(bevacizumab)
For intravenous use only.
warn
Gastrointestinal perforation/wound healing complications
Avastin can cause gastrointestinal perforation and wound dehiscence, sometimes even fatal. Gastrointestinal perforation, sometimes accompanied by abdominal abscess, can occur during the whole process of using Avastin (but it has nothing to do with the length of use). When Avastin combined with IFL intravenous chemotherapy, the incidence of gastrointestinal perforation was 2%.
According to reports, the typical performance is abdominal pain accompanied by constipation or vomiting. The diagnosis of gastrointestinal perforation should be considered if the patient has abdominal pain during the application of Avastin.
If the patient has gastrointestinal perforation or wound dehiscence during the application of Avastin and needs medical intervention, Avastin should be permanently stopped. In order to avoid the influence of Avastin treatment on wound healing/wound cracking, it is inconclusive how long it will take to perform selective surgery after Avastin treatment. (See warnings: "Gastrointestinal perforation/wound dehiscence syndrome" and "Dosage and usage: dosage adjustment")
Bleeding problem
Severe bleeding, sometimes fatal. Avastin combined with chemotherapy for bleeding in patients with non-small cell lung cancer. In a small study of Avastin combined with chemotherapy in the treatment of non-small cell lung cancer, it was found that the incidence of severe or fatal bleeding in squamous cell carcinoma was 365,438 0%, and adenocarcinoma was only 4%, but chemotherapy alone did not occur. Patients with recent bleeding should not be treated with Avastin. (See warnings: "Bleeding" and "Dosage and Usage: Dose Adjustment").
abstract
Bevacizumab is a recombinant humanized monoclonal antibody. In vitro and in vivo detection system proved that IgG 1 antibody can bind to human vascular endothelial growth factor (VEGF) and block its biological activity. Avastin contains the structural region of human antibody and the complementary determinant region of mouse monoclonal antibody that can bind VEGF.
Avastin is produced by China hamster ovary expression system, and its circulating medium contains gentamicin. The molecular weight is about 149000 dalton. Avastin is a colorless, transparent, light milky white or grayish brown sterile liquid with a PH value of 6.2, which is used for intravenous infusion. Avastin is available in 100mg and 400mg, with a corresponding volume of 4ml 16ml(25mg/ml). Avastin is packaged in disposable vials without preservatives. The product composition of 100mg is: 240mga- of ga- trehalose dihydrate, 23.2 mg of sodium phosphate (monohydrate), 4.8 mg of sodium phosphate (dihydrate, anhydrous), 1.6 mg of Tween 20 and water for injection (U.S. patent). The product composition of 400mg is: α -trehalose dihydrate 960 mg, sodium phosphate (monohydrate) 92.8 mg, sodium phosphate (anhydrous dihydrate) 19.2 mg, Tween 20 6.4mg, and water for injection (US patent).
clinical pharmacology
Mechanism of action
Avastin can bind VEGF and prevent it from binding to receptors (Flt- 1 and KDR) on the surface of endothelial cells. In the in vitro angiogenesis model, the combination of VEGF and its corresponding receptors can lead to endothelial cell proliferation and neovascularization. Avastin can reduce angiogenesis and inhibit the progress of metastatic lesions in nude mice inoculated with colon cancer
pharmacokinetics
The pharmacokinetic curve of Avastin only detected the total serum concentration (that is, it did not distinguish between free Avastin and Avastin bound to VEGF ligand). Pharmacokinetic analysis based on a certain population: 49 1 patients receive 1~20mg/Kg Avastin once a week, once every two weeks, or once every three weeks. It is estimated that the half-life of Avastin is about 20 days (the range is 165438) and the time to reach steady state is estimated to be 100 days. When Avastin was treated at the dose of 10 mg/kg and every 2 weeks 1 time, the serum accumulation rate was 2.8. The serum clearance rate of Avastin varies with the patient's weight, sex and tumor load.
After weight adjustment, the clearance rate of men (0.262 L/ day versus 0.207 L/ day) is higher than that of women, and the clearance amount (3.25 L versus 2.66 L) is larger than that of women. Patients with large tumor load (greater than or equal to the median tumor body surface area) have higher clearance rate than patients with small tumor load (less than the median tumor body surface area) (0.249 liters/day versus 0. 199 liters/day). In a clinical randomized experimental study involving 8 13 patients, there is no evidence that when Avastin is used, the curative effect of male or high tumor load patients is worse than that of female and low tumor load patients. The relationship between clinical efficacy and exposure of Avastin is still inconclusive.
Special population
Demographic analysis data suggest that dose adjustment is not needed because of the patient's age or gender.
Patients with impaired renal function: At present, there is no pharmacokinetic study of Avastin in patients with impaired renal function.
Patients with hepatic insufficiency: At present, there is no pharmacokinetic study of Avastin in patients with hepatic insufficiency.
clinical research
There are two randomized clinical studies to evaluate the efficacy and safety of Avastin combined with 5-Fu-based chemotherapy in the treatment of metastatic colorectal cancer. Avastin combined with IFL regimen for intravenous injection. Study 1 is a double-blind, randomized clinical study to evaluate Avastin as a first-line treatment for metastatic colorectal cancer. Patients were randomly divided into three groups: 1 group was given IFL+ placebo (irinotecan 125 mg/m2, 5- fluorouracil 500 mg/m2, calcium tetrahydrofolate 20 mg/m2, 1 weekly 1 time, for 4 weeks, with 6 weeks as a week. The second group was IFL plus Avastin (5 mg/kg 1 time /2 weeks); The third group was 5-FU/LV+ Avastin (5 mg/kg 1 time /2 weeks).
It is decided in advance that the third group will be suspended when the toxicity of IFL static push+Avastin scheme is assessed as acceptable. 8 13 patients were randomly assigned to 1 group and the second group. The median age is 60 years old, 40% are female and 79% are white. The ECOG score of 57% patients was 0, 2 1% patients were primary rectal cancer, 28% patients received adjuvant chemotherapy, and 56% patients were mainly located in abdomen. The characteristics of patients in the study group are basically similar.
Figure 1: Study the survival curve of 1.
The two main experimental groups were also divided into different subgroups according to age, sex, race, ECOG score, primary tumor site, whether they had received adjuvant treatment, metastatic site and tumor load, and the clinical benefit rate of Avastin treatment was evaluated.
In the third group 1 10, the median survival time was 18.3 months, the median progression-free survival time was 8.8 months, the total effective rate was 39%, and the median remission time was 8.5 months.
Avastin combined with 5-FU/LV Study 2 1 is a randomized clinical study to evaluate Avastin combined with 5-FU/LV as a first-line treatment for metastatic colorectal cancer. The patients were randomly divided into three groups. 1 group received simple 5-FU/LV regimen (500 mg/m2 of 5- fluorouracil and 500 mg/m2 of calcium tetrahydrofolate 1 time per week, 6 weeks in total, and 8 weeks as a cycle). The second group, 5-FU/LV chemotherapy+Avastin 5 mg/kg 1 time /2 weeks; ) The third group was 5-FU/LV chemotherapy plus Avastin 10mg/kg 1 time /2 weeks; The patient was treated until his condition deteriorated. The main end points were effective rate and progression-free survival rate.
The progression-free survival time of the group receiving 5-Fu/LV+ Avastin 5 mg/kg was significantly better than that of the group not receiving Avastin. However, there was no significant difference between the two groups in terms of total survival and total effective rate. However, there was no significant difference between the group receiving 5-Fu/LV+ Avastin 10 mg/kg and the group not receiving Avastin.
Avastin monotherapy
At present, there is no curative effect of Avastin on colorectal cancer. However, there is an ongoing randomized study in which patients with metastatic colorectal cancer who are still receiving chemotherapy based on 5- fluorouracil+irinotecan are only given Avastin, but this study was suspended because the efficacy and survival time of Avastin alone are worse than that of FOLFOX regimen based on 5- fluorouracil+calcium tetrahydrofolate+oxaliplatin.
Tips and uses
It is suggested that Avastin combined with 5- fluorouracil-based chemotherapy can be used as the first-line treatment for metastatic colorectal cancer.
taboo
At present, Avastin has no contraindications.
drug interaction
At present, there is no formal study on the interaction between Avastin and anti-tumor drugs. In study 1, patients were treated with irinotecan /5-FU/CF (IFL) with or without Avastin.
The concentration of irinotecan is the same when IFL is simply pushed by static pressure and Avastin is used in combination. However, in patients with IFL combined with Avastin, the concentration of SN38, the active metabolite of irinotecan, was 33% higher than that of patients with IFL alone. In the study of 1, the incidence of grade 3~4 diarrhea and neutropenia was higher in patients given IFL combined with Avastin, but the influence of Avastin combined with irinotecan on the increase of SN38 level was not clear due to the diversity of patients and the limited samples.
Carcinogenicity, Mutagenicity and Damage to Fertility There are no data about the carcinogenicity of Avastin to humans and animals. Avastin may impair fertility. After continuous administration of 10 or 50mg/kg Avastin 13 or 26 weeks, it was found that there was a dose correlation between the weight of ovary and uterus, endometrial hyperplasia, decreased menstrual cycle, follicular retardation and corpus luteum loss.
Stop the drug and give recovery time of 4~ 12 weeks. Check the high dose group. The examination results of two female monkeys in the planned recovery group show that the injury is reversible. After recovery period 12 weeks, the follicular development block disappeared, but the ovarian weight was still moderately reduced, and the endometrial hyperplasia disappeared, but the uterine weight was still significantly reduced. Of the two monkeys, 1 still had corpus luteum loss and the number of menstrual cycles decreased (67%).
Effects of pregnancy
Taking mg/kg as the unit, when Avastin is given to rabbits at twice the recommended dose, it will cause deformity. The observed effects include maternal and fetal weight loss, increased fetal abortion, and increased incidence of fetal physical and skeletal changes. Observe the influence of each dose group on fetus.
The formation of blood vessels is very important for fetal development. The inhibition of angiogenesis caused by Avastin therapy may be the cause of pregnancy side effects. However, there is no sufficient and well-controlled clinical study on the effect of Avastin on pregnant women. Only after fully weighing the potential danger of Avastin to the fetus can pregnant women and women who have not taken proper contraceptive measures be treated with Avastin. Before starting treatment, all patients should be informed of the potential danger of Avastin to fetal development.
If the patient is pregnant during Avastin treatment, she should be informed of the harm of Avastin to the fetus and the potential risk of miscarriage. Even if the patient stops taking the drug, he should be informed of the residue after stopping the drug (the half-life of Avastin is about 20 days) and its possible impact on fetal development.
Lactating mother
It is not clear whether Avastin can be secreted into human milk. Because human IgG 1 can be secreted into human milk, the harm that it may be ingested and absorbed by the fetus is unknown. Therefore, the remaining time after Avastin treatment is about 20 days (1 1~50 days), during which breastfeeding should be stopped.
(See Clinical Pharmacology: Pharmacokinetics)
Children's use
At present, there is no study on the safety and effectiveness of Avastin in children. However, in young monkeys, after using Avastin at a dose lower than the recommended dose (mg/kg) for 4 weeks, abnormal development was observed. The incidence and severity of dysplasia are related to dose, but at least some of it can be recovered after stopping treatment.
Used by the elderly
In the study of 1, the number of people with grade 3-4 side effects (according to the toxicity standard of National Cancer Institute) included all subjects (396 IFL+ placebo, 392 IFL+ Avastin, 109 5-Fu/LV+ Avastin). However, the number of people with 1~2 grade side effects only included 309 subjects in the subgroup.
Therefore, we haven't collected enough samples of patients over 65 with the grade of 1~4 to prove that the overall side effects of elderly patients are different from those of young patients. Of the 392 patients treated with IFL ++ Avastin, 126 were over 65 years old. The incidence of side effects in these patients is lower than that in tall patients < 65 years old. As far as the overall survival time is concerned, the curative effect of Avastin in the elderly group and the young group is the same.
A clinical study sponsored by Genentech recorded all the side effects of 742 patients. Among them, 2 12 (29%) were over 65 years old, and 43 (6%) were over 75 years old. The incidence of any degree of side effects in the elderly group is higher than that in the young group. As mentioned above, there are dyspepsia, gastrointestinal bleeding, edema, nosebleed, cough aggravation and voice change.
side effect
The most serious side effects associated with Avastin are:
Gastrointestinal perforation/wound dehiscence syndrome (see warning)
Bleeding (see Warning)
Hypertensive crisis (see warning)
Nephrotic syndrome (see warning)
Congestive heart failure (see warning)
Among 1032 patients who participated in the clinical research funded by Genentech and received Avastin, the most common serious side effects were anemia, pain, hypertension, diarrhea and leukopenia.
Among the 742 patients who participated in the clinical research funded by Genentech and received Avastin, the most common side effects at all levels were anemia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory tract infection, nosebleed, dyspnea, exfoliative dermatitis and proteinuria.
Because there are many different situations in clinical trials, the incidence of side effects of one drug observed in the experiment cannot be directly compared with that of another drug. The same is true of the side effects information obtained from clinical trials. However, it can be used as a basis for determining drug-related side effects and their incidence.
A total of 1032 patients (568 patients with metastatic colorectal cancer and 473 patients with other tumors) participated in the clinical research funded by Genentech and received Avastin treatment. 157 patients received single drug treatment and 875 patients received chemotherapy. All side effects of 742 patients except 290 patients were collected, and all (NCI-CTC) grade 3 and grade 4 side effects were collected, while 1 and grade 2 side effects (such as hypertension, proteinuria and thrombotic events) were selectively collected.
The side effects collected in the clinical experimental research funded by Genentech will be used to further identify the specific side effects in the future. (See Warning: Hemorrhage, Hypertension, Proteinuria, Congestive Heart Failure and Precautions: for the elderly. The comparative data of side effects is currently limited to the study 1, which is a randomized study involving 897 patients with metastatic colorectal cancer.
All grade 3 and grade 4 side effects and some selected 1 grade 2 side effects (hypertension, proteinuria, thrombotic events) were reported. In the study of 1, the median age was 60 years old, 60% of men, 78% had primary colon disease, and 29% had received adjuvant or neoadjuvant chemotherapy. Study 1, the median exposure time of Avastin in the second group was 8 months, and that in the third group was 7 months. In a subgroup of 309 people, all side effects were reported, including 1 and secondary side effects (NCI-CTC). The entry criteria of this safety subgroup of 309 people are the same as those of the whole study, and the three study groups have a good balance. The incidence of serious or life-threatening (NCI-CTC grade 3 and 4) side effects in IFL group+Avastin group (2%) was higher than that in IFL group+placebo group. See Table 4:
mucocutaneous hemorrhage
In the study 1, the incidence of severe or non-severe bleeding was higher among patients treated with Avastin (see Warning: Hemorrhage). Among 309 patients with 1~4 bleeding, epistaxis is more common, and the incidence rate of IFL+ Avastin group is 35%, while that of IFL+ placebo group is only 10%. This side effect is usually mild (NCI-CTC 1 grade) and can be recovered without treatment. The incidence of some mild to moderate side effects in IFL+ Avastin group was higher than that in IFL+ placebo group, including gastrointestinal bleeding (24% vs 5 18.6%), mild gingival bleeding (2% vs 0) and vaginal bleeding (4% vs 2%).
thromboembolism
In this study, 1 and 18% of patients in IFL+ Avastin group and 15% of patients in IFL+ placebo group had grade 3-4 thromboembolic events. In the following grades 3-4, the incidence of thromboembolism in IFL+ Avastin group was higher than that in IFL+ placebo group, including cerebrovascular events (4 vs. 0 patients), myocardial infarction (6 vs. 3), deep vein thrombosis (34 pairs 19) and intra-abdominal thrombosis (13 vs. 5). On the contrary, the incidence of pulmonary embolism in IFL+ placebo group was higher than that in IFL+ Avastin group (16 vs. 20).
In the study of 1 392 patients who received IFL+ Avastin, 53 patients who received IFL+ placebo (14%) and 396 patients, 30 patients (8%) had thrombotic events and received full-dose warfarin. Two patients (***4 patients) in each group had bleeding and it was confirmed. In two patients treated with Avastin and full-dose warfarin, these events were related to the international standardized ratio of their coagulation function. Of the 53 patients who received IFL+ Avastin, 30 patients who received IFL+ placebo had another thrombotic event in 1 1 (2 1%) and 1 (3%).
Other serious side effects
The following serious side effects are not common in tumor patients receiving cytotoxic drug chemotherapy, but at least 1 person occurred in Avastin's clinical study.
Body: serositis
Digestive system: intestinal obstruction, intestinal necrosis, mesenteric vein obstruction and anastomotic ulcer formation.
Blood and lymphatic system: pancytopenia
Metabolic/nutritional disorders: hyponatremia
Urogenital system: Ureteral stricture.
Too much
The maximum tolerated dose of Avastin is unknown. The maximum test dose of human body was (20 mg/kg IV), and 9 out of 6 patients (/kloc-0) had headache, among which 3 patients had severe headache.
Dosage and usage: The recommended dosage is 5 mg/kg, administered on 14/time, and given intravenously until the disease progresses. Avastin treatment should not be started within 28 days after major surgery. Before starting Avastin treatment, the surgical incision should be completely healed.
Dose adjustment
Dose reduction during Avastin treatment is not recommended. If necessary, Avastin shall be stopped or temporarily postponed as follows.
If the patient has digestive tract perforation; The wound that needs medical treatment has cracked; Severe bleeding; Nephrotic syndrome or hypertensive crisis should be stopped permanently. If the patient has moderate to severe proteinuria that needs further testing, and severe hypertension that has not been controlled by drug treatment, it is recommended to temporarily postpone the use. The risk of continuing or temporarily delaying the use of Avastin in patients with moderate to severe proteinuria is unclear. Avastin should be temporarily stopped for several weeks before elective surgery. (See Warning: Gastrointestinal Perforation/Wound Healing and Certification and Prevention: Surgery). Avastin should not be used again until the surgical incision is completely healed.
Preparation before use
Avastin should be diluted by professional health personnel with sterile technology before infusion. The required Avastin was extracted at a dose of 5 mg/kg and diluted to 0.9% sodium chloride injection with a total volume of 100 mL.
(American patent). Since the product does not contain preservatives, the rest of the medicine bottle should be discarded. As a drug for injection, it is necessary to observe with the naked eye whether there are particles and discoloration before use.
The diluted Avastin solution should be stored at 2-8℃ for 8 hours. Avastin is incompatible with PVC and polyolefin bags.
Avastin should not be prepared or mixed with sugar solution.
use
Avastin should be infused intravenously for more than 90 minutes after the first chemotherapy. If the first infusion is well tolerated, the second infusion can last more than 60 minutes. If the tolerance of 60 minutes is good, the subsequent infusion can be controlled over 30 minutes.
Stability and preservation
Avastin should be kept in the refrigerator at 2-8 degrees, and kept in the original carton in the dark until it is used.
Packaging: 4ml and 16ml, which are sterile solutions in disposable glass bottles, each containing 100 and 400 mg bevacizumab respectively. Single 100 mg package: contains a 4ml bottle of Avastin. (25 mg/ml). NDC 50242-060-0 1 606 Single 400 mg package: contains a bottle of Avastin 16ml. (25 mg/ml). NDC 50242-060-02 608 .
References: 1. Prestag, Chen H, O 'Connor SJ, Chisholm V, Meng, Krugman L, et al. Humanized monoclonal antibodies against vascular endothelial growth factor receptor are used to treat solid tumors and other diseases. Cancer research1997; 57:4593-9.
Avastin was approved as a second-line treatment for advanced colon cancer (June 22, 2006).
Genentech, a biopharmaceutical company, said on June 20 that the FDA had approved Avastin as a second-line treatment for advanced colon cancer.
Previously, Avastin+chemotherapy has been approved as a first-line treatment for advanced colon cancer.