ades 3/4 All Grades Grades 3/4
Investigations
Neutropenia 230 (78) 101 (34) 212 (73) 83 (29)
Hypokalemia 83 (28) 28 (10) 69 (24) 16 (6)
Anemia 81 (28) 36 (12) 61 (21) 30 (10)
Thrombocytopenia 47 (16) 14 (5) 33 (11) 8 (3)
Blood and Lymphatic System Disorders
Febrile Neutropenia — 15 (5) — 8 (3)
Gastrointestinal Disorders
Diarrhea 109 (37) 27 (9) 80 (28) 11 (4)
Stomatitis 72 (24) 2 (1) 43 (15) 6 (2)
Dysphagia 19 (6) 7 (2) 10 (3) 1 (≤ 1)
Body as a Whole
Fatigue 102 (35) 12 (4) 82 (28) 7 (2)
Fever 54 (18) 3 (1) 36 (12) 0 (0)
Mucosal Inflammation 37 (13) 6 (2) 18 (6) 2 (1)
Chills 23 (8) 1 (≤ 1) 0 (0) 0 (0)
Metabolism and Nutrition Disorders
Weight Decrease 69 (23) 6 (2) 40 (14) 7 (2)
Infections and Infestations
Upper Respiratory Tract Infections 56 (19) 0 (0) 29 (10) 0 (0)
Nasopharyngitis 37 (13) 0 (0) 17 (6) 0 (0)
Renal and Urinary Disorders
Renal Failure and Impairment 53 (18) 8 (3) 42 (15) 5 (2)
Nervous System Disorders
Dysgeusia 28 (10) 0 (0) 14 (5) 0 (0)
The following subsections provide additional detail regarding adverse reactions observed in clinical trials ofadjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience.
Cardiomyopathy
Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment ofbreast cancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observationarm; 12.6 months in the 1-year trastuzumab arm); and in Studies 1 and 2, 7.9 years in the AC-T arm, 8.3 yearsin the AC-TH arm. In Studies 1 and 2, 6% of all randomized patients with post-AC LVEF eva luation were notpermitted to initiate trastuzumab following completion of AC chemotherapy due to cardiac dysfunction (LVEF< LLN or ≥ 16 point decline in LVEF from baseline to end of AC). Following initiation of trastuzumab therapy,
the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receivingtrastuzumab and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patientsreceiving one-year trastuzumab monotherapy compared to observation in Study 3 (see Table 6, Figures 1 and
2). The per-patient incidence of new-onset cardiac dysfunction, as measured by LVEF, remained similar whencompared to the analysis performed at a median follow-up of 2.0 years in the AC-TH arm. This analysis alsoshowed evidence of reversibility of left ventricular dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group being asymptomatic at latest follow-up, and 90.3% having full or partialLVEF recovery.
Table 6a
Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4LVEF <50%and Absolute Decrease from BaselineAbsolute LVEF Decrease
LVEF <
50%
≥ 10%
decrease
≥ 16%
decrease
< 20% and
≥ 10%
≥ 20%
Studies 1 & 2b,c
AC→TH
(n = 1856)
23.1%
(428)
18.5%
(344)
11.2%
(208)
37.9%
(703)
8.9%
(166)
AC→T
(n = 1170)
11.7%
(137)
7.0%
(82)
3.0%
(35)
22.1%
(259)
3.4%
(40)
Study 3d
Trastuzumab
(n = 1678)
8.6%
(144)
7.0%
(118)
3.8%
(64)
22.4%
(376)
3.5%
(59)
Observation
(n = 1708)
2.7%
(46)
2.0%
(35)
1.2%
(20)
11.9%
(204)
1.2%
(21)
Study 4e
TCH
(n = 1056)
8.5%
(90)
5.9%
(6 |
