mnolence and syncope have been reported with Avastin use (see table 1 in section 4.8). If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate.
4.8 Undesirable effects
Summary of the safety profile
The overall safety profile of Avastin is based on data from over 5,200 patients with various malignancies, predominantly treated with Avastin in combination with chemotherapy in clinical trials.
The most serious adverse reactions were:
• Gastrointestinal perforations (see section 4.4).
• Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non- small cell lung cancer patients (see section 4.4).
• Arterial thromboembolism (see section 4.4).
The most frequently observed adverse reactions across clinical trials in patients receiving Avastin were hypertension, fatigue or asthenia, diarrhoea and abdominal pain.
Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with Avastin therapy are likely to be dose-dependent.
Tabulated list of adverse reactions
The adverse reactions listed in this section fall into the following frequency categories: 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).
Tables 1 and 2 list adverse reactions associated with the use of Avastin in combination with different chemotherapy regimens in multiple indications.
Table 1 provides all adverse reactions by frequency that were determined to have a causal relationship with Avastin through:
• comparative incidences noted between clinical trial treatment arms (with at least a 10% difference compared to the control arm for NCI-CTCAE Grade 1-5 reactions or at least a 2% difference compared to the control arm for NCI-CTCAE Grade 3-5 reactions,
• post-authorisation safety studies,
• spontaneous reporting,
• epidemiological studies\non-interventional or observational studies,
• or through an eva luation of individual case reports.
Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3-5 reactions. Table 2 also includes adverse reactions which are considered by the MAH to be clinically significant or severe.
Post-marketing adverse reactions are included in both Tables 1 and 2, where applicable. Detailed information about these post-marketing reactions are provided in Table 3.
Adverse reactions are added to the appropriate frequency category in the tables below according to the highest incidence seen in any indication.
Within each frequency category, adverse reactions are presented in the order of decreasing seriousness.
Some of the adverse reactions are reactions commonly seen with chemotherapy; however, Avastin may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorders or alopecia with pacli
