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The safety profile of Herceptin subcutaneous formulation (evaluated in 298 and 297 patients treated with the intravenous and subcutaneous formulations respectively) from the pivotal trial in EBC was overall similar to the known safety profile of the intravenous formulation.
Severe adverse events (defined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE grade ≥3) version 3.0) were equally distributed between both Herceptin formulations (52.3% versus 53.5% in the intravenous formulation versus subcutaneous formulation respectively).
Some adverse events/reactions were reported with a higher frequency for the subcutaneous formulation: Serious adverse events (most of which were identified because of in-patient hospitalisation or prolongation of existing hospitalisation): 14.1% for the intravenous formulation versus 21.5% for the subcutaneous formulation. The difference in serious adverse event rates between formulations was mainly due to infections with or without neutropenia (4.4% versus 8.1%) and cardiac disorders (0.7% versus 1.7%).
Post-operative wound infections (severe and/or serious): 1.7% versus 3.0% for the intravenous formulation versus subcutaneous formulation, respectively.
Administration-related reactions: 37.2% versus 47.8% for the intravenous formulation versus subcutaneous formulation, respectively during the treatment phase.
Hypertension: 4.7% versus 9.8% for the intravenous formulation versus subcutaneous formulation respectively.
Tabulated list of adverse reactions with the intravenous formulation: In this section, the following categories of frequency have been used: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Presented in Table 13 are adverse reactions that have been reported in association with the use of intravenous Herceptin 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. In addition, terms reported in the postmarketing setting are included in Tables 13. (See Tables 13A and B.)
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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 to Herceptin. It has been associated with a fatal outcome. Signs and symptoms of cardiac dysfunction such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, or reduced ventricular ejection fraction, have been observed in patients treated with Herceptin (see Precautions).
In 3 pivotal EBC clinical trials of adjuvant intravenous Herceptin 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 (ie did not receive Herceptin) and in patients who were administered Herceptin sequentially after a taxane (0.3-0.4%). The rate was highest in patients who were administered Herceptin concurrently with a taxane (2.0%). In the neoadjuvant setting, the experience of concurrent administration of Herceptin and low dose anthracycline regimen is limited (see Precautions).
When Herceptin 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 Herceptin 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 Herceptin-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 Herceptin.
In the pivotal metastatic trials of intravenous Herceptin, 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 Herceptin 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 Herceptin 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.
Administration-related reactions/hypersensitivity: Administration-related reactions (ARRs)/hypersensitivity reactions such as chills and/or fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratory distress, rash, nausea, vomiting and headache were seen in Herceptin clinical trials (see Precautions).
The rate of ARRs 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.
Anaphylactoid reactions have been observed in isolated cases.
Haematotoxicity: Febrile neutropenia, leukopenia, anaemia, 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 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 Precautions).
Description of selected adverse reactions with the subcutaneous formulation: Administration-related reactions: In the pivotal trial, the rate of all grade ARRs was 37.2% with the Herceptin intravenous formulation and 47.8% with the Herceptin subcutaneous formulation; severe grade 3 reactions were reported in 2.0% and 1.7% of the patients, respectively during the treatment phase; no severe grade 4 or 5 reactions were observed. All of the severe ARRs with the Herceptin subcutaneous formulation occurred during concurrent administration with chemotherapy. The most frequent severe reaction was drug hypersensitivity.
The systemic reactions included hypersensitivity, hypotension, tachycardia, cough, and dyspnoea. The local reactions included erythema, pruritus, oedema, rash and pain at the site of the injection.
Infections: The rate of severe infections (NCI CTCAE grade ≥3) was 5.0% versus 7.1%, in the Herceptin intravenous formulation arm and the Herceptin subcutaneous formulation arm respectively.
The rate of serious infections (most of which were identified because of in-patient hospitalisation or prolongation of existing hospitalisation) was 4.4% in the Herceptin intravenous formulation arm and 8.1% in the Herceptin subcutaneous formulation arm. The difference between formulations was mainly observed during the adjuvant treatment phase (monotherapy) and was mainly due to postoperative wound infections, but also to various other infections such as respiratory tract infections, acute pyelonephritis and sepsis. They resolved within a mean of 13 days in the Herceptin intravenous treatment arm and a mean of 17 days in the Herceptin subcutaneous treatment arm.
Hypertensive events: In the pivotal trial BO22227, there were more than twice as many patients reporting all grade hypertension with the Herceptin subcutaneous formulation (4.7% versus 9.8% in the intravenous and subcutaneous formulations respectively), with a greater proportion of patients with severe events (NCI CTCAE grade ≥3) <1% versus 2.0% the intravenous and subcutaneous formulations respectively. All but one patient who reported severe hypertension had a history of hypertension before they entered the study. Some of the severe events occurred on the day of the injection.
Immunogenicity: In the neoadjuvant-adjuvant EBC study (BO22227), at a median follow-up exceeding 70 months, 10.1% (30/296) of patients treated with Herceptin intravenous and 15.9% (47/295) of patients receiving Herceptin subcutaneous vial developed antibodies against trastuzumab. Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in the Herceptin intravenous arm and 3 of 47 in the Herceptin subcutaneous arm. 21.0% of patients treated with Herceptin subcutaneous formulation developed antibodies against the excipient hyaluronidase (rHuPH20).
The clinical relevance of these antibodies is not known. The presence of anti-trastuzumab antibodies had no impact on pharmacokinetics, efficacy (determined by pathological Complete Response [pCR] and event free survival [EFS]) and safety determined by occurrence of administration related reactions (ARRs) of Herceptin intravenous and Herceptin subcutaneous.
Switching treatment between Herceptin intravenous and Herceptin subcutaneous formulation and vice versa: Study MO22982 investigated switching between the Herceptin intravenous and Herceptin subcutaneous formulation with a primary objective to evaluate patient preference for either the intravenous or the subcutaneous route of trastuzumab administration. In this trial, 2 cohorts (one using subcutaneous formulation in vial and one using subcutaneous formulation in administration system) were investigated using a 2-arm, cross-over design with 488 patients being randomized to one of two different three-weekly Herceptin treatment sequences (IV [Cycles 1-4]→ SC [Cycles 5-8], or SC [Cycles 1-4]→ IV [Cycles 5-8]). Patients were either naïve to Herceptin IV treatment (20.3%) or pre-exposed to Herceptin IV (79.7%). For the sequence IV→SC (SC vial and SC formulation in administration system cohorts combined), adverse event rates (all grades) were described pre-switching (Cycles 1-4) and post-switching (Cycles 5-8) as 53.8% vs. 56.4%, respectively; for the sequence SC→IV (SC vial and SC formulation in administration system cohorts combined), adverse event rates (all grades) were described pre- and post-switching as 65.4% vs. 48.7%, respectively.
Pre-switching rates (Cycles 1-4) for serious adverse events, grade 3 adverse events and treatment discontinuations due to adverse events were low (<5%) and similar to post-switching rates (Cycles 5-8). No grade 4 or grade 5 adverse events were reported.
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