Versavo Special Precautions

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 and Fistulae: Patients may be at increased risk for the development of gastrointestinal perforation (see Clinical Studies under Adverse Reactions) and gallbladder perforation (see Post marketing experience under Adverse Reactions) when treated with bevacizumab. Bevacizumab should be permanently discontinued in patient who develop gastrointestinal perforation. Patients treated for persistent, recurrent, or metastatic cervical cancer with Bevacizumab may be at increased risk of fistulae between the vagina and any parts of the GI tract (Gastrointestinal-vaginal fistulae) (See Clinical Studies: Gastrointestinal perforation and fistulae under Adverse Reactions).
Non-GI Fistulae (see Clinical Studies under Adverse Reactions): Patients may be at increased risk for the development of fistulae when treated with bevacizumab (See also Clinical Studies under Adverse Reactions). Permanently discontinue bevacizumab in patients with Tracheoesophageal (TE) fistulae or any Grade 4 fistulae. Limited information is available on the continued use of bevacizumab in patients with other fistulae. In case of internal fistulae not arising in the GI tract, discontinuation of Bevacizumab should be considered.
Hemorrhage (see Clinical Studies under Adverse Reactions): Patients treated with bevacizumab may have an increased risk of bleeding, especially for tumor-associated hemorrhage (see Clinical Studies: Hemorrhage under Adverse Reactions). 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 of bevacizumab, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS hemorrhage in such patient has not been prospectively evaluated in randomized clinical studies (see Clinical Studies: Hemorrhage under Adverse Reactions). Patients should be monitored for signs and symptoms of CNS bleeding and Bevacizumab treatment discontinued in cases of intracranial bleeding.
There is not information on the safety profile of Bevacizumab in patient with congenital bleeding diathesis, acquired coagulopathy or in patient receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting bevacizumab treatment, as such patients were excluded from clinical trials. Therefore, caution should be exercised before initiating Bevacizumab therapy in these patients. However, patient who developed 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 concomitantly.
Severe Eye Infections Following Compounding for Unapproved Intravitreal Use (see Post marketing experience under Adverse Reactions): 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 patient. Some of these events have resulted in various degree of vision loss, including permanent blindness.
Pulmonary Hemorrhage/Hemoptysis (see Adverse Reactions): Patients with non-small cell lung cancer treated with bevacizumab may be at risk for serious, and in some cases fatal, pulmonary hemorrhage/hemoptysis (see Clinical Studies: Hemorrhage under Adverse Reactions). Patients with recent pulmonary hemorrhage/hemoptysis (> ½ teaspoon read blood) should not be treated with Bevacizumab.
Hypertension: An increased incidence of hypertension was observed in patient treated with Bevacizumab. Clinical safety data suggest that the incidence of hypertension is likely to be be dose-dependent. Pre-existing hypertension should be adequately controlled before starting bevacizumab treatment. There is no information on the effects of bevacizumab in patient with uncontrolled hypertension at the time of initiating Bevacizumab therapy. Monitoring of blood pressure is recommended during Bevacizumab therapy. (See Clinical Studies under Adverse Reactions.)
In most cases hypertension was controlled adequately using standard antihypertensive treatment appropriate for the individual situation of the affected patient. Bevacizumab should be permanently discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive therapy, or if, the patients develops hypertensive crisis or hypertensive encephalopathy (see Clinical Studies and Post marketing experience under Adverse Reactions).
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, headaches, 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 patient 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 (see Clinical Studies and Post marketing experience under Adverse Reactions).
Arterial thromboembolism: In clinical studies, the incidence of arterial thromboembolism events including cerebrovascular accidents, transient ischemic attack (TIA) and myocardial infarction (MI) was higher in patients treated with bevacizumab plus chemotherapy compared to those who treated with chemotherapy alone.
Bevacizumab should be permanently discontinued in patients who develop arterial thromboembolic events.
Patients treated with bevacizumab plus chemotherapy with a history of arterial thromboembolism, diabetes, or age greater than 65 years have an increased risk of developing arterial thromboembolism events during bevacizumab therapy.
Caution should be taken when treating such patients with bevacizumab.
Venous thromboembolism (see Adverse Reactions): Patients may be at risk of developing venous thromboembolism 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 (see Clinical Studies: Venous thromboembolism under Adverse Reactions).
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 (see Adverse Reactions): Events consistent with congestive heart failure (CHF) were reported in clinical trials. The finding 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 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 factor for CHF were present.
In AVF3694g trial, the treatment group with Anthracyclines plus bevacizumab compared to the Anthracyclines only group had no increase in the incidence of all grades CHF, even in patients previously treated with anthracyclines or patients who had never used anthracyclines. However, in both trials, AVF3694g and AVF3693g, CHF grade 3 or higher events were somewhat more frequent among patients receiving bevacizumab plus chemotherapy than those receiving chemotherapy alone. This is consistent with results in patients in other studies of metastatic breast cancer who did not receive concurrent Anthracyclines treatment (see Clinical Studies under Adverse Reactions).
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 (see Clinical Studies under Adverse Reactions).
Necrotizing 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 necrotizing fasciitis, and appropriate treatment should be promptly initiated (see Post marketing experience under Adverse Reactions).
Proteinuria (see Adverse Reactions): In clinical trials, the incidence of proteinuria was higher in patients receiving bevacizumab plus chemotherapy compared to those who received chemotherapy alone. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of patients treated with Bevacizumab. In the event of nephrotic syndrome, Bevacizumab treatment should be permanently discontinued.
Hypersensitivity reactions, infusion reactions (see Clinical Studies and Post marketing experience under Adverse Reactions): Patients may be at risk of developing infusion/hypersensitivity reactions. Close observation of the patients during and following the administration of Bevacizumab is recommended as expected for any infusion of a therapeutic humanized monoclonal antibody. If a reactions occur, the infusion should be discontinued and appropriate medical therapies should be administered. A systematic premedication is not warranted.
Ovarian Failure/Fertility (see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation and Clinical Studies under Adverse Reactions): Bevacizumab may impair female fertility. Therefore, fertility preservation strategies should be discussed with women of childbearing potential prior to starting treatment with bevacizumab.
RENAL IMPAIRMENT: The safety and efficacy of Bevacizumab have not been studied in patients with renal impairment.
HEPATIC IMPAIRMENT: The safety and efficacy of Bevacizumab have not been studied in patients with hepatic impairment.
DRUG ABUSE AND DEPENDENCE: Not applicable.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: No studies on the effect on the ability to drive and use machines have been performed. However, there is no evidence that Bevacizumab treatment result in an increase in adverse events that might lead to impairment of the ability to drive or operate machinery or impairment of mental ability.
Use in Children: Bevacizumab is not approved for use in patients under 18 years of age. The safety and efficacy of bevacizumab in this population have not been established. Addition of Bevacizumab to standard of care did not demonstrate clinical benefit in pediatric patients in two phase II clinical trials; one in pediatric high grade glioma and one in pediatric metastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma.
In published reports, cases of osteonecrosis at sites other than the jaw have been observed in patient under the age of 18 years exposed to Bevacizumab (see Post marketing experience under Adverse Reactions and Pharmacology: Toxicology: Non-clinical Safety: Other: Physeal Development under Actions).
Use in the Elderly: Refer to Arterial thromboembolism as previously mentioned.