Altuzan

Avastin (Bevacizumab) instructions

Common name: Avastin

Trade name: Bevacizumab

All names: Avastin, Bevacizumab, Bevacizumab, Avastin, Avastin, Bevacizumab,Avastin

1. Indications of Avastin:

In combination with fluorouracil for the treatment of metastatic colorectal cancer

In combination with paclitaxel and docetaxel Combined with first-line treatment of metastatic breast cancer

In combination with platinum-based chemotherapy as first-line treatment of unresectable advanced, metastatic or recurrent non-small cell lung cancer (except squamous type)

With interferon-2α as first-line treatment of advanced and/or metastatic renal disease Cell carcinoma

Monotherapy for previously treated glioblastoma multiforme with disease progression

2. Avastin dosage

Colorectal cancer: 5 mg/kg or 10 mg/kg, administered every 2 weeks; or 7.5 mg/kg or 15 mg/kg, administered every 3 weeks

Breast cancer: 10 mg/kg, administered every 2 weeks; or 15 mg/kg, administered every 3 weeks

Lung cancer: 7.5 mg/kg or 15 mg/kg, administered every 3 weeks, in combination with platinum-containing chemotherapy for a total of 6 cycles, followed by monotherapy

Renal cell carcinoma: 10 mg/kg every 2 weeks

Glioblastoma multiforme: 10 mg/kg, once every 2 weeks

3. Avastin administration method

(1) Bevacizumab injection and dextrose or glucose solution cannot be administered simultaneously or mixedly

(2) Intravenous bolus or rapid injection (Bolus) cannot be used.

(3) Bevacizumab should be diluted by professional health personnel using aseptic techniques before infusion.

The first intravenous infusion should last for more than 90 minutes.

Subsequent infusions: If the first infusion is well tolerated, the second infusion can be shortened to 60 minutes; if the patient also tolerates the 60-minute infusion well, all subsequent infusions can be completed in 30 minutes.

It is recommended that the first infusion should be after chemotherapy drugs, and subsequent infusions can be before or after chemotherapy drugs

(4) Extract the required bevacizumab, and the final concentration of bevacizumab solution should be maintained between 1.4 and 16.5 mg/ml. It is recommended to dilute 0.9% sodium chloride injection to a total volume of 100ml

(5) Because the product does not contain preservatives, all remaining medicine in the vial must be discarded.

4. Avastin dose adjustment
Reducing the dose of bevacizumab is not recommended.
Discontinue bevacizumab if the following occurs:
Gastrointestinal perforation (gastrointestinal perforation, gastrointestinal fistula formation, abdominal abscess) involving visceral fistula formation
Wound dehiscence requiring intervention and wound healing complications
Severe bleeding (e.g., requiring intervention)
Severe arterial thrombotic events
Hypertensive crisis or hypertensive encephalopathy
Reversible posterior leukoencephalopathy syndrome (RPLS)
Nephrotic syndrome
If In these circumstances, bevacizumab needs to be suspended:
4 weeks before elective surgery
Severe hypertension that is poorly controlled with medications
Moderate to severe proteinuria requires further evaluation
Severe infusion reactions

5. Adverse reactions of Avastin

Adverse reactions in clinical trials

A number of clinical trials of bevacizumab in the treatment of different malignant tumors have been carried out, most of which were combined with chemotherapy. Safety results obtained from a clinical trial population of more than 3,500 patients are described in this section.

The most serious adverse drug reactions are:

Gastrointestinal perforation [see Precautions]

Bleeding, including pulmonary hemorrhage/hemoptysis, which is more common in patients with NSCLC (non-small cell lung cancer) [see Precautions]

Arterial thromboembolism [see Precautions]

Analysis of clinical safety data suggests that the occurrence of hypertension and proteinuria may be dose-dependent when receiving bevacizumab.

The most frequent adverse drug reactions in patients receiving bevacizumab in various clinical trials include hypertension, fatigue or asthenia, diarrhea and abdominal pain.

Gastrointestinal perforation

Severe gastrointestinal perforation has occurred in some patients receiving bevacizumab. According to clinical trial reports, the incidence of gastrointestinal perforation is only 1% in patients with metastatic breast cancer or non-squamous non-small cell lung cancer, and up to 2% in patients with metastatic colorectal cancer or metastatic renal cell carcinoma, or in patients receiving first-line treatment for ovarian cancer. Cases of gastrointestinal perforation have also been observed in patients with recurrent glioblastoma.

Approximately one-third of cases of severe gastrointestinal perforation are fatal, accounting for 0.2%-1% of all bevacizumab-treated patients.

These gastrointestinal perforations vary in type and severity, ranging from free air observed on a plain abdominal radiograph, which resolves without treatment, to intestinal perforations with abdominal abscess and fatal outcome. In some cases, there is underlying intra-abdominal inflammation, which may result from gastric ulcer, tumor necrosis, diverticulitis, or chemotherapy-induced colitis. Whether there is a causal relationship between intra-abdominal inflammatory processes and gastrointestinal perforation and bevacizumab has not been established.

Fistulas

Some patients receiving bevacizumab have developed serious fistulas, including cases resulting in death. In clinical trials of bevacizumab, gastrointestinal fistulas occurred in 2% of patients with metastatic colorectal and ovarian cancer and were less common in patients with other types of cancer. Among other indications, fistulas in sites other than the gastrointestinal tract (eg, bronchopleural, genitourinary, and bile duct fistulas) have been rarely reported (≥0.1% to [1%]). Fistulas have also been reported in postmarketing experience. Fistulas occurred at various times during treatment, from one week to more than one year after starting bevacizumab treatment, with most occurring within the first 6 months of treatment.

Bleeding

In clinical trials for all indications, the overall incidence of NCI-CTC grade 3-5 bleeding events was 0.4%-6.5% in patients receiving bevacizumab and 0-2.9% in control patients receiving chemotherapy. The type of bleeding observed in clinical trials of bevacizumab was primarily tumor-related bleeding (see below), followed to a lesser extent by mucosal and cutaneous bleeding (eg, epistaxis).

Tumor-related bleeding

Severe or massive pulmonary hemorrhage/hemoptysis has been observed primarily in studies of patients with non-small cell lung cancer (NSCLC). Possible risk factors include squamous tumor histology, treatment with antirheumatic/anti-inflammatory drugs, treatment with anticoagulants, previous radiation therapy, bevacizumab treatment, previous history of atherosclerosis, central lung cancer, and tumor cavitation before or during treatment. Variables with statistically significant associations with bleeding were bevacizumab treatment and squamous cell tissue. In subsequent studies, patients with NSCLC with known squamous tissue or mixed cell types with predominantly squamous cells were excluded, but patients with unknown tumor histology were included.

In patients with NSCLC excluding squamous cell carcinoma as the primary histological type, the incidence of adverse events of all grades was observed in 9% when bevacizumab was combined with chemotherapy and in 5% of patients who received chemotherapy alone. Grade 3-5 adverse events occurred in 2.3% of patients receiving bevacizumab plus chemotherapy and <1% in patients receiving chemotherapy alone. Severe or massive pulmonary hemorrhage/hemoptysis can occur suddenly, and two-thirds of severe pulmonary hemorrhages are fatal (see Precautions).

Gastrointestinal bleeding, including rectal bleeding and melena, has been reported in patients with colorectal cancer, and these bleeding events were evaluated as tumor-related bleeding.

In rare cases, tumor-related bleeding can also be observed in patients with other tumor types and sites, such as patients with central nervous system (CNS) metastases and CNS bleeding in patients with glioblastoma.

The incidence of CNS bleeding after treatment with bevacizumab in patients with previously untreated CNS metastases has not been prospectively evaluated in randomized clinical trials. An exploratory retrospective analysis of the results of 13 completed randomized trials involving various types of tumors: 3 (3.3%) of 91 patients with brain metastases who received bevacizumab developed central nervous system bleeding (all grade 4), compared with only 1 (1%) of 96 patients not exposed to bevacizumab (grade 5). In two follow-up studies of the treatment of brain metastases (approximately 800 patients), one case had a grade 2 central nervous system bleed.

Patients with glioblastoma may develop intracranial hemorrhage when they relapse. In study AVF3708g, the incidence of CNS bleeding was reported to be 2.4% (2/84) (Grade 1 bleeding) in the bevacizumab alone group and 3.8% (3/79) (Grade 1, 2, and 4) in the group receiving bevacizumab plus irinotecan.

In all bevacizumab clinical trials, a 50% incidence of mucosal and cutaneous bleeding was observed in patients treated with bevacizumab. The most common of these is NCI-CTC grade 1 epistaxis, which lasts less than 5 minutes, resolves without medical intervention, and does not require any changes to the bevacizumab regimen. Clinical safety data suggest that the occurrence of mild mucosal and cutaneous bleeding (e.g., epistaxis) may be dose-dependent.

Mild mucosal and skin bleeding occurring in other areas, such as gum bleeding or vaginal bleeding, is uncommon.

Hypertension (see Precautions)

The incidence of hypertension (grades of hypertension) has been observed in 42.1% of patients treated with bevacizumab, significantly higher than the 14% in the control group. In clinical trials across indications, the overall incidence of NCI-CTC grade 3 and 4 hypertension in patients receiving bevacizumab ranged from 0.4% to 17.9%. The incidence of grade 4 hypertension (hypertensive crisis) was 1.0% in patients treated with bevacizumab and did not exceed 0.2% in patients receiving only the same chemotherapy as in the trial group.

Hypertension can usually be adequately controlled with oral antihypertensive medications such as angiotensin-converting enzyme inhibitors, diuretics, and calcium channel blockers. There have been rare cases of discontinuation of bevacizumab therapy or hospitalization due to hypertension.

Rare case reports of hypertensive encephalopathy have occurred, with fatal outcome in some individuals (see also Precautions). The risk of hypertension with bevacizumab was not related to baseline patient characteristics, underlying disease, or concomitant treatment.

Reversible posterior leukoencephalopathy syndrome (RPLS)

Two patients (0.8%) diagnosed with RPLS were reported in a clinical study. Although some patients have neurological sequelae, RPLS symptoms usually disappear or resolve within a few days.

Thromboembolism

Arterial thromboembolism

An increased incidence of arterial thromboembolic events has been observed in patients treated with bevacizumab for various indications, including cerebrovascular accidents, myocardial infarction, transient ischemic attacks, and other arterial thromboembolic events.

In different clinical trials, the overall incidence of arterial thromboembolism was 3.8% in the bevacizumab group, compared with 1.7% in the chemotherapy control group. Fatal outcomes occurred in 0.8% of patients who received bevacizumab plus chemotherapy and 0.5% of patients who received chemotherapy alone. Cerebrovascular accidents (including transient ischemic attacks) occurred in 2.3% of patients treated with bevacizumab compared with 0.5% in the control group; myocardial infarction occurred in 1.4% of patients treated with bevacizumab compared with 0.7% in the control group.

Clinical trial AVF2192g included patients with metastatic colorectal cancer who were ineligible for irinotecan treatment. In this trial, the incidence of arterial thromboembolism was observed in 11% (11/100) of patients in the bevacizumab group and 5.8% (6/104) in the chemotherapy control group.

Venous thromboembolism (see Precautions)

In clinical trials for various indications, the overall incidence of venous thromboembolism was 2.8%-17.3% in the bevacizumab group and 3.2%-15.6% in the chemotherapy control group. Venous thromboembolic events include deep vein thrombosis and pulmonary embolism.

The highest incidence of grade 3-5 venous thromboembolic events was 7.8% in patients treated with chemotherapy plus bevacizumab and 4.9% in patients treated with chemotherapy alone. Patients who have experienced venous thromboembolism may be at higher risk of recurrence when treated with bevacizumab plus chemotherapy compared with patients treated with chemotherapy alone.

Congestive Heart Failure

To date, congestive heart failure (CHF) has been observed in all oncology indications in bevacizumab clinical trials, but primarily in patients with metastatic breast cancer. In five phase III studies (AVF2119g, E2100, BO17708, AVF3694g, and AVF3693g) in patients with metastatic breast cancer, the incidence of grade 3 or higher CHF was as high as 3.5% in patients treated with bevacizumab plus chemotherapy, compared with no more than 0.9% in the control group.

Most patients who developed CHF in the metastatic breast cancer trial experienced improvement in symptoms and/or left ventricular function with appropriate treatment.

In most clinical trials of bevacizumab, patients with prior NYHA class II-IV CHF were excluded, and therefore, no information about the risk of CHF in this population was available.

Previous exposure to anthracyclines and/or previous radiation therapy to the chest wall may be risk factors for the development of CHF (see Precautions).

In a clinical study in the treatment of diffuse large B-cell lymphoma, an increased incidence of CHF was observed when patients received bevacizumab in combination with doxorubicin at a cumulative dose exceeding 300 mg/m2. This phase III clinical trial compared the combination of rituximab/cyclophosphatide/doxorubicin/vincristine/prednisone (R-CHOP) and bevacizumab with R-CHOP without bevacizumab. Although the incidence of CHF was higher in both groups than previously observed with doxorubicin, the incidence was higher in the group treated with R-CHOP in combination with bevacizumab.

Wound Healing (see Precautions)

Because bevacizumab may have adverse effects on wound healing, patients who had undergone major surgery within 28 days before starting bevacizumab treatment were not included in the Phase III trial.

Results from a metastatic colorectal cancer clinical trial showed no increased risk of postoperative bleeding or wound healing complications in patients who underwent major surgery 28-60 days before the start of bevacizumab treatment. However, it was observed in the study that if patients were treated with bevacizumab during surgery, the incidence of postoperative bleeding or wound healing complications was increased within 60 days after major surgery. The incidence is between 10% (4/40) and 20% (3/15).

In clinical trials in patients with locally recurrent and metastatic breast cancer, the incidence of grade 3-5 wound healing complications was 1.1% in patients receiving bevacizumab and 0.9% in control patients.

In a study of patients with recurrent glioma (AVF3708g), the incidence of postoperative wound healing complications (craniotomy wound dehiscence and cerebrospinal fluid leakage) was 3.6% in the bevacizumab alone group and 1.3% in the bevacizumab plus irinotecan group.

Proteinuria (see Precautions)

Clinical trial results show that the incidence of proteinuria in patients treated with bevacizumab ranges from 0.7% to 38%. The severity of proteinuria ranges from clinically asymptomatic, transient, microalbuminuria to nephrotic syndrome. As many as 8.1% of patients in the treatment group developed grade 3 proteinuria. The incidence of grade 4 proteinuria (nephrotic syndrome) was observed in 1.4% of patients in the treatment group. Proteinuria observed in bevacizumab clinical trials was not associated with renal injury, and few individuals required permanent discontinuation of bevacizumab therapy.

Patients with a history of hypertension may be at increased risk of developing proteinuria when treated with bevacizumab. There is evidence that the occurrence of grade 1 proteinuria may be dose-related to bevacizumab. Testing for urinary protein is recommended before initiating treatment with bevacizumab.

In most clinical trials, when urine protein levels are ≥2 g/24 hours, bevacizumab treatment needs to be postponed until urine protein levels return to <2 g/24 hours before starting treatment.

Hypersensitivity reactions, infusion reactions (see Precautions)

In some clinical trials, anaphylaxis and anaphylactoid reactions occurred more frequently in patients treated with bevacizumab plus chemotherapy compared with chemotherapy alone. The occurrence of these reactions was common in some trials of bevacizumab (approximately 5% of bevacizumab-treated patients).

Ovarian failure/fertility (see Precautions and Use in Pregnant and Lactating Women)

Evaluation of ovarian failure (criterion used here as amenorrhea lasting 3 months or more, FSH level ≥30 mIU/mL, and negative beta-HCG pregnancy test): New reports of adverse events of ovarian failure were more common in patients treated with bevacizumab. Ovarian function recovers in most women after discontinuation of bevacizumab therapy. The long-term effects of treatment with bevacizumab on fertility have not been established.

Geriatric patients

In randomized clinical trials, the risk of arterial thromboembolic events, including cerebrovascular accidents, transient ischemic attacks, and myocardial infarction, may be greater in patients >65 years of age when treated with bevacizumab than in patients ≤65 years of age (see Precautions and Adverse Reactions, Thromboembolism). Other adverse reactions observed at higher rates in patients over 65 years of age included grade 3-4 leukopenia and thrombocytopenia, and all grades of neutropenia, diarrhea, nausea, headache, and fatigue.

In older patients (>65 years) who received bevacizumab, the incidence of other adverse reactions, including gastrointestinal perforation, wound healing complications, hypertension, proteinuria, congestive heart failure, and bleeding, was no higher than in those patients ≤65 years of age who received bevacizumab.

Serious adverse events in clinical studies of bevacizumab in China

As of January 5, 2009, a total of 86 serious adverse events (SAEs) have been reported in 77 patients in China s) report, these SAEs came from 7 clinical studies of bevacizumab conducted in China, and an estimated 625 patients received bevacizumab treatment. Among them, the patients who experienced SAE were 12.3% (77/625) of the patients who received bevacizumab treatment. Among serious adverse events, 29.1% (25/86) SAEs (including 2 deaths) were assessed by the investigators as possibly related to bevacizumab. A medical review of these SAE reports revealed that these SAEs reflect known safety issues listed in this labeling or are expected events considering the medical history and concomitant medications of patients with various advanced or metastatic tumors in these studies.

Laboratory test abnormalities

Bevacizumab treatment may result in decreased neutrophil counts, decreased white blood cell counts, and the development of proteinuria.

The results of various clinical trials show that compared with those patients in the control group, the incidence of the following grade 3 and 4 laboratory test abnormalities is increased (≥2%) in patients treated with bevacizumab: increased blood sugar, decreased hemoglobin, increased serum potassium, decreased serum potassium, decreased white blood cell count, prolonged PT (coagulation time), increased normalized ratio, etc.

Immunogenicity

Like all therapeutic proteins, this product also has potential immunogenicity. There are no adequate methods for detecting antibody production in patients receiving bevacizumab due to insufficient sensitivity at low titers. Enzyme-linked immunosorbent assays (ELISAs) were used to detect antibodies in approximately 500 patients receiving bevacizumab treatment (mainly in combination with chemotherapy) and failed to detect high titers of human anti-bevacizumab antibodies.

Immunogenicity results mainly depend on the sensitivity and specificity of the detection method. In addition, the positivity of detected antibodies is also affected by the following factors: including blood sample processing, sampling time, combined medications, and combined diseases. For these reasons, comparing the incidence of antibodies to bevacizumab with the incidence of antibodies to other drugs may be misleading.

Post-marketing experience

The following adverse reactions have been reported during the use of bevacizumab after its marketing abroad. Since these adverse reaction reports are spontaneous reports from a population of uncertain sample size, it is impossible to truly and reliably estimate their incidence and establish a causal relationship with drug use.

Systemic: polyserosositis

Cardiovascular: pulmonary hypertension, reversible posterior leukoencephalopathy syndrome (RPLS), hypertensive encephalopathy

Digestive: intestinal necrosis, mesenteric venous occlusion, anastomotic ulcer

Blood and lymph: pancytopenia

Kidney: renal thrombotic microangiopathy (severe manifestations) proteinuria)

Respiratory: Nasal septum perforation, dysphonia

Gastrointestinal disorders: Gastrointestinal ulcers

Hepatobiliary disorders: Gallbladder perforation (incidence unknown)

Immune system disorders: Hypersensitivity reactions, infusion reactions; with the following common manifestations: dyspnea, flushing/redness/rash, hypotension or hypertension, decreased oxygen saturation, chest pain, stiffness, and nausea/vomiting. (See Precautions)

Ocular Disorders (reported from unapproved intravitreal use): Infectious endophthalmitis (some conditions cause permanent blindness) (incidence unknown); Intraocular inflammation (some conditions cause permanent blindness) e.g.: Sterility endophthalmitis, uveitis and vitritis; retinal detachment (incidence unknown); retinal pigment epithelial tear (incidence unknown); increased intraocular pressure (incidence unknown); intraocular hemorrhage, such as vitreous hemorrhage or retinal hemorrhage (incidence unknown); conjunctival hemorrhage (incidence unknown)

An observational study based on the U.S. Medicare database comparing unapproved intravitreal bevacizumab with approved treatments in the treatment of wet age-related macular degeneration found an increased risk of endophthalmitis in the bevacizumab group ( Adjusted HR: 1.82; 99% CI: 1.20, 2.76) (incidence: 0.46 adverse events/100 patient-years; control: 0.26 adverse events/100 patient-years), and there was also an increased risk of cataract surgery (adjusted HR: 1.11; 99% CI: 1.01, 1.23) (incidence rate 6.33 adverse events/100 patient-years; control group 5.64 adverse events/100 patient-years).

There have been reports of serious ocular adverse events (including infective endophthalmitis and other ocular infections) in a large number of patients due to inconsistent and incorrect mixing, storage and disposal methods of bevacizumab.

Systemic events (data derived from reports of unapproved intravitreal use): An observational study based on the Medicare database comparing unapproved intravitreal bevacizumab with approved treatments for the treatment of wet age-related macular degeneration found an increased risk of hemorrhagic stroke in the bevacizumab group (adjusted HR: 1.57; 99% CI: 1.04, 2.3 7) (incidence 0.41 adverse events/100 patient-years; control group 0.26 adverse events/100 patient-years), and the risk of overall mortality was also increased (adjusted HR: 1.11; 99% CI: 1.01, 1.23) (incidence rate 6.03 adverse events/100 patient-years; control group 5.51 adverse events/100 patient-years). A second observational study found similar results in terms of all-cause mortality. A randomized controlled clinical trial comparing the unapproved bevacizumab with an approved treatment in the treatment of wet age-related macular degeneration found an increased risk of serious systemic adverse events in the bevacizumab group, most of which resulted in hospitalization (adjusted hazard ratio: 1.29; 95% CI: 1.01, 1.66) (incidence 24.1%; 19.0% in the control group).

Muscle/Skeletal Disorders: Osteonecrosis of the jaw (ONJ) ​​has been observed in patients receiving bevacizumab, primarily related to prior or concomitant bisphosphonate therapy.

6. Bevacizumab contraindications

Bevacizumab is contraindicated in patients with known allergies to the following substances:

Any component of the product;

Chinese hamster ovary cell products or other recombinant human or humanized antibodies.

7. Bevacizumab Precautions

Gastrointestinal perforation

During treatment with bevacizumab, patients may be at increased risk of gastrointestinal perforation and gallbladder perforation (see Adverse Reactions).

Bevacizumab should be permanently discontinued in patients who develop gastrointestinal perforation.

Fistulas

Patients may be at increased risk of developing fistulas when treated with bevacizumab (see Adverse Reactions).

Bevacizumab should be permanently discontinued in patients who develop a tracheoesophageal (TE) fistula or any type of grade 4 fistula. There is limited information on continuing bevacizumab in the setting of other fistulas. Discontinuation of bevacizumab should be considered in patients who develop fistulas outside the gastrointestinal tract.

Bleeding

Patients treated with bevacizumab are at increased risk of bleeding, particularly tumor-related bleeding (see Adverse Reactions). Patients who develop grade 3 or 4 bleeding while being treated with bevacizumab should have bevacizumab permanently discontinued.

Patients who are generally judged to have central nervous system metastasis based on imaging or clinical symptoms and signs are excluded from clinical trials of bevacizumab. Therefore, there are no relevant prospective randomized trials assessing the risk of CNS bleeding in this population. Patients should be monitored for symptoms and signs related to central nervous system hemorrhage, and bevacizumab therapy should be interrupted if intracranial hemorrhage occurs.

No information is available regarding the safety of bevacizumab in patients with congenital bleeding diathesis and acquired coagulopathies, or in patients taking full doses of anticoagulants for thromboembolism before initiating bevacizumab therapy, as such patients are often excluded from clinical trials. Therefore, careful consideration should be given before initial treatment with bevacizumab in such patients. However, in patients who developed venous thrombosis while receiving bevacizumab, there was no increase in the incidence of grade 3 or higher bleeding when full-dose warfarin was concurrently treated with bevacizumab.

Serious eye infection caused by mixing for unapproved intravitreal use (see Adverse Reactions)

There have been reports of individual and population-based serious ocular adverse events (including infective endophthalmitis and other ocular infections) caused by mixing Avastin bottled formulations approved for intravenous administration in cancer patients for unapproved intravitreal use. Some of these events result in varying degrees of vision loss, including permanent blindness.

Bevacizumab is not available for intravitreal use.

Pulmonary hemorrhage/hemoptysis (see Adverse Reactions)

Patients with non-small cell lung cancer treated with bevacizumab may be at risk for severe, and in some cases fatal, pulmonary hemorrhage/hemoptysis (see Hemorrhage). Patients who have recently experienced pulmonary hemorrhage/hemoptysis (>1/2 teaspoon of bright 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 development of hypertension may be dose-dependent. In patients with a history of hypertension, preexisting hypertension should be adequately controlled before initiating bevacizumab therapy. There is no information on the effects of bevacizumab in patients whose blood pressure is not controlled when initiating bevacizumab therapy. Monitoring of blood pressure is recommended during treatment with bevacizumab (see Adverse Reactions).

In most cases, patients who develop hypertension can have their blood pressure adequately controlled with standard antihypertensive treatment on an individual basis. Bevacizumab should be permanently discontinued in patients with overt hypertension that is not adequately controlled with antihypertensive therapy or who develop hypertensive crisis or hypertensive encephalopathy (see Adverse Reactions and Postmarketing Experience).

Reversible posterior leukoencephalopathy syndrome (RPLS)

Reversible posterior leukoencephalopathy syndrome (RPLS)-like signs/symptoms have been rarely reported in patients treated with bevacizumab. RPLS is a rare neurological disorder characterized by seizures, headache, mental status changes, visual impairment, or cortical blindness, with or without hypertension. The diagnosis of RPLS needs to be confirmed by brain imaging findings, with MRI being preferred. In patients who develop RPLS, specific symptomatic treatment including control of hypertension and discontinuation of bevacizumab is recommended. The safety of reinitiating bevacizumab therapy in patients with previous RPLS is not known (see Postmarketing Experience).

Arterial thromboembolism (see Adverse Reactions)

In clinical trials, the incidence of arterial thromboembolism, including cerebrovascular accidents, transient ischemic attacks (TIA), and myocardial infarction (MI), was observed to be higher in patients who received bevacizumab plus chemotherapy than in those who received chemotherapy alone.

Bevacizumab should be permanently discontinued in patients who have developed arterial thromboembolism.

Patients with a history of arterial thromboembolism or who are older than 65 years of age and receiving bevacizumab combined with chemotherapy are at increased risk of developing arterial thromboembolism during bevacizumab treatment. Caution should be used when treating such patients with bevacizumab.

Venous thromboembolism (see Adverse Reactions)

Patients may be at risk for venous thromboembolic events, including pulmonary embolism, during treatment with bevacizumab. Bevacizumab should be discontinued if a patient develops a life-threatening (Grade 4) venous embolism event, including pulmonary embolism. Patients with grade ≤3 embolic events require close monitoring.

Congestive Heart Failure (see Adverse Reactions)

Events meeting diagnostic criteria for congestive heart failure (CHF) have been reported in clinical trials. From asymptomatic reduced left ventricular ejection fraction to symptomatic CHF requiring treatment or hospitalization.

Use caution when using this product to treat patients with clinically severe cardiovascular disease (such as a history of coronary heart disease or congestive heart failure).

Most patients who develop CHF have metastatic breast cancer and have been treated with anthracyclines before, or have received radiation therapy to the left chest wall before, or have other risk factors for CHF.

Bevacizumab should be treated with caution in patients with clinically significant cardiovascular disease or previous congestive heart failure.

Neutropenia

An increased incidence of severe neutropenia, neutropenic fever, or infection with severe neutropenia (even death in some cases) has been observed in patients treated with certain myelotoxic chemotherapy regimens plus bevacizumab compared with patients treated with chemotherapy alone.

Wound healing complications

Bevacizumab may have adverse effects on wound healing. Bevacizumab therapy should not be started for at least 28 days after major surgery or should wait until the surgical wound has completely healed before starting bevacizumab therapy. Patients who develop wound healing complications during bevacizumab treatment should have bevacizumab treatment withheld until the wound has completely healed. Bevacizumab therapy should also be withheld in patients requiring elective surgery (see Adverse Reactions).

Proteinuria (see Adverse Reactions)

Clinical trial results show that the incidence of proteinuria is higher in patients who received bevacizumab in combination with chemotherapy than in those who received chemotherapy alone. Grade 4 proteinuria (nephrotic syndrome) is uncommon in patients treated with bevacizumab. If grade 4 proteinuria develops, bevacizumab therapy should be permanently discontinued.

Hypersensitivity reactions, infusion reactions (see Adverse Reactions)

Patients may be at high risk for developing infusion reactions/hypersensitivity reactions. Recommendations should be made, as with all therapeutic humanized mAb infusions, to observe patients closely during and after bevacizumab administration. If a reaction occurs, the infusion should be discontinued and appropriate treatment instituted. Systemic prophylactic administration does not prevent such reactions.

Ovarian Failure/Fertility (see Adverse Reactions and Use in Pregnant and Lactating Women)

Bevacizumab may impair female fertility. Therefore, fertility preservation methods should be discussed with potentially fertile women before treatment with bevacizumab.

8. Use of bevacizumab in special populations

Pregnancy

Research has shown that angiogenesis is crucial to fetal development. Inhibitory effects on angiogenesis following administration of bevacizumab may result in adverse pregnancy outcomes.

Adequate studies have not been conducted in pregnant women (see Teratogenicity). IgG is known to cross the placental barrier, and bevacizumab may inhibit fetal angiogenesis. Therefore, bevacizumab should not be used during pregnancy. It is recommended that women of childbearing potential use appropriate contraceptive measures when treated with bevacizumab. Due to pharmacokinetic considerations, contraception is recommended for at least 6 months after the last dose of bevacizumab.

Fertility (see Adverse Reactions and Precautions)

Repeated-dose safety studies in animals indicate that bevacizumab may have adverse effects on female fertility (see Pharmacology and Toxicology). A substudy of 295 premenopausal women found that the incidence of ovarian failure was higher in the bevacizumab group than in the control group. After discontinuation of bevacizumab therapy, ovarian function recovered in most patients. The long-term effects of bevacizumab on fertility have not been established.

Nursing mothers

It is not known whether bevacizumab is excreted in human milk. Because maternal IgG is excreted in breast milk and bevacizumab may harm the growth and development of the infant, women should be advised to discontinue breastfeeding while treated with bevacizumab and not to breastfeed for at least 6 months after the last dose of bevacizumab.

Pediatric Use

The safety and effectiveness of bevacizumab in children and adolescents is unclear.

Drug use in the elderly

See "Arterial Thromboembolism".

8. Bevacizumab drug interactions

Interactions with other drugs and other forms of interactions

Effect of antineoplastic drugs on the pharmacokinetics of bevacizumab

Based on the results of population PK analysis, no clinically significant interaction between concomitant chemotherapy and bevacizumab metabolism was observed. The effect of bevacizumab monotherapy on bevacizumab clearance was neither statistically significant nor clinically relevant compared with bevacizumab plus alpha-2a interferon or other chemotherapy (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine or doxorubicin, cisplatin/gemcitabine).

The effect of bevacizumab on the pharmacokinetics of other anti-tumor drugs

The results of the drug-drug interaction study AVF3135g showed that bevacizumab had no significant effect on the pharmacokinetics of irinotecan and its active metabolite SN38.

The results of the study NP18587 showed that bevacizumab had no significant impact on the pharmacokinetics of capecitabine and its metabolites. At the same time, it was determined by measuring free platinum and total platinum that it had no significant impact on the pharmacokinetics of oxaliplatin.

The results of study BO17705 confirmed that bevacizumab has no significant effect on the pharmacokinetics of alpha-2a interferon.

The results of study BO17704 showed that bevacizumab did not have a significant impact on the pharmacokinetics of cisplatin. Due to the high variability between patients and the limited sample size, firm conclusions regarding the effect of bevacizumab on gemcitabine pharmacokinetics cannot be drawn based on the results of BO17704.

Bevacizumab in combination with sunitinib malate

In two clinical studies of metastatic renal cell carcinoma, bevacizumab (10 mg/kg every 2 weeks) was combined with sunitinib malate (50 mg daily). Microvascular hemolytic anemia (MAHA) was reported in 7 of 19 patients.

MAHA is a hemolytic disorder characterized by fragmentation of red blood cells, anemia and thrombocytopenia. Additionally, hypertension (including hypertensive crisis), elevated creatinine, and neurological symptoms have been observed in some patients. All these findings were reversible, reverting with discontinuation of bevacizumab and sunitinib. (See Precautions Hypertension, Proteinuria, RPLS).

Radiation therapy

The safety and effectiveness of combined therapy with radiation therapy and bevacizumab have not been established.

9. Overdose of bevacizumab

The highest dose tested in humans (20 mg/kg body weight, intravenously administered every 2 weeks) may cause severe migraines in some patients.

10. Storage of bevacizumab

Bevacizumab should be used before the expiry date marked on the package.

Avoid light, store and transport in original packaging at 2℃-8℃.

Do not freeze. Don't shake.

Bevacizumab does not contain any antimicrobial preservatives, therefore, care must be taken to ensure the sterility of the prepared solution. It has been confirmed that the chemical and physical stability of bevacizumab can be maintained for 48 hours during use in 0.9% sodium chloride solution at 2℃-30℃. From a microbiological perspective, the product should be used immediately after preparation. If it cannot be used immediately, the user is responsible for ensuring the storage time and conditions during use, strictly controlling and confirming dilution under sterile conditions. Under normal circumstances, the storage time at 2℃-8℃ should not exceed 24 hours.

11. Packaging

Cillin bottle, 1 bottle/box.

12. Validity period

24 months