Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 22 May 2017

Indication(s)

INDICATIONS AND USAGE Thymoglobulin is indicated for the treatment of renal transplant acute rejection in conjunction with concomitant immunosuppression.

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Advisory information

contraindications
CONTRAINDICATIONS Thymoglobulin is contraindicated in patients with history of allergy or anaphylaxis to rabbit proteins or to any product excipients, or who have active acute or chronic infections which contraindicate any additional immunosuppression.
Special warnings and precautions

PRECAUTIONS General Appropriate dosing for Thymoglobulin 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.

Thymoglobulin should be used under strict medical supervision in a hospital setting, and patients should be carefully monitored during the infusion.

The first dose should be infused over a minimum of 6 hours into a high-flow vein.

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 IARs.

Premedication with corticosteroids, acetaminophen, and/or an antihistamine and/or slowing the infusion rate may reduce reaction incidence and intensity (See DOSAGE AND ADMINISTRATION).

Rapid infusion rates have been reported with case reports consistent with cytokine release syndrome (CRS).

Severe acute CRS can be fatal.

Hematologic Effects Thrombocytopenia and/or leukopenia (including lymphopenia and neutropenia) have been identified and are reversible following dose adjustments (See DOSAGE AND ADMINISTRATION).

Infection Infections, reactivation of infection, and sepsis have been reported after Thymoglobulin administration in combination with multiple immunosuppressive agents.

Careful patient monitoring and appropriate anti-infective prophylaxis are recommended.

Malignancy Use of immunosuppressive agents, including Thymoglobulin, may increase the incidence of malignancies, including lymphoma or lymphoproliferative disorders (which may be virally mediated).

These events have been associated with fatal outcome (See ADVERSE REACTIONS: Post-Marketing Experience).

Special Considerations for Thymoglobulin Infusion Reactions at the infusion site can occur and may include pain, swelling, and erythema.

The recommended route of administration for Thymoglobulin is intravenous infusion using a high-flow vein (See DOSAGE AND ADMINISTRATION).

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.

Laboratory Tests During Thymoglobulin therapy, monitoring the lymphocyte count (i.e., total lymphocyte and/or T-cell subset) may help assess the degree of T-cell depletion (See Pharmacokinetics and Immunogenicity).

For safety, WBC and platelet counts should also be monitored (See DOSAGE AND ADMINISTRATION).

Drug Interactions No drug interaction studies have been performed.

Because Thymoglobulin is administered to patients receiving a standard immunosuppressive regimen, this may predispose patients to overimmunosuppression.

Many transplant centers decrease maintenance immunosuppression therapy during the period of antibody therapy.

Thymoglobulin can stimulate the production of antibodies which crossreact with rabbit immune globulins (See Pharmacokinetics and Immunogenicity).

Drug/Laboratory Test Interactions Thymoglobulin has not been shown to interfere with any routine clinical laboratory tests which do not use immunoglobulins.

Thymoglobulin may interfere with rabbit antibody-based immunoassays and with cross-match or panel-reactive antibody cytotoxicity assays.

Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic and mutagenic potential of Thymoglobulin and its potential to impair fertility have not been studied.

Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with Thymoglobulin.

It is also not known whether Thymoglobulin can cause fetal harm or can affect reproduction capacity.

Thymoglobulin should be given to a pregnant woman only if clearly needed.

Nursing Mothers 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, breast-feeding should be discontinued during Thymoglobulin therapy.

Pediatric Use The safety and effectiveness of Thymoglobulin in pediatric patients has not been established in controlled trials.

However, the dose, efficacy, and adverse event profile are not thought to be different from adults based on limited European studies and US compassionate use.

Adverse reactions

ADVERSE REACTIONS Clinical Trials US Phase 3 Study Thymoglobulin adverse reactions are generally manageable or reversible.

In the US Phase 3 randomized controlled clinical trial (n=163) comparing the efficacy and safety of Thymoglobulin and Atgam, adverse reactions occurring at least 5 % more frequently in the Thymoglobulin group than in the Atgam comparison group are shown in Table 2.

Malignancies were reported in 3 patients who received Thymoglobulin and in 3 patients who received Atgam during the one-year follow-up period.

These included two post-transplant lymphoproliferative diseases (PTLDs) in the Thymoglobulin group and two PTLDs in the Atgam group.

Table 2.

Adverse Reactions More Frequently Reported Following Thymoglobulin Infusion (incidence?5 %) than following AtgamTreatment Emergent Adverse Events/Reactions (TEAE) are summarized.

Preferred Term Thymoglobulin n=82 Atgam n=81 No. of Patients (%) No. of Patients (%) Frequently Reported Events Chills 47 (57.3) 35 (43.2)

Leukopenia 47 (57.3) 24 (29.6) Headache 33 (40.2) 28 (34.6) Abdominal pain 31 (37.8) 22 (27.2) Hypertension 30 (36.6) 23 (28.4) Nausea 30 (36.6) 23 (28.4) Dyspnea 23 (28.0) 16 (19.8) Hyperkalemia 22 (26.8) 15 (18.5) Myalgia 16 (19.5) 10 (12.3) Insomnia 16 (19.5) 10 (12.3) Hypotension 13 (15.9) 6 (7.4) Rash 11 (13.4) 6 (7.4) Sweating 11 (13.4) 4 (4.9) Malaise 11 (13.4) 3 (3.7) Acne 10 (12.2) 4 (4.9) Overdose 5 (6.1) 0 (0.0) Treatment-emergent thrombocytopenia was reported in 30 (37 %) of patients following Thymoglobulin infusion and in 36 (44 %) of patients following Atgam infusion.

Infections occurring more frequently in the Thymoglobulin group during the 3-month follow-up are summarized in Table 3.

No significant differences were seen between the Thymoglobulin and Atgam groups for all types of infections, and the incidence of cytomegalovirus (CMV) infection was equivalent in both groups.

(Viral prophylaxis was by the center 's discretion during antibody treatment, but all centers used gancyclovir infusion during treatment.)

Table 3.

Infections BODY SYSTEM Preferred Term Thymoglobulin n=82 Atgam n=81 No. of Patients (%) Total Reports No. of Patients (%) Total Reports BODY AS A WHOLE 30 (36.6) 36 22 (27.2) 29 Infection 25 (30.5) 26 19 (23.5) 21 Other 14 (17.1) 15 11 (13.6) 12 CMV 11 (13.4) 11 9 (11.1) 9 Sepsis 10 (12.2) 10 7 (9.6) 7 DIGESTIVE 5 (6.1) 5 3 (3.7) 3 Gastrointestinal moniliasis 4 (4.9) 4 1 (1.2) 1 Gastritis 1 (1.2) 1 0 (0.0) 0 SKIN 4 (4.9) 4 0 (0.0) 0 Herpes simplex 4 (4.9) 4 0 (0.0) 0 Adverse reactions occurring during or shortly following Thymoglobulin infusion (infusion-associated adverse reactions) are generally manageable or reversible.

Adverse reactions occurring during or within 24 hours of infusion in at least 5 % of patients in the Thymoglobulin group are listed in Table 4.

Table 4.

Infusion-Associated Adverse Reactions Occurring in at Least 5 % of Thymoglobulin SubjectsTreatment-emergent adverse events that occurred during or within 24 hours of an infusion are summarized Preferred term Thymoglobulin (N=82) Atgam (N=81) No. of Patients (%) No. of Patients (%) Chills 45 (54.9 %) 28 (34.6 %) Leukopenia 40 (48.8 %) 10 (12.3 %) Fever 38 (46.3 %) 39 (48.1 %) Nausea 24 (29.3 %) 17 (21.0 %) Thrombocytopenia 24 (29.3 %) 30 (37.0 %) Headache 22 (26.8 %) 22 (27.2 %) Hypertension 22 (26.8 %) 16 (19.8 %) Pain 21 (25.6 %) 19 (23.5 %) Tachycardia 19 (23.2 %) 16 (19.8 %) Diarrhea 16 (19.5 %) 15 (18.5 %) Peripheral edema 16 (19.5 %) 13 (16.0 %) Vomiting 16 (19.5 %) 12 (14.8 %) Abdominal pain 14 (17.1 %) 13 (16.0 %) Hyperkalemia 14 (17.1 %) 12 (14.8 %)

Arthralgia 12 (14.6 %) 11 (13.6 %) Constipation 12 (14.6 %) 16 (19.8 %) Dyspnea 12 (14.6 %) 11 (13.6 %) Asthenia 11 (13.4 %) 11 (13.6 %) Leukocytosis 11 (13.4 %) 9 (11.1 %) Anemia 10 (12.2 %) 11 (13.6 %) Back pain 10 (12.2 %) 8 (9.9 %) Hypokalemia 10 (12.2 %) 7 (8.6 %) Insomnia 10 (12.2 %) 4 (4.9 %) Lung disorder 10 (12.2 %) 6 (7.4 %) Myalgia 9 (11.0 %) 7 (8.6 %) Dyspepsia 8 (9.8 %) 6 (7.4 %) Hypotension 8 (9.8 %) 2 (2.5 %) Acidosis 7 (8.5 %) 4 (4.9 %)

Chest pain 7 (8.5 %) 7 (8.6 %) Malaise 7 (8.5 %) 3 (3.7 %) Anxiety 6 (7.3 %) 8 (9.9 %) Anorexia 5 (6.1 %) 1 (1.2 %) Cough increased 6 (7.3 %) 8 (9.9 %) Rash 6 (7.3 %) 4 (4.9 %) Edema 5 (6.1 %) 12 (14.8 %) Hypophosphatemia 5 (6.1 %) 3 (3.7 %) Pruritus 5 (6.1 %) 4 (4.9 %) Sweating 5 (6.1 %) 4 (4.9 %) Treatment-emergent serum sickness was reported in 2 (2.4 %) of patients following Thymoglobulin infusion and in no patients following Atgam infusion.

Post-marketing Experience The following adverse reactions have been identified during post approval use of Thymoglobulin.

Because these 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.

Infusion-Associated Adverse Reactions and Immune System Disorders IARs may occur following the administration of Thymoglobulin and may occur as soon as the first or second infusion during a single course of Thymoglobulin treatment.

Clinical manifestations of IARs have included any of the following signs and symptoms: fever, chills/rigors, dyspnea, nausea/vomiting, diarrhea, hypotension or hypertension, malaise, rash, urticaria, decreased oxygen saturation, and/or headache.

IARs with Thymoglobulin are generally manageable with a reduction in infusion rates and/or with medications.

(See PRECAUTIONS).

Transient reversible elevations in aminotransferases without any clinical signs or symptoms have also been reported during Thymoglobulin administration.

Serious and fatal anaphylactic reactions have been reported (See WARNINGS).

The fatalities occurred in patients who did not receive epinephrine during the event.

IARs consistent with cytokine release syndrome (CRS) have been reported.

Severe and potentially life-threatening CRS cases have also been reported.

Post-marketing reports of severe CRS have included cardiorespiratory dysfunction (including hypotension, acute respiratory distress syndrome, pulmonary edema, myocardial infarction, tachycardia, and/or death).

During post-marketing surveillance, reactions such as fever, rash, urticaria, arthralgia, lymphadenopathy, proteinuria, decreased oxygen saturation, and/or myalgia, indicating possible serum sickness, have been reported.

Serum sickness tends to occur 5 to 15 days after onset of Thymoglobulin therapy.

Symptoms are manageable with corticosteroid treatment.

Adverse Events Due to Immunosuppression Infections, reactivation of infection, febrile neutropenia and sepsis have been reported after Thymoglobulin administration in combination with multiple immunosuppressive agents.

These infections can be fatal.

(See WARNINGS and PRECAUTIONS).

Malignancies including, but not limited to lymphoproliferative disorders (LPD) and other lymphomas (which may be virally mediated) as well as solid tumors have been reported.

These events have been associated with fatal outcome.

(See PRECAUTIONS).

These adverse events were reported with use of a combination of multiple immunosuppressive agents.

Blood and lymphatic system disorders Coagulopathy has been reported without clinical signs or symptoms related to bleeding, and generally resolves within a few days.

Cases of disseminated intravascular coagulopathy have occurred secondary to anaphylaxis or infusion associated reaction.

Usage information

Dosing and administration

DOSAGE AND ADMINISTRATION The recommended dosage of Thymoglobulin for treatment of acute renal graft rejection is 1.5 mg/kg of body weight administered daily for 7 to 14 days.

The recommended route of administration is intravenous infusion using a high-flow vein.

Thymoglobulin should be infused over a minimum of 6 hours for the first infusion and over at least 4 hours on subsequent days of therapy.

Thymoglobulin should be administered through an in-line 0.22 micrometer filter.

Thymoglobulin is supplied as a 10 mL vial containing lyophilized (solid) Thymoglobulin (25 mg).

Please see Preparation for Administration for vial reconstitution and dilution in infusion solution recommendations.

Investigations indicate that Thymoglobulin is less likely to produce side effects when administered at the recommended flow rate.

Administration of antiviral prophylactic therapy is recommended.

Premedication with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to the infusion is recommended and may reduce the incidence and intensity of side effects during the infusion (See PRECAUTIONS: General and ADVERSE REACTIONS: Post-Marketing Experience).

Medical personnel should monitor patients for adverse events during and after infusion.

Monitoring T-cell counts (absolute and/or subsets) to assess the level of T-cell depletion is recommended.

Total white blood cell and platelet counts should be monitored.

Overdosage of Thymoglobulin may result in leukopenia (including lymphopenia and neutropenia) and/or thrombocytopenia.

The Thymoglobulin dose should be reduced by one-half if the WBC count is between 2,000 and 3,000 cells/ mm3 or if the platelet count is between 50,000 and 75,000 cells/ mm3.

Stopping Thymoglobulin treatment should be considered if the WBC count falls below 2,000 cells/ mm3 or platelets below 50,000 cells/ mm3.

Preparation for 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).

Reconstituted Thymoglobulin is physically and chemically stable for up to 24 hours at room temperature; however, room temperature storage is not recommended.

As Thymoglobulin contains no preservatives, reconstituted product should be used immediately.

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).

Mix the solution by inverting the bag gently only once or twice.

Infusion 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.

Pregnancy and lactation
Nursing Mothers 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, breast-feeding should be discontinued during Thymoglobulin therapy.

Interactions

Drug Interactions No drug interaction studies have been performed.

Because Thymoglobulin is administered to patients receiving a standard immunosuppressive regimen, this may predispose patients to overimmunosuppression.

Many transplant centers decrease maintenance immunosuppression therapy during the period of antibody therapy.

Thymoglobulin can stimulate the production of antibodies which crossreact with rabbit immune globulins (See Pharmacokinetics and Immunogenicity).

More information

Category Value
Authorisation number BLA103869
Agency product number D7RD81HE4W
Orphan designation No
Product NDC 58468-0080
Date Last Revised 20-04-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 107050
Storage and handling

Storage Store in refrigerator at 2°C to 8°C (36°F to 46°F).

Protect from light.

Do not freeze.

Do not use after the expiration date indicated on the label.

Reconstituted Thymoglobulin is physically and chemically stable for up to 24 hours at room temperature; however, room temperature storage is not recommended.

As Thymoglobulin contains no preservatives, reconstituted product should be used immediately.

Infusion solutions of Thymoglobulin must be used immediately.

Any unused drug remaining after infusion must be discarded.

Marketing authorisation holder Genzyme Corporation