Anti-thymocyte Globulin (Rabbit) (Thymoglobulin)

1. Health Canada Product Monograph — Anti-thymocyte Globulin (Rabbit)

• Anti-thymocyte globulin is indicated, together with concomitant immunosuppression, for the treatment of acute rejection in kidney transplant recipients.
• Anti-thymocyte globulin is also indicated for induction therapy in adult kidney transplant recipients to help prevent acute rejection.

• There is no information on the risks of anti-thymocyte globulin use during pregnancy, and animal reproduction studies have not been conducted.
• Women of childbearing age should use adequate contraception during and for a period after treatment, and anti-thymocyte globulin should only be given during pregnancy if the benefits clearly outweigh the risks.

• Anti-thymocyte globulin has not been studied in nursing women, and it is not known whether it passes into breast milk.
• Because other immunoglobulins are known to be excreted in human milk, breastfeeding should be discontinued during anti-thymocyte globulin therapy.

• No data on use in older adults have been submitted to Health Canada, so no specific geriatric dosing recommendation has been authorized; dosing should be based on the individual patient's clinical status and laboratory monitoring.

• Safety and effectiveness of anti-thymocyte globulin have not been established in controlled pediatric trials, though limited data suggest the dose, efficacy, and side-effect profile are similar to those in adults.

• For treatment of acute kidney transplant rejection, the usual dose is 1.5 mg/kg of body weight given daily by intravenous infusion for 7 to 14 days.
• For induction and prophylaxis in adult kidney transplant recipients, the usual dose is 1.5 mg/kg/day intravenously for at least 7 days, starting during the transplant surgery.
• The first infusion is given over a minimum of 6 hours, and subsequent infusions over at least 4 hours, through a high-flow vein and an in-line 0.22 micron filter.
• The dose should be reduced by half if the white blood cell count falls to between 2,000 and 3,000 cells/mm3 or if the platelet count falls to between 50,000 and 75,000 cells/mm3.
• Treatment should be stopped if the white blood cell count falls below 2,000 cells/mm3 or the platelet count falls below 50,000 cells/mm3.
• If a dose is missed, the remaining schedule should be adjusted based on the patient's clinical status and the treating physician's judgment.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Inadvertent overdose can cause leukopenia (including low lymphocyte and neutrophil counts) and low platelet counts.
• These blood count changes can be managed with dose reduction.
• Prolonged use or overdose, especially combined with other immunosuppressive drugs, may cause excessive immunosuppression.
• Monitoring lymphocyte, white blood cell, and platelet counts can help assess the degree of immune suppression after overdose.

• Fever is very commonly reported.
• Chills may occur.
• Low white blood cell counts (leukopenia) are common.
• General pain may occur.
• Headache may occur.
• Abdominal pain may occur.
• Diarrhea may occur.
• High blood pressure (hypertension) may occur.
• Nausea may occur.
• Low platelet counts (thrombocytopenia) are common.
• Swelling of the legs or ankles (peripheral edema) may occur.
• Shortness of breath (dyspnea) may occur.
• Weakness or fatigue (asthenia) may occur.
• High potassium levels (hyperkalemia) may occur.
• A fast heart rate (tachycardia) may occur.
• Malaise or a general feeling of being unwell may occur.
• Dizziness may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Anti-thymocyte globulin may cause serious immune-mediated reactions, including anaphylaxis.
• Severe cytokine release syndrome (CRS) can occur, particularly with rapid infusion rates, and in rare cases has been fatal.
• Severe CRS can be associated with serious cardiorespiratory events, including low blood pressure, acute respiratory distress syndrome, pulmonary edema, heart attack, and rapid heart rate.
• Serum sickness, with fever, rash, joint pain, and muscle pain, may develop 5 to 15 days after starting treatment.
• Serious infections, including bacterial, fungal, viral, and protozoal infections, may occur, and in rare cases have been fatal.
• Reactivation of latent infections, particularly cytomegalovirus, can occur.
• Sepsis has been reported, particularly when anti-thymocyte globulin is combined with other immunosuppressive agents.
• Malignancies, including lymphoma and post-transplant lymphoproliferative disorder, have been reported with prolonged immunosuppression.
• Thrombotic microangiopathy may occur, particularly when combined with calcineurin inhibitors.
• Severe or persistent low white blood cell or platelet counts may require stopping treatment.
• Liver problems, including hepatocellular injury, hepatotoxicity, and rare cases of hepatic failure, have been reported.
• Seek urgent medical attention for signs of a severe reaction, such as difficulty breathing, chest pain, fainting, widespread rash, or a very fast or irregular heartbeat during or after an infusion.

• Anti-thymocyte globulin should only be used by physicians experienced in immunosuppressive therapy for transplant patients.
• Use with caution and only in a hospital setting with close medical monitoring during each infusion.
• Use with caution and consider reducing the infusion rate, since this can reduce the incidence and severity of infusion-associated reactions.
• Use with caution and consider premedication with corticosteroids, antihistamines, and acetaminophen before each infusion to reduce reaction risk.
• Use with caution and monitor white blood cell and platelet counts closely throughout treatment.
• Use with caution and monitor lymphocyte subsets, since changes can persist for up to a year after treatment.
• Use with caution around live vaccines; these should not be given to patients about to receive, receiving, or recently treated with anti-thymocyte globulin, since immunosuppression may allow uncontrolled viral replication.
• Skin testing is not recommended before starting anti-thymocyte globulin.
• Use with caution and provide appropriate antiviral, antibacterial, antifungal, and antiprotozoal prophylaxis given the increased risk of infection.
• Use with caution in patients receiving other immunosuppressive agents, since maintenance immunosuppression is often reduced during antibody therapy to avoid over-immunosuppression.
• Patients should avoid driving or operating machinery during the course of therapy given the risk of reactions such as cytokine release syndrome.

• Contraindicated in patients with hypersensitivity to rabbit proteins or to any ingredient in the product.
• Contraindicated in patients with an active acute or chronic infection that would make additional immunosuppression unsafe.

• Concomitant use with other immunosuppressive agents, such as corticosteroids, azathioprine, or cyclosporine, may lead to over-immunosuppression; many transplant centres reduce maintenance immunosuppression during antibody therapy.
• Live vaccines should be avoided during and for a period after treatment, as anti-thymocyte globulin may interfere with vaccine effectiveness and increase infection risk.
• Anti-thymocyte globulin can stimulate the production of antibodies that cross-react with rabbit immune globulins, which may affect the response to repeat courses of treatment.
• Anti-thymocyte globulin should not be mixed with other medicinal products in the same infusion; combining it with heparin and hydrocortisone in a dextrose solution has been shown to cause precipitation.

• No interactions with food or drink are expected, since anti-thymocyte globulin is given only by intravenous infusion.

• Anti-thymocyte globulin is administered as a timed intravenous infusion in hospital under medical supervision; timing and duration are determined by the treating physician rather than by meals or time of day.

• Store anti-thymocyte globulin vials refrigerated between 2 degrees C and 8 degrees C.
• Protect from light.
• Do not freeze.
• Once reconstituted, use the solution as soon as possible, and discard any unused drug remaining after the infusion.

• Anti-thymocyte globulin is a powerful immune-suppressing medication given by infusion in hospital to treat or help prevent kidney transplant rejection; report fever, chills, breathing problems, or unusual symptoms to your transplant team right away, and keep all scheduled blood tests to monitor your blood counts and infection risk.