These highlights do not include all the information needed to use THYMOGLOBULIN

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.

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).

1. Allow THYMOGLOBULIN vials to reach room temperature before reconstituting the lyophilized product.
2. Aseptically remove caps to expose rubber stoppers.
3. Clean stoppers with germicidal or alcohol swab.
4. Aseptically reconstitute each vial of THYMOGLOBULIN lyophilized powder with the 5 mL of SWFI.
5. Rotate vial gently until powder is completely dissolved. Each reconstituted vial contains 25 mg or 5 mg/mL of THYMOGLOBULIN.
6. 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

1. 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.
2. 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)].

1. Follow the manufacturer's instructions for the infusion administration set. Infuse through a 0.22 micrometer filter into a high-flow vein.
2. 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.

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).

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.

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.

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.

Risk Summary

THYMOGLOBULIN has not been studied in nursing women. It is not known whether this drug is excreted in human milk. Because other immunoglobulins are excreted in human milk, breastfeeding should be discontinued during THYMOGLOBULIN therapy.

Contraception

Study 1 (NCT00235300)

THYMOGLOBULIN was evaluated in an open-label, randomized, active-controlled study in kidney transplant patients (n=278) at increased risk of acute rejection or delayed graft function.

The treatment failure rate within 12 months post-transplantation was statistically significantly lower in the THYMOGLOBULIN group than in the Active Comparator group (25% vs 38%; p=0.02), based on the composite endpoint (biopsy-proven acute rejection [BPAR], graft loss [GL], or death, with "lost to follow-up" considered as a treatment failure). The individual elements of the composite endpoint were BPAR (13% vs 21%), GL (8% vs 10%), and death (4% vs 4%) for the THYMOGLOBULIN and Active Comparator groups, respectively (Table 7).

The composite endpoint is defined as the occurrence of any of the following: BPAR (Grade I–III), graft loss, death, or lost to follow-up. Except for patients counted as "lost to follow-up," a patient can be counted in more than one category for the individual components (BPAR, graft loss, death).

In Study 1, patients received either THYMOGLOBULIN (n=141) 1.5 mg/kg daily for a total of 5 doses (Day 0 to Day 4) or Active Comparator (n=137) 2 doses of 20 mg each (Day 0, Day 4). For both treatment groups, the first induction treatment was initiated prior to the reperfusion of the kidney. All patients received triple maintenance immunosuppression (cyclosporine, mycophenolate mofetil, and corticosteroids) throughout the 12 months of the study.

Recipient disease characteristics were balanced between the 2 treatment groups with similar distribution of prior transplant, degree of sensitization and number of mismatched human leukocyte antigens (HLA). Overall, the mean percentage of pretransplant panel-reactive antibody (PRA) was 6% and the historical peak was 14%. The number of patients having a higher level of sensitization with PRA >20% was similar in the THYMOGLOBULIN (9%) and Active Comparator (10%) groups. The mean number of mismatched HLAs was evenly distributed across the 2 treatment groups.

Study 2 (NCT00682292)

THYMOGLOBULIN was evaluated in an open-label, parallel-arm, randomized, active-controlled, investigator-sponsored study in kidney transplant patients (n=230) at higher immunological risk of rejection.

The noninferiority of THYMOGLOBULIN to Active Comparator was achieved with treatment failure rates of 25% versus 34%, with an estimated treatment group difference (THYMOGLOBULIN – Active Comparator) of -9% (95% CI: -19.9% to 3.6%), based on the composite endpoint (BPAR, GL, or death, with lost to follow-up considered as a treatment failure) in the 12 months after transplantation. The individual elements of the composite endpoint were BPAR (11% vs 21%), GL (15% vs 11%), and death (4% vs 3%) for the THYMOGLOBULIN and Active Comparator groups, respectively (Table 8).

In Study 2, patients received either THYMOGLOBULIN (n=114) 1.25 mg/kg daily for a total of 8 doses (Day 0 to Day 7) or Active Comparator (n=116) 1 mg/kg (maximum dose 100 mg) on Days 0, 14, 28, 42, and 56. For both treatment groups, the first induction treatment was initiated prior to the beginning of the surgical procedure. All patients received triple maintenance immunosuppression (tacrolimus, mycophenolate mofetil, and corticosteroids) throughout the 12 months of the study.

Recipient disease characteristics were balanced between the 2 treatment groups, including similar distribution of prior transplant, degree of sensitization and number of HLA mismatches. The number of patients having prior transplants was 163 of 230 (71%). Overall, the mean percentage of pretransplant PRA was 35% and the historical peak was 72%. The number of patients having a higher level of sensitization with PRA >20% was similar in the THYMOGLOBULIN (55%) and Active Comparator (58%) groups. The mean number of HLA mismatches was evenly distributed across the 2 treatment groups.

Study 3

A controlled, double-blind, multicenter, randomized clinical trial comparing THYMOGLOBULIN and Active Comparator was conducted at 28 US transplant centers in renal transplant patients (n=163) with biopsy-proven Banff Grade II (moderate), Grade III (severe), or steroid-resistant Grade I (mild) acute graft rejection. This clinical trial met the non-inferiority criteria for THYMOGLOBULIN relative to Active Comparator in reversing acute rejection episodes with a 20% non-inferiority margin. The overall weighted estimate of the treatment difference (THYMOGLOBULIN – Active Comparator success rate) was 11% with a lower 95% confidence bound of 0.07%. Therefore, THYMOGLOBULIN was not inferior to Active Comparator in reversing acute rejection episodes.

In the study, patients were randomized to receive 7 to 14 days of THYMOGLOBULIN (1.5 mg/kg/day) or Active Comparator (15 mg/kg/day). For the entire study, the two treatment groups were comparable with respect to donor and recipient characteristics. In Table 9, successful treatment is presented as those patients whose serum creatinine levels (14 days from the diagnosis of rejection) returned to baseline and whose graft was functioning on Day 30 after the end of therapy.

There were no statistically significant differences between the two treatments with respect to (1) serum creatinine levels 30 days after treatment relative to baseline, (2) improvement rate in post-treatment histology, (3) one-year post-rejection Kaplan-Meier patient survival (THYMOGLOBULIN 93%, n=82 and Active Comparator 96%, n=80), (4) Day 30 post-rejection graft survival and (5) one-year post-rejection graft survival (THYMOGLOBULIN 83%, n=82; Active Comparator 75%, n=80).