ADVERSE REACTIONS
Clinical Trials
US Phase 3 Study
Thymoglobulin adverse events are generally manageable or reversible. In
the US Phase 3 controlled clinical trial (n=163) comparing the efficacy and safety
of Thymoglobulin and Atgam, there were no significant differences in clinically
significant adverse events between the two treatment groups (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. Frequently Reported and Significant Adverse Events
|
Preferred Term
|
Thymoglobulin
n=82
|
Atgam
n=81
|
p Value
|
No.
of
Patients |
(%) |
No.
of
Patients |
(%) |
|
Frequently Reported Events
|
|
Fever |
52 |
(63.4) |
51 |
(63.0) |
1.0 |
|
Chills |
47 |
(57.3) |
35 |
(43.2) |
0.086 |
|
Leukopenia |
47 |
(57.3) |
24 |
(29.6) |
<0.001 |
|
Pain |
38 |
(46.3) |
35 |
(43.2) |
0.753 |
|
Headache |
33 |
(40.2) |
28 |
(34.6) |
0.518 |
| Abdominal
pain |
31 |
(37.8) |
22 |
(27.2) |
0.181 |
|
Diarrhea |
30 |
(36.6) |
26 |
(32.1) |
0.622 |
|
Hypertension |
30 |
(36.6) |
23 |
(28.4) |
0.316 |
|
Nausea |
30 |
(36.6) |
23 |
(28.4) |
0.316 |
|
Thrombocytopenia |
30 |
(36.6) |
36 |
(44.4) |
0.341 |
| Peripheral
edema |
28 |
(34.1) |
28 |
(34.6) |
1.0 |
|
Dyspnea |
23 |
(28.0) |
16 |
(19.8) |
0.271 |
| Asthenia |
22 |
(26.8) |
26 |
(32.1) |
0.495 |
|
Hyperkalemia |
22 |
(26.8) |
15 |
(18.5) |
0.262 |
|
Tachycardia |
22 |
(26.8) |
19 |
(23.5) |
0.719 |
|
Significant Events
|
|
|
|
|
|
| Leukopenia |
47 |
(57.3) |
24 |
(29.6) |
<0.001 |
| Malaise |
11 |
(13.4) |
3 |
(3.7) |
0.047 |
| Dizziness |
7 |
(8.5) |
20 |
(24.7) |
0.006 |
Infections occurring in both treatment groups 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
|
p Value
|
No.
of
Patients
|
(%)
|
Total
Reports
|
No.
of
Patients |
(%) |
Total
Reports |
| BODY AS A
WHOLE |
30 |
(36.6) |
36 |
22 |
(27.2) |
29 |
0.240 |
|
Infection |
25 |
(30.5) |
26 |
19 |
(23.5) |
21 |
0.378 |
| Other |
14 |
(17.1) |
15 |
11 |
(13.6) |
12 |
0.665 |
| CMV |
11 |
(13.4) |
11 |
9 |
(11.1) |
9 |
0.812 |
|
Sepsis |
10 |
(12.2) |
10 |
7 |
(9.6) |
7 |
0.610 |
|
Moniliasis |
0 |
(0.0) |
0 |
1 |
(1.2) |
1 |
0.497 |
| DIGESTIVE |
5 |
(6.1) |
5 |
3 |
(3.7) |
3 |
0.720 |
|
Gastrointestinal moniliasis
|
4 |
(4.9) |
4 |
1 |
(1.2) |
1 |
0.367 |
| Oral
moniliasis |
3 |
(3.7) |
0 |
2 |
(2.5) |
1 |
0.497 |
|
Gastritis |
1 |
(1.2) |
1 |
0 |
(0.0) |
0 |
1.000 |
| RESPIRATORY |
0 |
(0.0) |
0 |
1 |
(1.2) |
1 |
0.497 |
|
Pneumonia |
0 |
(0.0) |
0 |
1 |
(1.2) |
1 |
0.497 |
| SKIN |
4 |
(4.9) |
4 |
0 |
(0.0) |
0 |
0.120 |
| Herpes
simplex |
4 |
(4.9) |
4 |
0 |
(0.0) |
0 |
0.120 |
| UROGENITAL |
15 |
(18.3) |
15 |
22 |
(29.2) |
22 |
0.195 |
| Urinary
tract infection |
15 |
(18.3) |
15 |
21 |
(25.9) |
21 |
0.262 |
|
Vaginitis |
0 |
(0.0) |
0 |
1 |
(1.2) |
1 |
0.497 |
| NOT
SPECIFIED |
0 |
(0.0) |
0 |
2 |
(2.5) |
2 |
0.245 |
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 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 infusion-associated reactions
IARs have included some of the following signs and symptoms: fever, chills/rigors,
dyspnea, nausea/vomiting, diarrhea, hypotension or hypertension, malaise, rash,
and/or headache. IARs with Thymoglobulin are generally manageable with a reduction
in infusion rates and/or with medications (See
PRECAUTIONS
). 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 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,
arthralgia, 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, and sepsis have been reported
after Thymoglobulin administration in combination with multiple immunosuppressive
agents (See
WARNINGS
and
PRECAUTIONS
). Malignancies including, but not limited to post-transplant
lymphoproliferative disorder (PTLD) and other lymphomas as well as solid tumors
have been reported (See
PRECAUTIONS
). These adverse events were reported with use of a combination of
multiple immunosuppressive agents.
|
