s
Cardiotoxicity
Cardiotoxicity (heart failure), NYHA II - IV is a common adverse reaction associated with the use of Herceptin and has been associated with a fatal outcome (see section 4.4).
In 3 pivotal clinical trials of adjuvant trastuzumab given in combination with chemotherapy, the incidence of grade 3/4 cardiac dysfunction (symptomatic Congestive Heart Failure) was similar in patients who were administered chemotherapy alone (ie did not receive Herceptin) and in patients who were administered Herceptin sequentially to a taxane (0.3-0.4%). The rate was highest in patients who were administered Herceptin concurrently with a taxane (2.0%).
The safety of continuation or resumption of Herceptin in patients who experience cardiotoxicity has not been prospectively studied. However, most patients who developed heart failure in the pivotal trials (H0648g, H0649g, M77001, BO16216, BO16348, BO18255, B-31, N9831, BCIRG 006) improved with standard medical treatment. This included diuretics, cardiac glycosides, beta-blockers and/or angiotensin-converting enzyme inhibitors. The majority of patients with cardiac symptoms and evidence of a clinical benefit of Herceptin treatment continued on therapy with Herceptin without additional clinical cardiac events (for information on identification of risk factors and management see section 4.4).
Infusion reactions, allergic-like reactions and hypersensitivity
It is estimated that approximately 40 % of patients who are treated with Herceptin 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, but are not limited to, chills, fever, rash, nausea and vomiting, dyspnoea and headache (see section 4.4).
Severe anaphylactic reactions requiring immediate additional intervention can occur usually during either the first or second infusion of Herceptin (see section 4.4) and have been associated with a fatal outcome.
Haematotoxicity
Febrile neutropenia occurred very commonly. Commonly occurring adverse reactions included anaemia, leukopenia, thrombocytopenia and neutropenia. 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 Herceptin 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 oedema and respiratory insufficiency (see section 4.4).
Details of risk minimisation measures that are consistent with the EU Risk Management Plan are presented in (section 4.4) Warnings and Precautions.
4.9 Overdose
There is no experience with overdose in human clinical trials. Single doses of Herceptin alone greater than 10 mg/kg have not been administered in the clinical trials. Doses up to this level were well tolerated.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03
Trastuzumab is a recomb |
