 (10) 7 Digestive 5 (6) 5 3 (4) 3 Gastrointestinal moniliasis 4 (5) 4 1 (1) 1 Gastritis 1 (1) 1 0 (0) 0 Skin 4 (5) 4 0 (0) 0 Herpes simplex 4 (5) 4 0 (0) 0 Adverse reactions occurring during or within 24 hours of infusion in at least 5% of patients in the THYMOGLOBULIN group are listed in Table 6. Table 6: Adverse Reactions* Occurring within 24 Hours of Infusion and with >5% Incidence in THYMOGLOBULIN Patients Adverse Reaction THYMOGLOBULIN (N=82) Active Comparator ATG-E (N=81) * Treatment-emergent adverse events that occurred during or within 24 hours of an infusion are summarized. Chills 45 (55%) 28 (35%) Leukopenia 40 (49%) 10 (12%) Fever 38 (46%) 39 (48%) Nausea 24 (29%) 17 (21%) Thrombocytopenia 24 (29%) 30 (37%) Headache 22 (27%) 22 (27%) Hypertension 22 (27%) 16 (20%) Pain 21 (26%) 19 (24%) Tachycardia 19 (23%) 16 (20%) Diarrhea 16 (20%) 15 (19%) Peripheral edema 16 (20%) 13 (16%) Vomiting 16 (20%) 12 (15%) Abdominal pain 14 (17%) 13 (16%) Hyperkalemia 14 (17%) 12 (15%) Arthralgia 12 (15%) 11 (14%) Constipation 12 (15%) 16 (20%) Dyspnea 12 (15%) 11 (14%) Asthenia 11 (13%) 11 (14%) Leukocytosis 11 (13%) 9 (11%) Anemia 10 (12%) 11 (14%) Back pain 10 (12%) 8 (10%) Hypokalemia 10 (12%) 7 (9%) Insomnia 10 (12%) 4 (5%) Lung disorder 10 (12%) 6 (7%) Myalgia 9 (11%) 7 (9%) Dyspepsia 8 (10%) 6 (7%) Hypotension 8 (10%) 2 (3%) Acidosis 7 (9%) 4 (5%) Chest pain 7 (9%) 7 (9%) Malaise 7 (9%) 3 (4%) Anxiety 6 (7%) 8 (10%) Anorexia 5 (6%) 1 (1%) Cough increased 6 (7%) 8 (10%) Rash 6 (7%) 4 (5%) Edema 5 (6%) 12 (15%) Hypophosphatemia 5 (6%) 3 (4%) Itchiness 5 (6%) 4 (5%) Sweating 5 (6%) 4 (5%) Treatment-emergent serum sickness was reported in 2 (2%) of patients following THYMOGLOBULIN infusion and in no patients following Active Comparator infusion. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of THYMOGLOBULIN. Because these adverse 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. Hepatobiliary disorders: Hepatic dysfunction including transient reversible elevations in aminotransferases without any clinical signs or symptoms, hepatic failure, hyperbilirubinemia. Blood and lymphatic system disorders: Febrile neutropenia, coagulopathy without clinical signs or symptoms of bleeding, disseminated intravascular coagulopathy, anemia including hemolytic anemia, thrombotic microangiopathy. Immune system disorders: Hypersensitivity reactions including anaphylaxis, CRS.

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.