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General: In order to improve 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 perforations: Patients may be at increased risk for the development of gastrointestinal perforation and gallbladder perforation when treated with Bevacizumab. Bevacizumab should be permanently discontinued in patients who develop gastrointestinal perforation.
Patients treated for persistent, recurrent, or metastatic cervical cancer with Bevacizumab may be at increased risk of fistula between the vagina and any part of the GI tract (Gastrointestinal vaginal fistula).
Intra-abdominal inflammatory process may be at risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when treating these patients.
Non-GI Fistula: Patients may be increased risk for the development of fistula when treated with Bevacizumab.
Permanently discontinue Bevacizumab in patients with tracheoesophangeal (TE) fistula or any Grade 4 fistula. Limited information is available on the continued use of Bevacizumab in patients with other fistula. In cases of internal fistula not arising in the GI tract, discontinuation of Bevacizumab should be considered.
Haemorrhage: Patients treated with Bevacizumab have an increased risk of haemorrhage, especially tumour-associated haemorrhage. Bevacizumab should be permanently discontinued in patients who experience grade 3 or 4 bleeding during Bevacizumab therapy.
Patients with untreated CNS metastases were routinely excluded from clinical trials with Bevacizumab innovator, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in such patient has not been prospectively evaluated. Patients should be monitored for signs and symptoms of CNS bleeding, and Bevacizumab innovator treatment discontinued in cases of intracranial bleeding.
There is no information on the safety profile of Bevacizumab in patients with congenital bleeding diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting Bevacizumab treatment. Therefore, caution should be exercised before initiating Bevacizumab therapy in these patients. However, patients who develop venous thrombosis while receiving Bevacizumab therapy did not appear to have an increased rate of Grade 3 or above bleeding when treated with full dose of Warfarin and Bevacizumab innovator concomitantly.
Severe Eye Infections Following Compounding for Unapproved Intravitreal Use: Individual cases and clusters of serious ocular adverse events have been reported (including infectious endophthalmitis and other ocular inflammatory conditions) following unapproved intravitreal use of Bevacizumab compounded from vials approved for intravenous administration in cancer patients. Some of these events have resulted in various degrees of visual loss, including permanent blindness.
Pulmonary hemorrhage/hemoptysis: Patients with non-small cell lung cancer treated with Bevacizumab may be at risk for serious, and in some cases fatal, pulmonary hemorrhage/hemoptysis. Patients with recent pulmonary hemorrhage/hemoptysis (> ½ teaspoon red blood) should not be treated with Bevacizumab.
Hypertension: An increased incidence of hypertension was observed in patients treated with Bevacizumab. Clinical safety data suggest that the incidence of hypertension is likely to be dose-dependent. Pre-existing hypertension should be adequately controlled before starting Bevacizumab treatment. There is no information on the effect of Bevacizumab in patients with uncontrolled hypertension at the time of initiating Bevacizumab therapy. Monitoring of blood pressure is recommended during Bevacizumab 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. Bevacizumab 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): There have been rare reports of Bevacizumab-treated patients developing signs and symptoms that are consistent with Posterior Reversible Encephalopathy Syndrome (PRES), a rare neurological 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 Bevacizumab. The safety of reinitiating Bevacizumab therapy in patients previously experiencing PRES is not known.
Arterial thromboembolism: In clinical trials, the incidence of arterial thromboembolism events including cerebrovascular accidents, transient ischaemic attack (TIA) and myocardial infarction (MI) was higher in patients receiving Bevacizumab innovator in combination with chemotherapy compared to those who received chemotherapy alone.
Bevacizumab should be permanently discontinued in patients who develop arterial thromboembolic events.
Patients receiving Bevacizumab plus chemotherapy with a history of arterial thromboembolism, diabetes or age greater than 65 years have an increased risk of developing arterial thromboembolic events during Bevacizumab therapy. Caution should be taken when treating such patients with Bevacizumab.
Venous thromboembolism: Patients may be at risk of developing venous thromboembolic events, including pulmonary embolism under Bevacizumab treatment.
Patients treated for persistent, recurrent, or metastatic cervical cancer with Bevacizumab may be at increased risk of venous thromboembolic events.
Bevacizumab should be discontinued in patients with life-threatening (grade 4) venous thromboembolic events, including pulmonary embolism. Patients with thromboembolic events ≤ grade 3 need to be closely monitored.
Congestive heart failure: Event consistent with congestive heart failure (CHF) were reported. The findings ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalization.
Caution should be exercised when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with Bevacizumab.
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 innovator group compared to the treatment with anthracyclines only. In both AVF3694g and AVF3693g, CHF grade 3 or higher events were somewhat more frequent among patients receiving Bevacizumab innovator in combination with chemotherapy than in patient receiving chemotherapy alone. This is consistent with result in patients in other studies of metastatic breast cancer who did not receive concurrent Anthracycline treatment.
Neutropenia: Increased rates of severe neutropenia, febrile neutropenia, or infection with severe neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus Bevacizumab in comparison to chemotherapy alone.
Wound healing: Bevacizumab may adversely affect the wound healing process. Serious wound healing complications with a fatal outcome have been reported.
Bevacizumab therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In patients who experience wound healing complications during Bevacizumab treatment, Bevacizumab should be withheld until the wound is fully healed. Bevacizumab therapy should be withheld for elective surgery.
Necrotising fasciitis including fatal cases, has rarely been reported in patients treated with Bevacizumab; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Bevacizumab therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated.
Proteinuria: In clinical trials, the incidence of proteinuria was higher in patients receiving Bevacizumab innovator in combination with chemotherapy compared to those who received chemotherapy alone. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% patients treated with Bevacizumab innovator. In the event of nephrotic syndrome, Bevacizumab should be permanently discontinued.
Hypersensitivity reactions, infusion 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 humanized monoclonal antibody. If a reaction occurs, the infusion should be discontinued and appropriate medical therapies should be administered. A systematic premedication is not warranted.
Ovarian Failure/Fertility: Bevacizumab may impair female fertility. Therefore, fertility preservation strategies should be discussed with women of childbearing potential prior to starting treatment with Bevacizumab.
Drug Abuse and Dependence: No information available.
Ability to drive and use machines: No studies on the effects on the ability to drive and use machine have been performed. However, there is no evidence that Bevacizumab treatment results in an increase in adverse events that might lead to impairment of the ability to drive or operate machinery or impairment of mental ability.
Renal impairment: The safety and efficacy of Bevacizumab has not been studied in patients with renal impairment.
Hepatic impairment: The safety and efficacy of Bevacizumab has not been studied in patients with hepatic impairment.
Use in Children: Bevacizumab is not approved for use in patients under the age of 18 years. The safety and efficacy of Bevacizumab in this population has not been established.
In published reports, cases of osteonecrosis at sites other than the jaw have been observed in patients under the age of 18 years exposed to Bevacizumab.
Use in the Elderly: Refer to Arterial Thromboembolism as previously mentioned.
