Bevacizumab

When ATH:
L01XC07

Characteristic.

Bevacizumab - rekombinantnыe giperhimernыe (humanized, close to the human) моноклональные IgG1 антитела, which selectively bind to and inhibit biological activity of vascular endothelial growth factor (VEGF) in vitro and live. Bevacizumab contains human framework regions with the complementarity determining regions of the murine antibody giperhimernogo, that bind to VEGF. Bevacizumab is produced by recombinant DNA technology in a system for the expression of, presented by Chinese Hamster Ovary.

Transparent or slightly opalescent liquid, colorless or light brown. The molecular weight of about 149 kilodaltons.

Pharmacological action.
Antitumor.

Application.

Metastaticheskiy kolorektalynыy cancer: as first-line therapy in combination with chemotherapy based on derivatives of fluoropyrimidine.

Contraindications.

Hypersensitivity, CNS metastases, kidney and / or liver failure, childhood (safety and effectiveness in children and adolescents, and in patients with renal and / or hepatic impairment has not been studied).

Restrictions apply.

Arterial hypertension, arterial thromboembolism, older than 65 years; wound healing, bleeding, perforation of the gastrointestinal tract.

Pregnancy and breast-feeding.

Animal studies (Rabbits) shown, that bevacizumab doses, close to the dose for humans (in terms of mg / kg), showed teratogenic effects. Observed effects included: body weight reduction and female fetuses, increase in the number of fetal resorption, increased frequency of specific and skeletal damage to the fetus. Side effects in the fetuses was observed at all doses tested.

Angiogenesis is an important step in the development of the fetus and the inhibition of angiogenesis due to the introduction of bevacizumab shown adverse effects on pregnancy.

The use of bevacizumab in pregnant women and women, do not use adequate contraceptive measures, perhaps, if the effect of therapy outweighs the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women have not held.

Patients, stopped treatment with bevacizumab, They shall be instructed about his prolonged exposure after therapy (T_1/2 about 20 days) and possible effects on fetal development. Men and women of childbearing age during treatment with bevacizumab and for at least 6 months after the end of treatment must use reliable methods of contraception.

Category actions result in FDA - C. (The study of reproduction in animals has revealed adverse effects on the fetus, and adequate and well-controlled studies in pregnant women have not held, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk.)

Unknown, whether bevacizumab is excreted in breast milk of women. As human IgG1 is secreted into breast milk, potential absorption and possible adverse effects on the fetus after injection. Breastfeeding is not recommended for at least 6 months after the end of bevacizumab.

Side effects.

The most serious side effects, observed in patients, bevacizumab: perforation of the gastrointestinal tract, difficulties in wound healing, hemorrhage, arterial thromboembolism, gipertenzivnye crisis, leykoentsefalopatichesky reversible syndrome, neutropenia and infection, nephrotic syndrome, congestive heart failure (cm. Precautions).

Patients, bevacizumab, the most frequently observed: asthenia, the pain of various localization, incl. Abdominal, headache, arterial hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory tract infection, nose bleed, dyspnoea, exfoliative dermatitis, proteinuria.

The following data were obtained by the treatment with bevacizumab 1529 patients, including 665 patients, get it for at least 6 Months, and 199 patients, get it for at least 1 year. Studies conducted in the placebo bevacizumab- and active-controlled trials (n = 501 and n = 1028, respectively).

Perforation of the gastrointestinal tract. The incidence of gastrointestinal perforation in the studies was 0-3,7%. The frequency of gastrointestinal perforation, in some cases fatal, in patients with mCRC with the bevacizumab or bevacizumab in combination with chemotherapy was 2,4% compared to 0,3% patients, treated with chemotherapy alone.

The difficulty in wound healing. Incidence of postoperative complications and / or bleeding was higher in patients with EGFR at bevacizumab as compared with patients, receiving chemotherapy.

Hemorrhage. Severe or fatal hemorrhage, incl. hemoptysis, bleeding in the gastrointestinal tract, gematemezis, CNS hemorrhage, nose bleed, vaginal bleeding - occurred in 5 times more likely in patients, bevacizumab, than patients, treated with chemotherapy alone.

Hemorrhagic complications of 3-5 degrees, in accordance with the common toxicity criteria of the National Cancer Institute (National Cancer Institute Common Toxicity Criteria — NCI–CTC), We observed in 4,7% patients with small cell lung cancer (NSCLC tumors) and 5,2% patients with mCRC, poluchavshimi bevacizumab, compared to 1,1% and 0,7% in the control groups.

The frequency of epistaxis was higher (35% against 10%) patients, bevacizumab in combination with IFL, compared to patients, receiving chemotherapy alone IFL and placebo. These were mild or bleeding severity srednevyrazhennoy (degree 1) and were without medical intervention. Besides, also easy- or srednevyrazhennymi were gastrointestinal hemorrhage (24% against 6%), Bleeding from the gums (2/0%) and vaginal bleeding (4/2%).

Arterial thromboembolism I observed in the 3% cases of patients with NSCLC in combination therapy carboplatin bevacizumab (3,0%) compared to patients, receiving only carboplatin (1,4%). Five deaths were in patients, treated with carboplatin bevacizumab, and one - in the group of patients, receiving only carboplatin. These data about the increased risk of arterial thromboembolism bevacizumab in the treatment of patients with NSCLC are consistent with the data in the treatment of patients with mCRC.

Venous thromboembolism. The frequency of venous thromboembolic complications grade 3-4 (according to NCI-CTC) was higher in patients with EGFR in NSCLC and bevacizumab in combination with chemotherapy, than patients, treated with chemotherapy alone. Besides, in patients with mCRC risk of secondary thromboembolic complications was also increased in patients, receiving bevacizumab and chemotherapy.

Arterial hypertension. In patients with mCRC, bevacizumab, there was an increased incidence of hypertension (FROM>150/100 mm Hg. Art.), incl. severe hypertension (FROM>200/110 mm Hg. Art.), compared to patients, receiving chemotherapy alone. Among patients with severe hypertension in 51% Dad values, exceeding 110 mm Hg. Art., They were associated with SBP less 200 mm Hg. Article. The frequency of hypertension 3 and 4 degrees (according to NCI-CTC) for all clinical trials of bevacizumab was 8-18%.

Neutropenia and infections. In the group of patients, bevacizumab in combination with IFL, compared with the group of patients, IFL chemotherapy alone, the incidence of neutropenia was higher. So, In a study in patients with EGFR neutropenia 3 and 4 degrees (in accordance with the NC-CTC) was 21% patients, bevacizumab in combination with IFL, whereas with IFL chemotherapy - 14%. In a study in patients with NSCLC incidence of neutropenia 4 degree in patients, treated with carboplatin bevacizumab, equal 26,2%, patients, receiving only carboplatin - 17,2%; incidence of febrile neutropenia was also increased in the group, poluchavshey carboplatin bevacizumab (5,4% against 1,8%). It has been recorded 19 cases (4,5%) neutropenic infection during neutropenia 3 and 4 degree in therapy with carboplatin bevacizumab, three of which were lethal (during therapy with carboplatin only - 9 cases (2%), no deaths were). During the first 6 treatment cycles frequency of serious infections, including, as pneumonia, febrile neutropenia, catheter-related infections, was higher in patients, treated with carboplatin bevacizumab: these infections have been observed in 58 patients (13,6%), while in patients, treated with carboplatin, It was observed 29 cases (6,6%).

Reversible leykoentsefalopatichesky syndrome He observed in clinical trials with a frequency <0,1%, as well as in post-marketing studies. Possible neurological disorders (incl. headache, seizures, lethargy, confusion, blindness, other visual disturbances), moderate to severe hypertension severity. To confirm the presence of the syndrome must be leykoentsefalopaticheskogo MRI. The onset of symptoms leykoentsefalopaticheskogo syndrome was noted in the period from 16 h to 1 years after the start of therapy with bevacizumab. In the case of this syndrome bevacizumab should be stopped and initiate correction of hypertension (if present). Symptoms usually resolve within a few days, although in some patients the consequences may be.

Proteinuria. The frequency and severity of proteinuria were increased in patients, bevacizumab, compared with the control. Proteinuria 3 and 4 extent according to NCI-CTC (>3,5 g / day) against the backdrop of bevacizumab was up 3%.

In clinical studies, nephrotic syndrome was observed in seven of 1459 patients (0,5%). One patient died, one needed dialysis. In three patients the severity of proteinuria decreased after a few months after discontinuation of bevacizumab. None of these patients after discontinuation of bevacizumab daily level of urinary protein excretion is not normalized.

Security continued treatment with bevacizumab in patients with moderate- and silnovyrazhennoy proteinuria has not been evaluated. In most clinical trials of bevacizumab was discontinued at the protein level ≥2 g / day, and resumed when proteinuria <2 g / day.

Fatal adverse events have been reported in 2,8% patients, IFL chemotherapy alone, and 2,6% patients, bevacizumab in combination with IFL. Adverse events, which led to the cancellation of treatment, It has been reported in 7,1% patients, IFL chemotherapy and 8,7% patients, receiving bevacizumab and IFL.

In a study in patients with metastatic carcinoma of the colon and rectum clinically significant toxicity (according to NCI-CTC) 3 or 4 degree was observed in 74% patients in the IFL (n=396) and 87% patients from the group, poluchavshey bevacizumab in combination with IFL (n=392).

Adverse reactions of any severity, common in patients, bevacizumab in combination with IFL or 5-fluorouracil / leucovorin included the following (in parentheses indicate the frequency of adverse events 3 and 4 degree - severe and life-threatening, observed in ≥2% of cases with bevacizumab in combination with IFL):

Cardio-vascular system and blood (hematopoiesis, hemostasis): arterial hypertension (12%), hypotension, deep vein thrombosis (9%), intraabdominal thrombotic complications (3%), arterial thromboembolism (including myocardial infarction, stroke, transient ischemic attack and other arterial embolism), congestive heart failure, leukopenia (7%), neutropenia (21%), thrombocytopenia, anemia.

From the digestive tract: diarrhea (34%), constipation (4%), abdominal pain (8%), vomiting, anorexia, stomatitis, dyspepsia, perforation of the gastrointestinal tract, weight loss, dry mouth, colitis, rectal bleeding, krovotochivosty right.

From the respiratory system: upper respiratory tract infection, nose bleed, breathlessness, voice alteration, rhinitis.

For the skin: alopecia, xerosis, exfoliative dermatitis, livor.

From the nervous system and sensory organs: headache, dizziness, ischemia, cerebrovascular, infringement of visual function, dysgeusia.

Other: asthenia (10%), pain (8%), syncope (3%), abscess, sepsis, fever, vaginal bleeding; Local reactions (pain at the injection site).

Violations by the laboratory parameters: violation of laboratory parameters 3 and 4 degrees, observed in patients, receiving bevacizumab with or without chemotherapy - proteinuria, kaliopenia, hyperkalemia, giponatriemiya, gipofosfatemiя, Hyperglycemia and increased blood levels of alkaline phosphatase.

Cooperation.

Drug interaction studies with other antineoplastic agents were not conducted. In patients with mCRC, bevacizumab in combination with IFL, marked increase in the concentration of the active metabolite of irinotecan to SN38 33%, compared to patients, Gets only the IFL (increasing the level of communication with the reception SN38 bevacizumab is not installed). Patients, treated with IFL bevacizumab, marked increase in the frequency of adverse events, as diarrhea and leukopenia (known adverse drug reactions of irinotecan), as well as more frequent dose reduction irinotecan. With the development of severe diarrhea, leukopenia or neutropenia during bevacizumab and irinotecan, a correction dose of irinotecan.

Existing data suggest, that bevacizumab does not affect the pharmacokinetics fluorouracil, carboplatin, paclitaxel and doxorubicin.

If concomitant use of warfarin (Treatment of venous thrombosis) bevacizumab and increasing the frequency of major bleeding were observed.

Pharmaceutically compatible with solutions of dextrose.

Overdose.

Symptoms: increased side effects. When you assign a maximum dose of bevacizumab 20 mg / kg / in several patients marked the severity of severe migraines. Spetsificheskiy antidote unknown.

Treatment: symptomatic.

Dosing and Administration.

Only / drip; introduce the drug in / jet can not be!

The standard dosing regimen: 5 mg / kg, as in / infusion, protractedly, once every 14 days. The initial dose is administered during the 90 min after chemotherapy, subsequent doses can be administered before or after chemotherapy. With good endurance first infusion, second administration can be performed during 60 m, All subsequent infusions can be performed during 30 min provided a good tolerability of the second infusion.

It is not recommended to reduce the dose of bevacizumab due to adverse events. If necessary, treatment with bevacizumab should be completely or temporarily stop.

Precautions.

Treatment with bevacizumab may be carried out only under the supervision of a physician, having experience of anticancer therapy.

Perforation of the gastrointestinal tract. In patients with metastatic cancer of the colon or rectum in the treatment of bevacizumab in combination with chemotherapy are at increased risk of developing gastrointestinal perforation. There were severe cases of gastrointestinal perforation with intra-abdominal inflammation, incl. and fatal. Despite the fact that a causal link intra inflammation, Resulting ulcer, Tumor Necrosis, diverticulum or colitis, with receiving bevacizumab has not been established, caution must be exercised in treating patients with bevacizumab signs of intra-abdominal inflammation. With the development of the perforation treatment of bevacizumab should be discontinued.

The difficulty in wound healing. Bevacizumab may adversely affect the wound healing. Treatment with bevacizumab should not be initiated for at least 28 days after surgery or until complete healing of the surgical wound. With the development of complications during treatment, associated with wound healing, Bevacizumab is necessary to temporarily lift to complete wound healing. Admission bevacizumab also need to suspend in the case of optional surgery.

Bleeding. In patients with mCRC increased risk of bleeding, tumor-associated. If during treatment there was bleeding 3 or 4 severity, Bevacizumab should be discontinued.

In patients with congenital bleeding diathesis, acquired coagulopathy or receiving full dose of anticoagulants on the thromboembolism, before the appointment of bevacizumab should be careful.

In patients with NSCLC (squamous carcinoma, or a central location close to the tumor adjacent to large blood vessels), bevacizumab, registered 6 serious bleeding, 4 of which were fatal. Bleeding occurs suddenly and flows by type of massive hemoptysis. In five cases, it was preceded by the formation of cavities and / or tumor necrosis. Rarely seen bleeding and in other types of tumors (hepatoma with metastatic CNS, thigh sarcoma with necrosis).

Arterial thromboembolism history or age over 65 years associated with an increased risk of arterial thromboembolism during treatment with bevacizumab. When treating such patients need to exercise caution. In the event of arterial thromboembolism bevacizumab should be stopped.

Arterial hypertension. Patients, bevacizumab, there was an increased incidence of hypertension. Clinical safety data suggest, that the incidence of hypertension is not dependent on the dose of bevacizumab. There is no information on the impact of bevacizumab during treatment initiation in patients with uncontrolled hypertension. When bevacizumab such patients need to exercise caution and to constantly monitor blood pressure.

In patients with hypertension, requiring drug therapy, it is recommended to temporarily discontinue therapy bevacizumab to achieve adequate blood pressure control. If you can not install the medical monitoring of blood pressure and / or the development of a hypertensive crisis should stop receiving bevacizumab.

Proteinuria. The risk of developing proteinuria increased in patients with a history of hypertension. Maybe, Chto proteinuria 1 dependent on the dose of bevacizumab. Prior to and during therapy bevacizumab is recommended urinalysis for proteinuria. With the development of proteinuria 4 degrees (nephrotic syndrome) bevacizumab should be abolished.

Therapy with anthracyclines and / or radiation therapy to the chest cells may contribute to the development history of congestive heart failure. Patients with these risk factors need to be cautious when bevacizumab.

When bevacizumab in patients older 65 years, there is an increased risk of arterial thromboembolism (including the development of stroke, transient ischemic attack, myocardial infarction) and leukopenia. Increasing the frequency of other side effects, including gastrointestinal perforation, wound healing complications, hypertension, proteinuria, bleeding, and congestive heart failure, associated with the use of bevacizumab in elderly patients, not observed.

Cooperation