Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
Thymoglobuline should be used under strict medical supervision in a hospital setting.
Thymoglobuline must only be administered according to the instructions of a physician with experience of immunosuppressive therapy in the transplant setting. Patients should be carefully monitored during the infusion. Particular attention must be paid to monitoring the patient for any symptoms of anaphylactic shock. Close monitoring of the patient must continue during the infusion and for a period of time following the end of the infusion until the patient is stable.


Prior to administration of Thymoglobuline it is advisable to determine whether the patient is allergic to rabbit proteins. Medical personnel and equipment, etc. must be readily at hand during the first days of therapy to provide emergency treatment if necessary.

Warnings

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

Very rarely, fatal anaphylaxis has been reported (see section 4.8).
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 Thymoglobuline to a patient who has a history of anaphylaxis to Thymoglobuline 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 (see below “Precautions“ and section 4.8).

Infection
Thymoglobuline is routinely used in combination with other immunosuppressive agents.
Infections (bacterial, fungal, viral and protozoal), reactivation of infection (particularly CMV) and sepsis have been reported after Thymoglobuline administration in combination with multiple immunosuppressive agents. In rare cases, these infections have been fatal.

Hepatic diseases
Thymoglobuline has to be administered with special caution in patients with hepatic diseases as pre-existing clotting disorders may aggravate. Careful monitoring of thrombocytes and coagulation parameters is recommended.

Precautions
General
Appropriate dosing for Thymoglobuline is different from dosing for other anti-thymocyte globulin (ATG) products, as protein composition and concentrations vary, depending on the source of ATG used. Physicians should therefore exercise care to ensure that the dose prescribed is appropriate for the ATG product being administered.

Thymoglobuline should be used under strict medical supervision in a hospital setting. Patients should be carefully monitored during the infusion and for a period of time following the end of the infusion until the patient is stable.

Close compliance with the recommended dosage and infusion time may reduce the incidence and severity of IARs. Additionally, reducing the infusion rate may minimize many of these 

adverse reactions. Premedication with antipyretics, corticosteroids, and/or antihistamines may decrease both the incidence and severity of these adverse reactions.

Rapid infusion rates have been associated with case reports consistent with cytokine release syndrome (CRS). In rare instances, severe CRS can be fatal.

Haematological Effects
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 Thymoglobuline 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/mm 3;
• Stopping Thymoglobuline treatment should be considered if persistent and severe thrombocytopenia (< 50,000 cells/mm3) occurs or leukopenia (< 2,000 cells/mm 3) develops.

White blood cell and platelet counts should be monitored during and after Thymoglobuline 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.

Infection
Infections, reactivation of infection (particularly CMV), and sepsis have been reported after Thymoglobuline administration in combination with multiple immunosuppressive agents.
Careful patient monitoring and appropriate anti-infective prophylaxis are recommended.

Malignancy
Use of immunosuppressive agents, including Thymoglobuline, may increase the incidence of malignancies, lymphoma or lymphoproliferative disorders (which may be virally mediated).
These events have sometimes been associated with fatal outcomes (see section 4.8).

Risk of Transmission of Infectious Agents
Human blood components (formaldehyde treated red blood cells), as well as thymus cells are used in the manufacturing process for Thymoglobuline. Standard measures to prevent infections resulting from the use of medicinal products prepared using human components include selection of donors, screening of individual donations for specific markers of infection and the inclusion of effective manufacturing steps for inactivation/removal of viruses.
Despite this, when medicinal products prepared using human components are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken for Thymoglobuline are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses such as HAV and parvovirus B19.

It is strongly recommended that every time Thymoglobulin is administered to a patient, the name and batch number of the medicinal product are recorded in order to maintain a link between the patient and the batch of the medicinal product.
Special Considerations for Thymoglobuline Infusion
As with any infusion, reactions at the injection site can occur and may include pain, swelling, and erythema.

The recommended route of administration for Thymoglobuline is intravenous infusion using a high-flow vein; however, it may be administered through a peripheral vein. When Thymoglobuline is administered through a peripheral vein, concomitant use of heparin and hydrocortisone in an infusion solution of 0.9% sodium chloride may minimize the potential for superficial thrombophlebitis and deep vein thrombosis.

The combination of Thymoglobuline, heparin and hydrocortisone in a dextrose infusion solution has been noted to precipitate and is not recommended (see section 6.2).

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

Thymoglobulin contains sodium.
This medicinal product contains 4 mg sodium per vial, equivalent to 0.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Traceability
In order to improve the traceability of biological medicinal products, the name of the administered product should be clearly recorded.
It is recommended to record the batch number as well.

Effects on Driving

4.7 Effects on ability to drive and use machines

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