THYMOGLOBULIN SIDE EFFECTS
- Generic Name: anti-thymocyte globulin (rabbit) intravenous administration
- Brand Name: Thymoglobulin
- Drug Class: Immune Globulins, Immunosuppressants
SIDE EFFECTS
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) |
| 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%) |
| * 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. |
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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 | |
| 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 |
| *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. |
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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) |
| 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%) |
| *Adverse reactions that occurred during or within 24 hours of an infusion, and where the incidence was higher in the THYMOGLOBULIN group †basiliximab |
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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 |
| 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 adverse events/reactions (TEAE) are summarized. †ATG-E |
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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
| Body System | THYMOGLOBULIN n=82 |
Active Comparator* n=81 |
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| No. of Patients | (%) | Total Reports | No. of Patients | (%) | Total Reports | |
| 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 |
| *ATG-E | ||||||
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) |
| 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 adverse events that occurred during or within 24 hours of an infusion are summarized *ATG-E |
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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. 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.
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.
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.
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.
SRC: NLM .