General: In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Gastrointestinal (GI) Perforations and Fistulae (see Adverse Reactions): Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder perforation when treated with Avastin Roche. Intra-abdominal inflammatory process may be a risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when treating these patients. Prior radiation is a risk factor for GI perforation in patients treated for persistent, recurrent or metastatic cervical cancer with Avastin Roche and all patients with GI perforation had a history of prior radiation. Therapy should be permanently discontinued in patients who develop gastrointestinal perforation.
GI-Vaginal Fistulae in Study GOG-0240: Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin Roche are at increased risk of fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginal fistulae). Prior radiation is a major risk factor for the development of GI-vaginal fistulae and all patients with GI-vaginal fistulae had a history of prior radiation. Recurrence of cancer within the field of prior radiation is an additional important risk factor for the development of GI-vaginal fistulae.
Non-GI Fistulae (see Adverse Reactions): Patients may be at increased risk for the development of fistulae when treated with Avastin Roche. Permanently discontinue Avastin Roche in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula [US National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v.3)]. Limited information is available on the continued use of Avastin Roche in patients with other fistulae.
In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of Avastin Roche should be considered.
Wound Healing Complications (see Adverse Reactions): Avastin Roche may adversely affect the wound healing process. Serious wound healing complications, including anastomotic complications, with a fatal outcome have been reported. 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.
Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated with Avastin Roche. This condition is usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Avastin Roche therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated.
Hypertension (see Adverse Reactions): An increased incidence of hypertension was observed in Avastin Roche-treated patients. 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 Roche treatment. There is no information on the effect of Avastin Roche 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 Roche 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.
Posterior Reversible Encephalopathy Syndrome (PRES) (see Adverse Reactions): There have been rare reports of Avastin Roche-treated patients developing signs and symptoms that are consistent with PRES, 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 PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). In patients developing PRES, treatment of specific symptoms including control of hypertension is recommended along with discontinuation of Avastin Roche. The safety of reinitiating Avastin Roche therapy in patients previously experiencing PRES is not known.
Proteinuria (see Adverse Reactions): Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with Avastin Roche. There is evidence suggesting that all Grade (US National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE v.3]) proteinuria may be related to the dose. Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of patients treated with Avastin Roche. Therapy should be permanently discontinued in patients who develop nephrotic syndrome (NCI-CTCAE v.3).
Arterial Thromboembolism (see Adverse Reactions): In clinical trials, the incidence of arterial thromboembolic reactions including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was higher in patients receiving Avastin Roche in combination with chemotherapy compared to those who received chemotherapy alone.
Patients receiving Avastin Roche plus chemotherapy, with a history of arterial thromboembolism, diabetes or age greater than 65 years have an increased risk of developing arterial thromboembolic reactions during therapy. Caution should be taken when treating these patients with Avastin Roche.
Therapy should be permanently discontinued in patients who develop arterial thromboembolic reactions.
Venous Thromboembolism (see Adverse Reactions): Patients may be at risk of developing venous thromboembolic reactions, including pulmonary embolism under Avastin Roche treatment.
Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin Roche in combination with paclitaxel and cisplatin may be at increased risk of venous thromboembolic events.
Avastin Roche should be discontinued in patients with life-threatening (Grade 4) thromboembolic reactions, including pulmonary embolism (NCI-CTCAE v.3). Patients with thromboembolic reactions ≤ Grade 3 need to be closely monitored (NCI-CTCAE v.3).
Haemorrhage: Patients treated with Avastin Roche have an increased risk of haemorrhage, especially tumour-associated haemorrhage. Avastin Roche should be discontinued permanently in patients who experience Grade 3 or 4 bleeding during Avastin Roche therapy (NCI-CTCAE v.3) (see Adverse Reactions).
Patients with untreated CNS metastases were routinely excluded from clinical trials with Avastin Roche, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in such patients has not been prospectively evaluated in randomised clinical trials (see Adverse Reactions). Patients should be monitored for signs and symptoms of CNS bleeding, and Avastin Roche treatment discontinued in cases of intracranial bleeding.
There is no information on the safety profile of Avastin Roche 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 Roche treatment, as such patients were excluded from clinical trials. Therefore, caution should be exercised before initiating therapy in these patients. However, 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 Roche concomitantly (NCI-CTCAE v.3).
Pulmonary Haemorrhage/Haemoptysis: Patients with non-small cell lung cancer treated with Avastin Roche may be at risk of serious, and in some cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent pulmonary haemorrhage/haemoptysis (>2.5 ml of red blood) should not be treated with Avastin Roche.
Congestive Heart Failure (CHF) (see Adverse Reactions): Reactions consistent with CHF were reported in clinical trials. The findings ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalisation. Caution should be exercised when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with Avastin Roche.
Most of the patients who experienced CHF had metastatic breast cancer and had received previous treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF were present.
In patients in AVF3694g who received treatment with anthracyclines and who had not received anthracyclines before, no increased incidence of all Grade CHF was observed in the anthracycline + bevacizumab group compared to the treatment with anthracyclines only. CHF Grade 3 or higher reactions were somewhat more frequent among patients receiving bevacizumab in combination with chemotherapy than in patients receiving chemotherapy alone. This is consistent with results in patients in other studies of metastatic breast cancer who did not receive concurrent anthracycline treatment (NCI-CTCAE v.3) (see Adverse Reactions).
Neutropenia and Infections (see Adverse Reactions): Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus Avastin Roche in comparison to chemotherapy alone. This has mainly been seen in combination with platinum- or taxane-based therapies in the treatment of NSCLC, mBC, and in combination with paclitaxel and topotecan in persistent, recurrent, or metastatic cervical cancer.
Hypersensitivity Reactions/Infusion Reactions (see Adverse Reactions): Patients may be at risk of developing infusion/hypersensitivity reactions. Close observation of the patient during and following the administration of bevacizumab is recommended as expected for any infusion of a therapeutic humanised monoclonal antibody. If a reaction occurs, the infusion should be discontinued and appropriate medical therapies should be administered. A systematic premedication is not warranted.
Osteonecrosis of the Jaw (ONJ) (see Adverse Reactions): Cases of ONJ have been reported in cancer patients treated with Avastin Roche, the majority of whom had received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified risk. Caution should be exercised when Avastin Roche and intravenous bisphosphonates are administered simultaneously or sequentially.
Invasive dental procedures are also an identified risk factor. A dental examination and appropriate preventive dentistry should be considered prior to starting the treatment with Avastin Roche. In patients who have previously received or are receiving intravenous bisphosphonates invasive dental procedures should be avoided, if possible.
Intravitreal use: Avastin Roche is not formulated for intravitreal use.
Eye Disorders: Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved intravitreal use of Avastin Roche compounded from vials approved for intravenous administration in cancer patients. These reactions included infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and vitritis, retinal detachment, retinal pigment epithelial tear, intraocular pressure increased, intraocular haemorrhage such as vitreous haemorrhage or retinal haemorrhage and conjunctival haemorrhage. Some of these reactions have resulted in various degrees of visual loss, including permanent blindness.
Systemic Effects Following Intravitreal Use: A reduction of circulating VEGF concentration has been demonstrated following intravitreal anti-VEGF therapy. Systemic adverse reactions including non-ocular haemorrhages and arterial thromboembolic reactions have been reported following intravitreal injection of VEGF inhibitors.
Ovarian Failure/Fertility: Avastin Roche may impair female fertility (see Fertility under Use in Pregnancy & Lactation and Adverse Reactions). Therefore fertility preservation strategies should be discussed with women of child-bearing potential prior to starting treatment with Avastin Roche.
Effects on Ability to Drive and Use Machines: Avastin Roche has no or negligible influence on the ability to drive and use machines. However, somnolence and syncope have been reported with Avastin Roche use (see table 23 in Clinical Trials under Adverse Reactions). 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.