h chemotherapy alone. The most common pulmonary toxicitywas dyspnea (NCI-CTC Grade 2–5: 11.8% vs. 4.6% [Study 1]; NCI-CTC Grade 2–5: 2.4% vs. 0.2% [Study
2]).
Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving trastuzumab compared with0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receivingtrastuzumab, one as a component of multi-organ system failure, as compared to 1 patient receivingchemotherapy alone.
In Study 3, there were 4 cases of interstitial pneumonitis in the one-year trastuzumab treatment armcompared to none in the observation arm at a median follow-up duration of 12.6 months.
Metastatic Breast Cancer
Among women receiving trastuzumab for treatment of metastatic breast cancer, the incidence of pulmonarytoxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experienceas part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia,dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratorydistress syndrome. For a detailed description, [see Warnings and Precautions (5.4)].
Thrombosis/Embolism
In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher inpatients receiving trastuzumab and chemotherapy compared to chemotherapy alone in three studies (2.6%vs. 1.5% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]).
Diarrhea
Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea(6.7% vs. 5.4% [Study 1]) and of NCI-CTC Grade 3–5 diarrhea (2.2% vs. 0% [Study 2]), and of Grade 1–4
diarrhea (7% vs. 1% [Study 3; one-year trastuzumab treatment at 12.6 months median duration offollow-up]) were higher in patients receiving trastuzumab as compared to controls. In Study 4, theincidence of Grade 3–4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1–4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving trastuzumab. Of patientsreceiving trastuzumab as a single agent for the treatment of metastatic breast cancer, 25% experienceddiarrhea. An increased incidence of diarrhea was observed in patients receiving trastuzumab incombination with chemotherapy for treatment of metastatic breast cancer.
Renal Toxicity
In Study 7 (metastatic gastric cancer) on the trastuzumab-containing arm as compared to the chemotherapyalone arm the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failurewas 2.7% on the trastuzumab-containing arm compared to 1.7% on the chemotherapy only arm.
Treatment discontinuation for renal insufficiency/failure was 2% on the trastuzumab-containing arm and0.3% on the chemotherapy only arm.
In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence ofglomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18months from initiation of trastuzumab therapy. Pathologic findings included membranousglomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complicationsincluded volume overload and congestive heart failure.
6.2 Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity.
The detection of antibody formation is highly dependent o |
