Sign Out
General: Initiate bevacizumab therapy under the supervision of a physician experienced in cancer treatment/oncologist.
Gastrointestinal Perforations and Fistulae: There is increased risk of developing gastrointestinal perforation (serious and sometimes fatal) and gall bladder perforation when treated with bevacizumab. Gastrointestinal perforation, some fatal, was reported in 0.3% to 3.2% of bevacizumab (Reference Product)-treated patients. Caution should be exercised in patients with metastatic carcinoma of the colon or rectum, as intra- abdominal inflammatory processes may be a risk factor for gastrointestinal perforations. Prior radiation is a risk factor for GI perforation in patients treated for persistent, recurrent or metastatic cervical cancer with bevacizumab.
Bevacizumab should be permanently discontinued in patients with gastrointestinal perforation.
Gastrointestinal-vaginal fistulae: Patients treated with bevacizumab for persistent, recurrent, or metastatic cervical cancer have a higher 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. An additional important risk factor for the development of GI-vaginal fistulae is recurrence of cancer within the field of prior radiation. Patients developing GI vaginal fistulas may also develop bowel obstructions and may require surgical intervention and diverting ostomies (see Dosage & Administration, Warnings, and Precautions).
Non-Gastrointestinal Fistulae: Bevacizumab treatment may increase the risk of patients developing fistulae. Bevacizumab should be permanently discontinued in patients with tracheoesophageal fistula or any Grade 4 fistula [US National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v.3)]. There is limited information on the continued use of bevacizumab in patients with other fistulae.
Consider discontinuation of bevacizumab for internal fistula not arising in the GI tract.
Wound Healing Complications: Bevacizumab may have adverse effects on wound healing. Serious complications, including anastomotic complications, have occurred; with fatal outcomes. Do not start therapy for at least 28 days after major surgery, or till the surgical wound has healed completely. If a patient experiences wound healing complications, withhold bevacizumab till the wound is fully healed. Patients undergoing elective surgery should have therapy withheld.
Rare cases of necrotising fasciitis have been reported in patients treated with bevacizumab (Reference Product), some of which were fatal. Usually necrotising fasciitis is secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue bevacizumab therapy in patients with necrotising fasciitis. Initiate the appropriate treatment without delay.
Hypertension: Bevacizumab (Reference Product)-treated patients showed a higher incidence of hypertension. Before bevacizumab treatment is initiated, pre-existing hypertension should be properly controlled. No information is available on the effect of bevacizumab in patients who have uncontrolled hypertension at the time of start of therapy. In general, it is recommended that blood pressure be monitored during bevacizumab treatment.
If a patient is receiving cisplatin, the use of diuretics to manage hypertension is not advised. Discontinue bevacizumab permanently if treatment with antihypertensives is not able to control medically significant hypertension, or in cases of hypertensive crisis or hypertensive encephalopathy.
Posterior Reversible Encephalopathy Syndrome (PRES): In rare cases, bevacizumab (Reference Product)-treated patients have developed signs and symptoms consistent with the rare neurologic disorder PRES. These includes: Seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. The diagnosis of PRES should be confirmed by brain imaging, preferably magnetic resonance imaging (MRI). Specific symptoms should be treated, and hypertension should be controlled, along with discontinuation of bevacizumab. There is no information on the safety of reinitiating bevacizumab therapy in patients who have experienced PRES.
Proteinuria: Patients who have had hypertension may have a higher risk of proteinuria if treated with bevacizumab. Proteinuria should be monitored by appropriate urinalysis, preferably by dipstick, before starting bevacizumab treatment, and during the treatment. If patients develop nephrotic syndrome (NCI-CTCAE v.3) permanently discontinue bevacizumab treatment.
Arterial thromboembolism: Arterial thromboembolic reactions such as cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) had a higher incidence in patients treated with bevacizumab (Reference Product) in combination with chemotherapy, than in patients receiving chemotherapy alone.
Patients who are on bevacizumab plus chemotherapy and have risk factors such as a history of arterial thromboembolism, diabetes or age >65 years are at higher risk of developing arterial thromboembolic reactions. Exercise caution when treating such patients with bevacizumab.
Permanently discontinue bevacizumab in patients with arterial thromboembolic reactions.
Venous thromboembolism: The risk of venous thromboembolic reactions, including pulmonary embolism, is higher in patients under bevacizumab treatment. Persistent, recurrent, or metastatic cervical cancer patients under treatment with bevacizumab in combination with paclitaxel and cisplatin may have increased risk of venous thromboembolic events.
Discontinue bevacizumab in patients with life-threatening (Grade 4, NCI-CTCAE v.3) thromboembolic reactions, including pulmonary embolism; and closely monitor patients with thromboembolic reactions ≤Grade 3 (NCI-CTCAE v.3).
Haemorrhage: Bevacizumab treatment increases the risk of haemorrhage, especially tumour-associated haemorrhage. Severe or fatal haemorrhage, including haemoptysis, gastrointestinal bleeding, CNS haemorrhage, epistaxis, and vaginal bleeding occurred up to 5 times more frequently in bevacizumab (Reference Product)-treated patients. Discontinued bevacizumab permanently in patients with Grade 3 or 4 bleeding (NCI-CTCAE v.3) during treatment.
Monitor patients for signs and symptoms of CNS bleeding, and discontinue bevacizumab treatment in cases of intracranial bleeding.
Exercise caution when initiating bevacizumab in patients with congenital bleeding diathesis, acquired coagulopathy or who are receiving a full dose of anticoagulants for the treatment of thromboembolism; as there is no information on the safety profile of bevacizumab in such patients. However, no increase occurred in the rate of ≥Grade 3 bleeding (NCI-CTCAE v.3) in patients who developed venous thrombosis and who were treated with a full dose of warfarin and bevacizumab (Reference Product) concomitantly.
Pulmonary haemorrhage/haemoptysis: There may be a risk of serious, and in some cases fatal, pulmonary haemorrhage/haemoptysis in patients with non-small cell lung cancer treated with bevacizumab. Do not administer bevacizumab to patients with recent pulmonary haemorrhage/ haemoptysis (>2.5 ml of red blood).
Congestive heart failure (CHF): Both asymptomatic and symptomatic CHF has been reported with bevacizumab (Reference Product) treatment. Exercise caution when administering bevacizumab to patients with clinically significant cardiovascular disease, such as pre-existing coronary artery disease, or congestive heart failure.
Patients with risk factors for CHF, treatment with anthracyclines, or radiotherapy to the left chest may be at a higher risk to exhibit CHF with bevacizumab therapy.
Reactions ranging from asymptomatic decline in left ventricular ejection fraction to symptomatic CHF requiring hospitalization have been reported with bevacizumab (Reference Product).
Neutropenia and Infection: Patients treated with some myelotoxic chemotherapy regimens plus bevacizumab (Reference Product) had increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia, in comparison to patients treated with chemotherapy alone. Some cases were fatal. A greater proportion of patients with persistent, recurrent, or metastatic cervical cancer treated with bevacizumab (Reference Product) plus paclitaxel and topotecan experienced Grade 3- 5 infections than patients treated with paclitaxel and topotecan.
Hypersensitivity reactions/infusion reactions: There is a risk of infusion/hypersensitivity reactions in patients treated with bevacizumab. As recommended for infusions of any therapeutic humanised monoclonal antibody, patients must be closely observed for such reactions during and following administration of bevacizumab. Discontinue therapy and administer appropriate treatment if such reactions occur. A systematic pre-medication is not warranted.
Osteonecrosis of the jaw (ONJ): Patients treated with bevacizumab (Reference Product) have experienced ONJ. The majority of cases occurred in patients who had prior or concomitant treatment with intravenous bisphosphonates (for which ONJ is an identified risk). Exercise caution when administering bevacizumab and intravenous bisphosphonates (simultaneously or sequentially).
Another identified risk factor is invasive dental procedures. Before starting bevacizumab, a dental examination with appropriate preventive dentistry should be considered. Patients who have received or are receiving intravenous bisphosphonates should be avoid such procedures where possible.
Eye disorders: Unapproved intravitreal use of bevacizumab (Reference Product) has been reported to cause serious ocular adverse reactions including 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 multiple degrees of visual loss, up to and including permanent blindness.
Systemic effects following intravitreal use: Anti-VEGF therapies have been reported to reduce circulating serum VEGF concentration with intravitreal injection. Nonocular events include haemorrhage and thromboembolic reactions.
Ovarian failure/fertility: Bevacizumab may impair fertility in female patients. Before initiating treatment in women of child-bearing potential, discuss fertility preservation strategies.
Laboratory abnormalities: Grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalities that occurred with greater incidence in patients treated with bevacizumab (Reference Product) than in the corresponding control groups were hyperglycaemia, decreased haemoglobin, hypokalaemia, hyponatraemia, decreased white blood cell count, and increased international normalised ratio (INR).
Bevacizumab (Reference Product) was associated with transient increases in serum creatinine, with and without proteinuria. The increase in serum creatinine was not associated with more frequent clinical manifestations of renal impairment in bevacizumab (Reference Product)-treated patients.
Bevacizumab treatment may be associated with decreased neutrophil count, decreased white blood cell count and presence of urine protein.
Use in Children: Bevacizumab is not approved for use in patients under the age of 18. The safety, effectiveness and pharmacokinetic profile of bevacizumab in paediatric patients is not known. There are reports in the literature of non-mandibular osteonecrosis in bevacizumab (Reference Product) -treated patients under 18 years. There is insufficient data on the safety and efficacy of bevacizumab in children with glioblastoma. Summary of Animal Data After 4 to 26 weeks exposure of bevacizumab (Reference Product) at 0.4 to 20 times the recommended human dose of bevacizumab (based on mg/kg and exposure), physeal dysplasia was observed in juvenile cynomolgus monkeys with open growth plates. The physeal dysplasia was partially reversible after stopping treatment, and incidence and severity were related to dose. Arrested follicular development or absent corpora lutea as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrual cycles, were seen in female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose.
Use in the Elderly: In patients aged ≥65 years given bevacizumab (Reference Product), the following severe adverse events occurred more frequently (≥2%) than in younger patients: asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhoea, constipation, anorexia, leukopenia, anaemia, dehydration, hypokalaemia, hypernatremia, arterial thromboembolic reactions, including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs); Grade 3-4 thrombocytopenia (NCI-CTCAE v.3); and all Grade neutropenia, nausea, headache and fatigue.
Bevacizumab (Reference Product) had a similar effect on overall survival in elderly patients and younger patients.
