Antithymocyte immunoglobulin Other names: ATG Anti-thymocyte globulin

The safety of immunisation with attenuated live vaccines following antithymocyte immunoglobulin therapy has not been studied; therefore, immunisation with attenuated live vaccines is not recommended for patients who have recently received antithymocyte immunoglobulin.

Use of immunosuppressive agents, including antithymocyte immunoglobulin, may increase the incidence of malignancies, lymphoma or lymphoproliferative disorders (which may be virally mediated). These events have sometimes been associated with fatal outcomes.

Thrombocytopenia and/or leukopenia (including lymphopenia and neutropenia) have been identified and are reversible following dose adjustments. When thrombocytopenia and/or leukopenia are not part of the underlying disease or associated with the condition for which antithymocyte immunoglobulin is being administered, the following dose reductions are suggested:

• A reduction in dosage must be considered if the platelet count is between 50,000 and 75,000 cells/mm³ or if the white cell count is between 2,000 and 3,000 cells/mm³;
• Stopping antithymocyte immunoglobulin treatment should be considered if persistent and severe thrombocytopenia (<50,000 cells/mm³) occurs or leukopenia (<2,000 cells/mm³) develops.

White blood cell and platelet counts should be monitored during and after antithymocyte immunoglobulin therapy. Patients with severe neutropenic aplastic anaemia require very careful monitoring, appropriate prophylaxis and treatment of fevers and infections as well as adequate platelet transfusion support.

In rare instances, serious immune-mediated reactions have been reported with the use of antithymocyte immunoglobulin and consist of anaphylaxis or severe cytokine release syndrome (CRS).

Very rarely, fatal anaphylaxis has been reported. If an anaphylactic reaction occurs, the infusion should be terminated immediately and appropriate emergency treatment should be initiated. Equipment for emergency therapy for anaphylactic shock must be readily available.

Any further administration of antithymocyte immunoglobulin to a patient who has a history of anaphylaxis to antithymocyte immunoglobulin should only be undertaken after serious consideration.

Severe, acute infusion-associated reactions (IARs) are consistent with CRS which is attributed to the release of cytokines by activated monocytes and lymphocytes. In rare instances, these reported reactions are associated with serious cardiorespiratory events and/or death.

Animal reproduction studies have not been conducted with antithymocyte immunoglobulin. It is not known whether antithymocyte immunoglobulin can cause foetal harm or can affect reproductive capacity. Antithymocyte immunoglobulin should be given to a pregnant woman only if clearly needed.

Antithymocyte immunoglobulin has not been studied in nursing women. It is not known whether this medicinal product is excreted in human milk. Because other immunoglobulins are excreted in human milk, breast-feeding should be discontinued during antithymocyte immunoglobulin therapy.

Antithymocyte immunoglobulin has not been studied in labour or delivery.

Given the possible adverse events which can occur during the period of antithymocyte immunoglobulin infusion, in particular cytokine release syndrome, it is recommended that patients should not drive or operate machinery.

List of adverse reactions

The adverse reactions observed in clinical studies and reported in post-marketing experience are detailed below.

Adverse reactions frequency is defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Adverse events from French Multi-centre Post-marketing Surveillance Study are also included in the list below.

From June 1997 to March 1998, 18 French transplantation centres participated in the French Multicentre Post-marketing Surveillance Study-00PTF0.

A total of 240 patients participated in this prospective, single arm, observational cohort study. All patients received antithymocyte immunoglobulin as prophylaxis of acute rejection for renal transplant.

Adverse reactions considered to be related to antithymocyte immunoglobulin reported in clinical trials and post-marketing:

Blood and lymphatic system disorders

Very common: anaemia, lymphopenia, neutropenia, thrombocytopenia

Common: febrile neutropenia

Gastrointestinal disorders

Common: diarrhoea, dysphagia, nausea, vomiting

General disorders and administrative site conditions

Very common: fever

Common: shivering

Uncommon: infusion related reactions (infusion associated reactions (IARs))*

Hepatobiliary disorders

Common: transaminases increased*

Uncommon: hepatocellular injury, hepatotoxicity, hepatic failure*

Unknown: Hyperbilirubinaemia

Immune system disorders

Uncommon: serum sickness*, cytokine release syndrome (CRS)*, anaphylactic reaction

Infections and infestations

Very common: infection (including reactivation of infection)

Common: sepsis

Musculoskeletal and connective tissue disorders

Common: myalgia

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common: malignancy, lymphomas (which may be virally mediated), neoplasms malignant (solid tumours)

Uncommon: lymphoproliferative disorder

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea

Skin and subcutaneous tissue disorder

Common: pruritus, rash

Vascular disorder

Common: hypotension

* = see below

Description of selected adverse reactions

Infusion-Associated Reactions and Immune System Disorders

Infusion-associated reactions (IAR) may occur following the administration of antithymocyte immunoglobulin and may occur as soon as the first or second dose. Clinical manifestations of IARs have included some of the following signs and symptoms: fever, chills/rigors, dyspnoea, nausea/vomiting, diarrhoea, hypotension or hypertension, malaise, rash, urticaria, and/or headache. IARs with antithymocyte immunoglobulin are usually mild and transient and are managed with reduced infusion rates and/or medications. Serious and in very rare instances, fatal anaphylactic reactions have been reported. These fatal reactions occurred in patients who did not receive adrenaline during the event.

IARs consistent with Cytokine Release Syndrome (CRS) have been reported. Severe and potentially life-threatening CRS is rarely reported. Post-marketing reports of severe Cytokine Release Syndrome have been associated with cardiorespiratory dysfunction (including hypotension, ARDS, pulmonary oedema, myocardial infarction, tachycardia, and/or death).

Hepatobiliary disorders

Transient reversible elevations in transaminases without any clinical signs or symptoms have also been reported during antithymocyte immunoglobulin administration.

Cases of hepatic failure have been reported secondary to allergic hepatitis and reactivation of hepatitis in patients with hematologic disease and/or stem cell transplant as confounding factors.

Serum Sickness

During post-marketing surveillance, reactions such as fever, rash, urticaria, arthralgia, and/or myalgia, indicating possible serum sickness, have been reported. Serum sickness tends to occur 5 to 15 days after onset of antithymocyte immunoglobulin therapy. Symptoms are usually self-limited or resolve rapidly with corticosteroid treatment.

Adverse events due to immunosuppression

Infections, reactivation of infection, febrile neutropenia, and sepsis have been reported after antithymocyte immunoglobulin administration in combination with multiple immunosuppressive agents. In rare cases, these infections have been fatal. Malignancies including, but not limited to lymphoproliferative disorders (LPD) and other lymphomas (which may be virally mediated) as well as solid tumours have been reported. These events have sometimes been associated with fatal outcome. These adverse events were always associated with a combination of multiple immunosuppressive agents.

For safety relating to transmissible agents.

Paediatric Population

Currently available data are limited. Available information indicates that the safety profile of antithymocyte immunoglobulin in paediatric patients is not fundamentally different to that seen in adults.