Thymoglobulin

Name: Thymoglobulin

Side effects

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 ³5%) than following Atgam*

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 Adverse Events/Reactions (TEAE) are summarized.

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 Subjects*

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 adverse events that occurred during or within 24 hours of an infusion are summarized

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. Cases of hepatocellular injury, hepatotoxicity, or hepatic failure have been reported mainly in patients treated with thymoglobulin for hematologic disease. These reports included patients with hypoxic hepatitis, reactivation of hepatitis, or other underlying conditions, and who received concomitant medications with hepatotoxic potential. 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.

Advice to Patients

  • Importance of informing patients about the potential benefits of ATG (rabbit) and attendant risks of immunosuppressive therapy.b

  • Risk of decreased number of platelets and/or WBCs, including lymphocytes.b Necessity of administration under supervision of a clinician with regular monitoring of platelet and WBC counts.b

  • Potential for reduction of lymphocyte counts, which could increase risk of infection or malignancy.b Importance of informing clinicians promptly if any signs or symptoms of infection or malignancy occur.b

  • Advise patient of risk of possible fever, chills, itching, and/or rash during ATG (rabbit) infusion and that medication will be given to help control these reactions.b

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal or nutritional supplements, as well as any concomitant illnesses.b

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.b

  • Importance of informing patients of other important precautionary information.b (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Antithymocyte Globulin (Rabbit)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

25 mg

Thymoglobulin

Genzyme

Commonly used brand name(s)

In the U.S.

  • Thymoglobulin

Available Dosage Forms:

  • Powder for Solution

Therapeutic Class: Immune Suppressant

Before Using Thymoglobulin

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of anti-thymocyte globulin (rabbit) injection in children. However, safety and efficacy have not been established.

Geriatric

No information is available on the relationship of age to the effects of anti-thymocyte globulin (rabbit) injection in geriatric patients.

Pregnancy

Pregnancy Category Explanation
All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Adenovirus Vaccine
  • Bacillus of Calmette and Guerin Vaccine, Live
  • Cholera Vaccine, Live
  • Influenza Virus Vaccine, Live
  • Measles Virus Vaccine, Live
  • Mumps Virus Vaccine, Live
  • Poliovirus Vaccine, Live
  • Rotavirus Vaccine, Live
  • Rubella Virus Vaccine, Live
  • Smallpox Vaccine
  • Typhoid Vaccine
  • Varicella Virus Vaccine
  • Yellow Fever Vaccine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Allergic to rabbit protein, history of—Should not be used in patients with this condition.
  • Infection—May decrease your body's ability to fight infection.
  • Liver disease—Use with caution. May make this condition worse.

Thymoglobulin Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common
  • Black, tarry stools
  • bladder pain
  • bleeding gums
  • blurred vision
  • chest pain
  • chills
  • cloudy or bloody urine
  • cold
  • confusion
  • cough or hoarseness
  • diarrhea
  • dizziness
  • fast heartbeat
  • fever
  • frequent urge to urinate
  • general feeling of discomfort or illness
  • headache
  • irregular or slow heartbeat
  • joint pain
  • loss of appetite
  • lower back or side pain
  • muscle aches and pains
  • nausea
  • nervousness
  • numbness or tingling around the lips, hands, or feet
  • painful or difficult urination
  • pounding in the ears
  • runny nose
  • shivering
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • swollen glands
  • troubled breathing
  • unexplained anxiety
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • vomiting
  • weakness or heaviness of the legs
Less common
  • Burning feeling in chest or stomach tenderness
  • burning or stinging of the skin
  • indigestion
  • inflammation of joints
  • painful cold sores or blisters on the lips, nose, eyes, or genitals
  • stomach upset
Rare
  • Difficulty swallowing
  • hives, itching, rash
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Abdominal or stomach pain
  • anxiety
  • loss of strength or energy
  • nausea
  • pain
  • swelling of the ankles, feet, and fingers
  • tightness in the chest

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

What do I need to tell my doctor BEFORE I take Thymoglobulin?

  • If you have an allergy to lymphocytic immune globulin, rabbit proteins, or any other part of Thymoglobulin (antithymocyte globulin (rabbit)).
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have an infection.
  • If you are breast-feeding. Do not breast-feed while you take this medicine.

This is not a list of all drugs or health problems that interact with Thymoglobulin.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some things I need to know or do while I take Thymoglobulin?

  • Tell all of your health care providers that you take Thymoglobulin. This includes your doctors, nurses, pharmacists, and dentists.
  • Some people have unsafe allergic effects or bad side effects during the infusion or within 24 hours of the infusion. Talk with the doctor.
  • Very bad and sometimes deadly allergic side effects have rarely happened. Talk with your doctor.
  • You may have more of a chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu. Some infections have been very bad and even deadly.
  • You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
  • The chance of cancer is higher after using this medicine. Talk with the doctor.
  • You may have a chance of getting post-transplant lymphoproliferative disorder (PTLD). PTLD happens when your white blood cells grow out of control and can lead to cancer and death.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take Thymoglobulin.
  • Talk with your doctor before getting any vaccines. Use with this medicine may either raise the chance of an infection or make the vaccine not work as well.
  • A very bad and sometimes deadly health problem called cytokine release syndrome (CRS) has happened in people getting Thymoglobulin. Call your doctor right away if you have chills, dizziness, feeling tired or weak, fever, headache, passing out, rash, swelling of the face, trouble breathing, upset stomach or throwing up, or wheezing.
  • Use birth control that you can trust to prevent pregnancy while taking this medicine and for 3 months after care ends.
  • If you get pregnant while taking Thymoglobulin or within 3 months after your last dose, call your doctor right away.

Adverse Reactions

The most common adverse reactions and laboratory abnormalities (incidence >5% higher than comparator) are urinary tract infection, abdominal pain, hypertension, nausea, shortness of breath, fever, headache, anxiety, chills, increased potassium levels in the blood, and low counts of platelets and white blood cells.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Prophylaxis of Acute Rejection

The efficacy and 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). There were more Adverse Reactions (incidence >5%) occurring within 12 months of transplantation in the Thymoglobulin group than in the Active Comparator group (Table 1).

Table 1: Adverse Reactions and Laboratory Abnormalities Reported More Frequently (incidence* >5%) Following Thymoglobulin versus Active Comparator †
Adverse Reaction
[n (%)*]
Thymoglobulin
(N=141)
Active Comparator
(N=137)
* Adverse reactions are treatment emergent adverse events (TEAE) reported as related to the study agent in at least 1 patient.
* Number (percentage) is shown regardless of causal relationship. † basiliximab ‡ Hyperkalemia: blood potassium ≥5.5 mmol/L; Leukopenia: WBC <3000 cells/mm3. Thrombocytopenia: platelet count <75,000 cells/mm3.
Urinary tract infection 55 (39%) 36 (26%)
Pyrexia
  (fever)
39 (28%) 25 (18%)
Headache 26 (18%) 17 (12%)
Hyperlipidemia
(high lipids in blood)
21 (15%) 9 (7%)
Anxiety 20 (14%) 12 (9%)
Chills 13 (9%) 5 (4%)
Laboratory Abnormalities‡
Hyperkalemia
  (high potassium)
81 (57%) 70 (51%)
Leukopenia
(low white blood cell count)
89 (63%) 20 (15%)
Thrombocytopenia
  (low platelet count)
23 (16%) 7 (5%)

Hematologic Abnormalities

The incidence of laboratory abnormalities of leukopenia with WBC<3000 cells/mm3 was 63% in Thymoglobulin patients and 15% in Active Comparator patients. The incidence of thrombocytopenia laboratory abnormalities with platelets <75,000 cells/ mm3 within 1 month following transplantation was 16% in Thymoglobulin patients and 5% in Active Comparator patients.

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.

Table 2: Infections Reported in ≥5% of Study Patients
Infection Thymoglobulin
(N=141)
Active Comparator*
(N=137)
All Severe/Unknown All Severe/Unknown
* basiliximab † Urinary tract infection group includes: Urinary tract infections, Urinary tract infection fungal, Urinary tract infection bacterial, Bacterial pyelonephritis, Urosepsis. ‡ Sepsis group includes: Sepsis, Escherichia sepsis, Staphylococcal bacteremia. § Lower respiratory tract and lung infections group includes: Lower respiratory tract and lung infections, and Pneumonia pseudomonal. ¶ The collective term "cytomegaloviral infections" includes CMV duodenitis, CMV gastritis, CMV hepatitis, CMV infection, and CMV viremia.
Urinary tract infections† 59 (42%) 12 (9%) 39 (29%) 3 (2%)
Sepsis‡ 9 (6%) 5 (4%) 1 (1%) 1 (1%)
Lower respiratory tract and lung infections§ 18 (13%) 2 (1%) 16 (12%) 4 (3%)
Upper respiratory tract infection 15 (11%) 0 15 (11%) 1 (1%)
Nasopharyngitis 7 (5%) 0 9 (7%) 0
Cytomegaloviral infections¶ 8 (6%) 2 (1%) 21 (18%) 7 (7%)
Herpes zoster 7 (5%) 0 2 (2%) 1 (1%)
Oral candidiasis 8 (6%) 0 11 (8%) 0

Adverse Drug Reactions Occurring within 24 Hours and Infusion-Associated Reactions

Adverse reactions occurring during or within 24 hours of infusion in >5% of patients in the Thymoglobulin group are summarized in Table 3.

Table 3: Adverse Drug Reactions* Occurring within 24 Hours of Infusion and with >5% Incidence in Patients who Received Thymoglobulin
Primary System Organ Class
n (%)
Thymoglobulin
(N=141)
Active Comparator†
(N=137)
* Adverse reactions that occurred during or within 24 hours of an infusion, and where the incidence was higher in the Thymoglobulin group † basiliximab
Constipation 47 (33%) 23 (17%)
Anemia
  (low red blood cell count)
35 (25%) 19 (14%)
Hyperkalemia
  (high potassium)
33 (23%) 18 (13%)
Hypertension
  (elevated blood pressure)
25 (18%) 19 (14%)
Leukopenia and White blood cell count decreased 29 (21%) 0
Pyrexia
(fever)
18 (13%) 3 (2%)
Vomiting 17 (12%) 14 (10%)
Thrombocytopenia
  (low platelet count)
13 (9%) 1 (1%)
Abdominal pain 11 (8%) 6 (4%)
Anxiety 10 (7%) 2 (2%)
Hyperphosphatemia
  (high phosphate)
10 (7%) 2 (2%)
Tachycardia
(fast heart rate)
10 (7%) 5 (4%)
Acidosis
  (accumulation of acid in the body)
9 (6%) 8 (6%)
Diarrhea 9 (6%) 1 (1%)
Hypokalemia
  (low potassium)
9 (6%) 4 (3%)

Infusion-associated reactions

Adverse reactions that occurred within 24 hours after the completion of the Thymoglobulin administration and are considered as possible infusion associated reactions (IARs) include the following: anxiety, confusional state, agitation, restlessness, headache, lethargy, dizziness, decreased sensitivity, fast heart rate, myocardial infarction, elevated blood pressure, decreased blood pressure, cough, throat irritation, reduced oxygen supply to tissues, shortness of breath, pulmonary edema, pain in mouth and throat, diarrhea, upper abdominal pain, abdominal tenderness, abdominal discomfort, nausea, pruritus, rash, joint pain, fever, chills, lack of energy, localized edema, malaise, and chest pain.

Serum sickness was reported in 6 of 405 patients enrolled across completed studies where patients had been treated with Thymoglobulin for the prophylaxis of acute rejection in patients receiving a kidney transplant. Anaphylactic shock was reported in 2 of 405 patients enrolled across completed studies.

Treatment of acute rejection

In the US Phase 3 randomized controlled clinical trial (n=163) comparing the efficacy and safety of Thymoglobulin® and Active Comparator in the treatment of acute rejection in kidney transplant patients, adverse reactions occurring at least 5% more frequently in the Thymoglobulin group than in the Active Comparator group are shown in Table 4. Malignancies were reported in 3 patients who received Thymoglobulin and in 3 patients who received Active Comparator during the one-year follow-up period. These included two cases of post-transplant lymphoproliferative disease (PTLD) in the Thymoglobulin group and two cases of PTLD in the Active Comparator group.

Table 4: Adverse Reactions* Reported More Frequently (incidence ≥5%) Following Thymoglobulin versus Active Comparator†
Frequently Reported Events Thymoglobulin
n=82
Active Comparator
n=81
* Treatment-emergent adverse events/reactions (TEAE) are summarized. † ATG-E
Chills 47 (57%) 35 (43%)
Leukopenia
  (low white blood cell count)
47 (57%) 24 (30%)
Headache 33 (40%) 28 (35%)
Abdominal pain 31 (38%) 22 (27%)
Hypertension
  (elevated blood pressure)
30 (37%) 23 (28%)
Nausea 30 (37%) 23 (28%)
Dyspnea 23 (28%) 16 (20%)
Hyperkalemia
  (high potassium)
22 (27%) 15 (19%)
Myalgia 16 (20%) 10 (12%)
Insomnia 16 (20%) 10 (12%)
Hypotension
  (decreased blood pressure)
13 (16%) 6 (7%)
Rash 11 (13%) 6 (7%)
Sweating 11 (13%) 4 (5%)
Malaise 11 (13%) 3 (4%)
Acne 10 (12%) 4 (5%)
Overdose 5 (6%) 0

Treatment-emergent thrombocytopenia was reported in 30 (37%) of patients following Thymoglobulin infusion and in 36 (44%) of patients following Active Comparator infusion.

Infections occurring more frequently in the Thymoglobulin group during the 3-month follow-up are summarized in Table 5. No significant differences were seen between the Thymoglobulin and Active Comparator groups for all types of infections. The incidence of CMV infection was the same in both groups. Viral prophylaxis was by the center's discretion during antibody treatment, but all centers used ganciclovir infusion during treatment.

Table 5: Infections
Thymoglobulin
n=82
Active Comparator*
n=81
Body System No. of Patients (%) Total Reports No. of Patients (%) Total Reports
* ATG-E
Body as a Whole 30 (37) 36 22 (27) 29
  Infection 25 (31) 26 19 (24) 21
  Other 14 (17) 15 11 (14) 12
  CMV 11 (13) 11 9 (11) 9
  Sepsis 10 (12) 10 7 (10) 7
Digestive 5 (6) 5 3 (4) 3
  Gastrointestinal moniliasis 4 (5) 4 1 (1) 1
  Gastritis 1 (1) 1 0 (0) 0
Skin 4 (5) 4 0 (0) 0
  Herpes simplex 4 (5) 4 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 6.

Table 6: Adverse Reactions Occurring within 24 Hours of Infusion and with >5% Incidence in Thymoglobulin Patients
Adverse Reaction Thymoglobulin
(N=82)
Active Comparator*
(N=81)
* Treatment-emergent adverse events that occurred during or within 24 hours of an infusion are summarized
* ATG-E
Chills 45 (55%) 28 (35%)
Leukopenia
(low white blood cell count)
40 (49%) 10 (12%)
Fever 38 (46%) 39 (48%)
Nausea 24 (29%) 17 (21%)
Thrombocytopenia
(low platelet count)
24 (29%) 30 (37%)
Headache 22 (27%) 22 (27%)
Hypertension 22 (27%) 16 (20%)
Pain 21 (26%) 19 (24%)
Tachycardia
(fast heart rate)
19 (23%) 16 (20%)
Diarrhea 16 (20%) 15 (19%)
Peripheral edema
(swelling)
16 (20%) 13 (16%)
Vomiting 16 (20%) 12 (15%)
Abdominal pain 14 (17%) 13 (16%)
Hyperkalemia
(increased potassium level)
14 (17%) 12 (15%)
Arthralgia
(joint pain)
12 (15%) 11 (14%)
Constipation 12 (15%) 16 (20%)
Dyspnea
(shortness of breath)
12 (15%) 11 (14%)
Asthenia
(lack of energy)
11 (13%) 11 (14%)
Leukocytosis
(increased amount of white blood cells)
11 (13%) 9 (11%)
Anemia
(decreased amount of red blood cells or hemoglobin)
10 (12%) 11 (14%)
Back pain 10 (12%) 8 (10%)
Hypokalemia
(decreased potassium level)
10 (12%) 7 (9%)
Insomnia 10 (12%) 4 (5%)
Lung disorder 10 (12%) 6 (7%)
Myalgia 9 (11%) 7 (9%)
Dyspepsia 8 (10%) 6 (7%)
Hypotension
(decreased blood pressure)
8 (10%) 2 (3%)
Acidosis
(accumulation of acid in the body)
7 (9%) 4 (5%)
Chest pain 7 (9%) 7 (9%)
Malaise 7 (9%) 3 (4%)
Anxiety 6 (7%) 8 (10%)
Anorexia 5 (6%) 1 (1%)
Cough increased 6 (7%) 8 (10%)
Rash 6 (7%) 4 (5%)
Edema 5 (6%) 12 (15%)
Hypophosphatemia
(decreased phosphate)
5 (6%) 3 (4%)
Itchiness 5 (6%) 4 (5%)
Sweating 5 (6%) 4 (5%)

Treatment-emergent serum sickness was reported in 2 (2%) of patients following Thymoglobulin infusion and in no patients following Active Comparator infusion.

Postmarketing Experience

The following adverse reactions have been identified during postapproval 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 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 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 Warnings and Precautions (5.3)]. Some of these reactions such as arthralgia/myalgia, lymphadenopathy, proteinuria, and decreased oxygen saturation tend to occur 5 to 15 days after Thymoglobulin infusion and are consistent with serum sickness. Symptoms are manageable with corticosteroid treatment.

Serious and fatal anaphylactic reactions have been reported. The fatalities occurred in patients who did not receive epinephrine during the event [see Warnings and Precautions (5.2)].

IARs consistent with cytokine release syndrome (CRS) have been reported. Severe and potentially life-threatening CRS cases have also been reported. Postmarketing reports of severe CRS have included cardiorespiratory dysfunction (including hypotension, acute respiratory distress syndrome, pulmonary edema, myocardial infarction, tachycardia, and/or death).

Hepatic Disorders

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

Immunosuppression-Related Disorders

Infections, reactivation of infection, febrile neutropenia, and sepsis have been reported after Thymoglobulin administration in combination with multiple immunosuppressive agents, which may be fatal [see Warnings and Precautions (5.5)].

Malignancies including, but not limited to, lymphoproliferative disorders (LPD) and solid tumors have been reported. These events have been associated with fatal outcome. These adverse reactions were reported with use of a combination of multiple immunosuppressive agents [see Warnings and Precautions (5.6)].

Blood and Lymphatic System Disorders

Coagulopathy has been reported without clinical signs or symptoms of bleeding, and generally resolves within a few days. Cases of disseminated intravascular coagulopathy have occurred secondary to anaphylaxis or infusion-associated reactions.

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