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Tabulated list of adverse reactions: Presented in Table 16 are adverse reactions that have been reported in association with the use of intravenous trastuzumab alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting.
All the terms included are based on the highest percentage seen in pivotal clinical trials. (See Tables 16a and 16b.)
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Click on icon to see table/diagram/imageDescription of selected adverse reactions: Cardiac dysfunction: Congestive heart failure (NYHA Class II-IV) is a common adverse reaction associated with the use of trastuzumab and has been associated with a fatal outcome (see Precautions). Signs and symptoms of cardiac dysfunction such as dyspnea, orthopnea, increased cough, pulmonary edema, S3 gallop, or reduced ventricular ejection fraction, have been observed in patients treated with trastuzumab (see Precautions).
In 3 pivotal clinical trials of adjuvant trastuzumab given in combination with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (specifically symptomatic Congestive Heart Failure) was similar in patients who were administered chemotherapy alone (i.e., did not receive trastuzumab) and in patients who were administered trastuzumab sequentially after a taxane (0.3-0.4%). The rate was highest in patients who were administered trastuzumab concurrently with a taxane (2.0%). In the neoadjuvant setting, the experience of concurrent administration of trastuzumab and low dose anthracycline regimen is limited (see Precautions).
When trastuzumab was administered after completion of adjuvant chemotherapy NYHA Class III-IV heart failure was observed in 0.6% of patients in the one-year arm after a median follow-up of 12 months. In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA Class III & IV) in the trastuzumab 1 year treatment arm was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%.
Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥ 50% after the event) was evident for 71.4% of trastuzumab-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5% of patients. Approximately 17% of cardiac dysfunction related events occurred after completion of trastuzumab.
In the pivotal metastatic trials of intravenous trastuzumab, the incidence of cardiac dysfunction varied between 9% and 12% when it was combined with paclitaxel compared with 1%-4% for paclitaxel alone. For monotherapy, the rate was 6%-9%. The highest rate of cardiac dysfunction was seen in patients receiving trastuzumab concurrently with anthracycline/cyclophosphamide (27%), and was significantly higher than for anthracycline/cyclophosphamide alone (7%-10%). In a subsequent trial with prospective monitoring of cardiac function, the incidence of symptomatic CHF was 2.2% in patients receiving trastuzumab and docetaxel, compared with 0% in patients receiving docetaxel alone. Most of the patients (79%) who developed cardiac dysfunction in these trials experienced an improvement after receiving standard treatment for CHF.
Infusion reactions, allergic-like reactions and hypersensitivity: It is estimated that approximately 40% of patients who are treated with trastuzumab will experience some form of infusion-related reaction. However, the majority of infusion-related reactions are mild to moderate in intensity (NCI-CTC grading system) and tend to occur earlier in treatment, i.e., during infusions one, two and three and lessen in frequency in subsequent infusions. Reactions include chills, fever, dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratory distress, rash, nausea, vomiting and headache (see Precautions). The rate of infusion-related reactions of all grades varied between studies depending on the indication, the data collection methodology, and whether trastuzumab was given concurrently with chemotherapy or as monotherapy.
Severe anaphylactic reactions requiring immediate additional intervention can occur usually during either the first or second infusion of trastuzumab (see Precautions) and have been associated with a fatal outcome.
Anaphylactoid reactions have been observed in isolated cases.
Hematotoxicity: Febrile neutropenia, leukopenia, anemia, thrombocytopenia and neutropenia occurred very commonly. The frequency of occurrence of hypoprothrombinemia is not known. The risk of neutropenia may be slightly increased when trastuzumab is administered with docetaxel following anthracycline therapy.
Pulmonary events: Severe pulmonary adverse reactions occur in association with the use of trastuzumab and have been associated with a fatal outcome. These include, but are not limited to, pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary edema and respiratory insufficiency (see Precautions).
Immunogenicity: In the neoadjuvant-adjuvant EBC study (BO22227), at a median follow-up exceeding 70 months, 10.1% (30/296) of patients treated with intravenous trastuzumab developed antibodies against trastuzumab. Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in the trastuzumab intravenous arm.
The clinical relevance of these antibodies is not known. The presence of anti-trastuzumab antibodies had no impact on the pharmacokinetics, efficacy (determined by pathological Complete Response [pCR] and event free survival [EFS]) and safety determined by occurrence of administration related reactions (ARRs) of intravenous trastuzumab.
There are no immunogenicity data available for trastuzumab in gastric cancer.
Trastuzumab (Trazimera) Comparative Clinical Studies: The results of the Trastuzumab (Trazimera) clinical trial program support comparable safety profiles for Trastuzumab (Trazimera) and Herceptin. (See Pharmacology: Pharmacodynamics under Actions.)
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