Events associated with Avastin therapy

GI(Complete penetration of the wall of the stomach, small intestine or large bowel, resulting in intestinal contents flowing into the abdominal cavity) perforations¹

Patients may be at an increased risk for the development of GI perforation(Complete penetration of the wall of the stomach, small intestine or large bowel, resulting in intestinal contents flowing into the abdominal cavity) when treated with Avastin

• In clinical trials, GI perforations have been reported in <1% in patients with mBC or non-squamous(Pertaining to cells not from squamous epithelium; relatively common, locally invasive and occasionally metastatic) NSCLC, and up to 2.0% in patients with mCRC.

Intra-abdominal inflammatory process may be a risk factor for GI perforations in patients with mCRC; therefore, caution should be exercised when treating these patients.

Therapy should be permanently discontinued in patients who develop GI perforation.

Fistulae¹

Patients may be at increased risk for the development of fistulae when treated with Avastin.

• GI fistulae have been reported with an incidence of up to 2% in patients with mCRC in clinical trials. The event is reported less commonly in patients with other types of cancers.

Permanently discontinue Avastin in patients with tracheoesophageal fistula(An abnormal connection or passageway between two epithelium-lined organs or vessels that normally do not connect) or any grade 4 fistula. In cases of internal fistula not arising in the GI tract, discontinuation of Avastin should be considered.

Wound-healing complications¹

Avastin may adversely affect the wound healing process.

• The incidence of post-operative bleeding or wound-healing complications occurring within 60 days of major surgery in mCRC patients receiving Avastin at the time of surgery ranged from 10% (4/40) to 20% (3/15).
• In locally recurrent and mBC trials, grade 3–5 wound-healing complications were reported in up to 1.1% of patients receiving Avastin compared with up to 0.9% of patients in the control arms.

Therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed.

In patients who experienced wound-healing complications during therapy, treatment should be withheld until the wound is fully healed.

Therapy should be withheld for elective surgery.

Hypertension(High blood pressure)¹

In clinical trials, an increased incidence of hypertension of up to 34% (all grades) was reported in Avastin-treated patients compared with up to 14% in those treated with comparator

• Grade 3/4 hypertension in patients receiving Avastin ranged from 0.4–17.9%.
• Grade 4 hypertension was reported in up to 1.0% of patients treated with Avastin plus chemotherapy compared with up to 0.2% of patients treated with chemotherapy alone.

Clinical safety data suggest that the incidence of hypertension is likely to be dose-dependent. Pre-existing hypertension should be adequately controlled before starting Avastin treatment.

There is no information on the effect of Avastin in patients with uncontrolled hypertension at the time of initiating therapy.

Monitoring of blood pressure is generally recommended during therapy.

In most cases hypertension was controlled adequately using standard antihypertensive treatment appropriate for the individual situation of the affected patient

• The use of diuretics to manage hypertension is not advised in patients who receive a cisplatin-based chemotherapy regimen.

Avastin should be permanently discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy.

Reversible posterior leukoencephalopathy syndrome¹

There have been rare reports of Avastin-treated patients developing signs and symptoms that are consistent with reversible posterior leukoencephalopathy syndrome, a rare neurologic disorder, which can present with the following signs and symptoms among others: seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension

• A diagnosis of reversible posterior leukoencephalopathy syndrome requires confirmation by brain imaging.

In patients developing reversible posterior leukoencephalopathy syndrome, treatment of specific symptoms including control of hypertension is recommended along with discontinuation of Avastin.

Proteinuria(The presence of an excess of serum proteins in the urine)¹

In clinical trials, proteinuria has been reported within the range of 0.7% to 38% of patients receiving Avastin, with the majority being grade 1 in severity

• Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with Avastin.
• Evidence suggests that grade 1 (US National Cancer Institute-Common Toxicity Criteria version 2.0) proteinuria may be related to the dose.

Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. Therapy should be permanently discontinued in patients who develop grade 4 proteinuria (nephrotic syndrome).

Arterial thromboembolism¹

Patients receiving Avastin plus chemotherapy, with a history of arterial thromboembolism or age >65 years have an increased risk of developing arterial thromboembolic events(An event pertaining to or emanating from the formation of a clot (thrombus) in an artery) during therapy. In clinical trials, the incidence of arterial thromboembolic events including cerebrovascular accidents, transient ischaemic attacks and myocardial infarctions ranged up to 3.8% in the Avastin containing arms compared with up to 1.7% in the chemotherapy control arms.

Caution should be taken when treating these patients with Avastin and therapy should be permanently discontinued in patients who develop arterial thromboembolic events.

Venous thromboembolism¹

Patients may be at risk of developing venous thromboembolic events(An event pertaining to or emanating from the formation of a clot (thrombus) in a vein), including pulmonary embolism(A blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream) under Avastin treatment. In clinical trials across indications, the overall incidence of venous thromboembolic events ranged from 2.8–17.3% of Avastin-treated patients compared with 3.2–15.6% in the control arms.

Avastin should be discontinued in patients with life-threatening (grade 4) pulmonary embolism, patients with ≤grade 3 need to be closely monitored.

Haemorrhage¹

Patients treated with Avastin have an increased risk of haemorrhage, especially tumour-associated haemorrhage. In clinical trials across all indications the overall incidence of grade 3–5 bleeding events ranged from 0.4–5% in Avastin treated patients, compared with up to 2.9% of patients in the chemotherapy control group.

Avastin should be discontinued permanently in patients who experience grade 3 or 4 bleeding during Avastin therapy.

Patients with untreated CNS metastases were routinely excluded from clinical trials with Avastin; therefore, the risk of CNS haemorrhage in such patients has not been prospectively evaluated in randomised(How subjects are assigned to a treatment arm in a study. The treatment a subject receives is determined by chance alone) clinical trials. Patients should be monitored for signs and symptoms of CNS bleeding, and Avastin treatment discontinued in cases of intracranial bleeding.

There is no information on the safety profile of Avastin in patients with congenital bleeding diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting Avastin treatment, as such patients were excluded from clinical trials

• Caution should be exercised before initiating therapy in these patients.
• Patients who developed venous thrombosis while receiving therapy did not appear to have an increased rate of grade 3 or above bleeding when treated with a full dose of warfarin and Avastin concomitantly.

Pulmonary haemorrhage/haemoptysis¹

Patients with NSCLC treated with Avastin may be at risk of serious, and in some cases fatal, pulmonary haemorrhage/haemoptysis

• Excluding patients with predominant squamous(Denoting a surface tissue consisting of a single layer of flat scale-like cells) histology, all grade events were seen with a frequency of up to 9% when treated with Avastin plus chemotherapy compared with 5% in the patients treated with chemotherapy alone.

Patients with recent pulmonary haemorrhage/haemoptysis (>2.5mL of red blood) should not be treated with Avastin.

CHF(A condition in which the heart's function as a pump is inadequate to deliver oxygen-rich blood to parts of the body, which become congested with fluid)¹

Events consistent with CHF were reported in clinical trials

• The symptoms ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalisation.
• Most of the patients who experienced CHF had mBC and had received previous treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF, such as pre-existing coronary heart disease or concomitant cardiotoxic therapy
  • in clinical trials, grade ≥3 CHF was reported in up to 3.5% of patients with mBC treated with Avastin compared with 0.9% in the control arms.

Caution should be exercised when treating patients with clinically significant(A measure of the importance of a therapy, treatment or a related side effect that may impact clinical practice) cardiovascular disease or pre-existing CHF with Avastin.

Summary

Avastin therapy is associated with some undesirable effects, the majority of which are of low grade and manageable.

The most frequently observed adverse reactions across clinical trials in patients receiving Avastin were hypertension, fatigue(A state of awareness describing a range of afflictions, usually associated with mental and/or physical and/or weakness (tiredness)) or asthenia, diarrhoea and abdominal pain.

The most serious adverse reactions associated with Avastin are

• GI perforations
• Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in NSCLC patients
• Arterial thromboembolism.

Dose reduction for AEs(Symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study) is not recommended. If indicated, therapy should either be permanently discontinued or temporarily suspended.