Avastin - instructions for use of the drug, structure, Contraindications
Active material: Bevacizumab
When ATH: L01XC07
CCF: Anticancer drug. Monoklonalynыe antibodies
ICD-10 codes (testimony): C18, C19, C20, C34, C50, C64
Manufacturer: F.Hoffmann-La Roche Ltd. (Switzerland)
AVASTIN: dosage form, composition and packaging
Concentrate for solution for infusion transparent or opalescent, colorless or light-brown.
| 1 ml | 1 fl. | |
| bevacizumab | 25 mg | 100 mg |
Excipients: a,a-трегалозы дигидрат, sodium dïgïdrofosfata monohydrate, sodium hydrogen phosphate, anhydrous, polysorbate 20, water d / and.
4 ml – glass bottles (1) – packs cardboard.
Concentrate for solution for infusion transparent or opalescent, colorless or light-brown.
| 1 ml | 1 fl. | |
| bevacizumab | 25 mg | 400 mg |
Excipients: a,a-трегалозы дигидрат, sodium dïgïdrofosfata monohydrate, sodium hydrogen phosphate, anhydrous, polysorbate 20, water d / and.
16 ml – glass bottles (1) – packs cardboard.
AVASTIN: pharmachologic effect
Anticancer drug, is a rekombinantnoe giperhimernoe (Humanized, close to human) monoclonal antibody, that selectively binds with biologically active vascular endothelial growth factor (VEGF) and neutralize its. AVASTIN® inhibits the binding of VEGF to its receptors on the surface of endothelial cells, that leads to reduced vascularization and oppression of tumour growth.
Bevacizumab contains fully human skeleton plots with fit giperhimernogo mouse antibodies areas of complementarity, that bind to VEGF. Bevacizumab is produced by recombinant DNA technology in a system for the expression of, presented by Chinese Hamster Ovary. Bevacizumab is composed of 214 amino acids and has a molecular weight of about 149 000 Dalton.
Introduction involving bevacizumab resulted in suppression of metastatic disease progression and reduce microvascular permeability in various human tumors, including colon cancer, Breast, Pancreatic and prostate cancer.
Metastaticheskiy kolorektalynыy cancer
AVASTIN® with irinotecan in combination with, 5-fluorouracil and leucovorin (IFL) as a first-line therapy in patients with metastatic colorectal cancer statistically increases overall survival in all subgroups of patients, regardless of age, gender, general condition, primary tumor localization, the number of affected organs and duration of metastatic disease. Adding Avastin® to chemotherapy prolongs survival of IPP RAS without progression of disease, overall frequency response and duration of response to treatment.
When prescribing Avastin® (5 mg / kg of body weight every 2 of the week) in combination with 5-ftoruracilom and lejkovorinom (5-FU/LV) as a first-line therapy in patients with metastatic colorectal cancer and the presence of contraindications to therapy with irinotecan marked: higher frequencies of objective response to treatment, a statistically significant increase in progression free survival and overall survival increase when compared with the appointment only chemotherapy (5-FU/LV).
When prescribing Avastin® (7.5 mg / kg of body weight every 3 of the week) in combination with kapecitabinom oral and Oxaliplatin/in (XELOX) or when assigning Avastin® (5 mg / kg every 2 of the week) in combination with 5-Fu and leucovorin bolusno, and then 5-fluorouracil and Oxaliplatin infusion/in (FOLFOX-4) noted a statistically significant increase in survival without disease progression compared to appointment only chemotherapy.
When prescribing Avastin® (10 mg / kg of body weight every 2 of the week) in combination with 5-Fu and leucovorin bolusno, and then infuzionno, and Oxaliplatin/in (FOLFOX-4) patients, previously received therapy (the second line therapy), with advanced colorectal cancer, noted a statistically significant increase in overall survival, progression-free survival and higher frequencies of objective response compared to the appointment only chemotherapy.
Locally recurrent or metastatic breast cancer
AVASTIN® (10 mg / kg of body weight every 2 of the week) in combination with paclitaxel as first-line therapy in patients with locally recurrent or metastatic breast cancer was statistically significantly increases survival without progression of the disease and the frequency of objective response compared to the appointment only chemotherapy.
Common inoperable, Metastatic or recurrent non-small cell lung cancer neploskokletočnyj
AVASTIN® (15 mg / kg every 3 of the week) in combination with the chemotherapy drugs platinum-based (carboplatin and paclitaxel/in) as a first-line therapy in patients with non-small cell lung cancer neploskokletočnym statistically significant increases overall survival, period survival without progression of the disease and the frequency of objective response compared to the appointment only chemotherapy.
AVASTIN® (7.5 mg / kg or 15 mg / kg every 3 of the week) in combination with the chemotherapy drugs platinum-based (cisplatin and Gemcitabine/in) as a first-line therapy in patients with non-small cell lung cancer neploskokletočnym statistically significant increases between survival without progression of the disease and the frequency of objective response compared to the appointment only chemotherapy.
Common and/or metastatic renal cell carcinoma
AVASTIN® (10 mg / kg every 2 of the week) in combination with interferon alfa-2A (9 million. ME 3 times a week) as a first-line therapy in patients with advanced and/or metastatic renal cell cancer statistically increases the period of survival without progression of the disease and the frequency of objective response compared with appointment only interferon alfa-2A.
AVASTIN: pharmacokinetics
Pharmacokinetics Of Avastin® studied in different doses (0.1-10 mg/kg every week; 3-20 mg / kg every 2 or 3 of the week; 5 mg / kg every 2 weeks or 15 mg / kg every 3 of the week) in patients with various solid tumors.
Pharmacokinetics describes involving bevacizumab bicameral model.
Distribution Of Avastin® has a low ground clearance, small Vd and long T1/2, that allows you to make maintain the required therapeutic concentration of the drug in plasma with the introduction 1 once every 2-3 of the week.
Pharmacokinetics involving bevacizumab in the range of doses from 1.5 to 10 mg/kg in a week has a linear nature.
Distribution
Vd is 2.66 l women and 3.25 l men, which corresponds to Vd IgG and other monoclonal antibodies. After dose adjustment, taking into account the body weight in men (V)d on 22% better, than in women.
Metabolism
After a single in / introduction 125I-involving bevacizumab his metabolic characteristics are similar to those of natural IgG molecules, which is not associated with any VEGF. Metabolism and excretion metabolism and excretion matches involving bevacizumab endogenous IgG, ie. mainly by proteolytic catabolism in all cells of the body, including endothelial cells, instead of kidney and liver. The binding of IgG to FcRn-receptors protects it from the cellular metabolism and ensures long T1/2.
Deduction
Clearance involving bevacizumab is 0.207 l/day for women and 0.262 l/d for men.
Vd and the ground correspond to primary T1/2 1.4 day and end T1/2 20 day and 19 SUT in women and men respectively. This T1/2 match the target T1/2 human endogenous IgG, which is 18-23 d.
After correction, taking into account the body weight for men involving bevacizumab clearance 26% higher, than in women. In patients with low content of albumin (≤ 29 g/dl) and high ALP (≥ 484 u/l) (both indicators are markers of the severity of the disease), involving bevacizumab clearance around the 20% higher, than patients with average values of these indicators.
Pharmacokinetics in special clinical situations
Clearance involving bevacizumab does not depend on the age of the patient.
We found no significant difference in pharmacokinetics involving bevacizumab depending on age.
There are limited data involving bevacizumab pharmacokinetics in children and adolescents. Available data indicate that there is a difference between Vd ground and involving bevacizumab in children, adolescent and adult patients with solid tumors
The safety and efficacy of involving bevacizumab in patients with renal or hepatic insufficiency have not studied, tk. kidneys and liver are not the major organs of metabolism and excretion involving bevacizumab.
AVASTIN: testimony
-metastatic colorectal cancer: in combination with chemotherapy on the basis of ftorpirimidina derivatives;
is locally recurrent or metastatic breast cancer: as a first-line therapy in combination with paclitaxel;
— common inoperable, Metastatic or recurrent non-small cell lung cancer neploskokletočnyj: as a first-line therapy in addition to chemotherapy drugs platinum-based;
— common and/or metastatic renal cell carcinoma: as a first-line therapy in combination with interferon alfa-2a.
AVASTIN: dosing regimen
AVASTIN® introduced only in / in the drip; introduce the drug in / jet can not be!
AVASTIN farmatsevticeski incompatible solutions of dextrose.
The necessary amount of Avastin® bred to total 100 ml sterile, non-pyrogenic 0.9% solution of sodium chloride in compliance with the rules of asepsis. Cooked solution involving bevacizumab concentration shall be within 1.4-16.5 mg / ml.
The starting dose introducing/in in the form of infusions over 90 min after chemotherapy, subsequent doses can be administered before or after chemotherapy. If the first infusion is well tolerated, the second infusion can be performed during 60 m. If infusion over 60 min is well tolerated, all subsequent infusions can be performed during 30 m.
It is not recommended to reduce the dose of bevacizumab due to adverse events. In case you need treatment with Avastin® It should be completely or suspend.
Metastaticheskiy kolorektalynыy cancer
As a first-line therapy: 5 mg / kg 1 once every 2 weeks or 7.5 mg / kg 1 once every 3 the week as in/in infusion, protractedly.
As a second-line therapy: 10 mg / kg 1 once every 2 weeks or 15 mg / kg 1 once every 3 the week as in/in infusion, protractedly.
When signs of disease progression therapy Avastinom® discontinue.
Locally recurrent or metastatic breast cancer
The drug is prescribed in a dose 10 mg / kg 1 once every 2 weeks or 15 mg / kg 1 once every 3 the week as in/in infusion, protractedly. When signs of disease progression therapy Avastinom® discontinue.
Common inoperable, Metastatic or recurrent non-small cell lung cancer neploskokletočnyj
AVASTIN® appoint in addition to chemotherapy drugs platinum-based (the maximum duration of chemotherapy 6 cycles), continue receiving Avastin® continues as monotherapy. When signs of disease progression therapy Avastinom® discontinue.
Recommended dose:
– 7.5 mg / kg 1 once every 3 the week as in/in infusion of cisplatin-based chemotherapy.
– 15 mg / kg 1 once every 3 the week as in/in infusion chemotherapy based on carboplatina.
Common and/or metastatic renal cell carcinoma
The drug is prescribed in a dose 10 mg / kg 1 once every 2 the week as in/in infusion, protractedly.
When signs of disease progression therapy Avastinom® discontinue.
Patients Seniors (senior 65 years) dose adjustment is required.
Safety and efficacy of involving bevacizumab at patients with hepatic and/or renal failure I have not been studied.
Instructions for use, the treatment and the destruction of drug
Before applying the solution to be examined for the presence of inclusions and changes colors.
AVASTIN® does not contain an antimicrobial preservative, It is therefore necessary to ensure sterility prepared solution and use it immediately. If the drug is not used immediately, the time and conditions of storage of prepared solution are the responsibility of the user.
Cooked solution can be stored for no more 24 hours at a temperature of from 2 ° to 8 ° C., If breeding is carried out in a controlled and validated aseptic conditions.
Chemical and physical stability of prepared solution (in 0.9% sodium chloride solution) It persists for 48 h at a temperature from 2° to 30° c. Unused solution, the remaining vial, destroy, tk. It contains no preservatives.
AVASTIN: side effects
The most serious adverse reactions: perforation of the gastrointestinal tract, hemorrhage, including pulmonary bleeding/hemoptysis (more commonly found in patients with non neploskokletočnym with lung cancer), arterial thromboembolism.
Raising HELL and proteinurii, probably, have a dose-dependent nature.
Patients, receiving only Avastin®, common There are: increased blood pressure, weakness or fatigue, diarrhea, nausea and abdominal pain.
Below lists the adverse reactions of varying degrees of severity, found in patients, treated with Avastin® in the form alone or in combination with chemotherapy.
Cardio-vascular system: arterial hypertension, arterial thromboembolism (including myocardial infarction, stroke, transient ischemic attack and other arterial embolism), deep vein thrombosis, congestive heart failure, supraventricular tachycardia, bleeding.
From the hematopoietic system: leukopenia, neutropenia, febrile neutropenia, anemia, thrombocytopenia.
From the digestive system: dysgeusia, abdominal pain, diarrhea, constipation, rectal bleeding, stomatitis, krovotochivosty right, perforation of the gastrointestinal tract, bowel obstruction, nausea, vomiting.
The respiratory system: pulmonary thromboembolism, gipoksiya, nose bleed, breathlessness, rhinitis.
Dermatological reactions: hand-foot syndrome, xerosis, exfoliative dermatitis, livor.
From the nervous system: anorexia, syncope, stroke, headache, drowsiness, perifericheskaya sensornaya neuropathy.
On the part of the organ of vision: infringement of visual function.
On the part of the musculoskeletal system: muscular weakness.
From the urinary system: urinary tract infection, proteinuria.
Violations of laboratory parameters 3 and 4 degree in accordance with the criteria of the National Cancer Institute (NCI-CTC), observed in patients, treated with Avastin® with or without chemotherapy: giperglikemiâ, decrease in hemoglobin, kaliopenia, giponatriemiya, leukopenia, neutropenia, thrombocytopenia, proteinuria, increased prothrombin time, an increase in INR.
Local reactions: pain at the site of administration.
Other: asthenia, increased fatigue, lethargy, the accession of secondary infections, abscess, sepsis, pain of various localization, fever, vaginal bleeding, degidratatsiya.
Post-marketing surveillance
Often: disfonija.
Rarely: reversible syndrome later lejkoèncefalopatii, includes an epileptic seizure, Headache, mental disorders, blurred vision, the defeat of the Visual centers of the brain, hypertension.
Rarely: perforation of the nasal septum; hypertensive encephalopathy (in some cases with fatal outcome).
The frequency of occurrence is unknown: pulmonary hypertension.
AVASTIN: Contraindications
-Metastatic lesion of central nervous system;
— renal and liver failure (efficacy and safety have not been established);
- Pregnancy;
- Lactation (breast-feeding);
- Children's age (efficacy and safety have not been established);
- Hypersensitivity to the drug;
-increased sensitivity to drugs based on Chinese hamster ovary cells or other recombinant human or close to human antibodies.
FROM caution should designate product in hypertension, arterial thromboembolism history, patients over the age of 65 years, wound healing, bleeding, hemoptysis, congenital hemorrhagic diathesis and the acquired coagulopathy, When taking anticoagulants in high doses, When GASTROINTESTINAL perforation, clinically significant cardio-vascular disease or congestive heart failure in history, neutropenia, proteinuria, reversible syndrome later encephalopathy.
AVASTIN: Pregnancy and lactation
The drug is contraindicated during pregnancy and lactation (breast-feeding).
The men and women of childbearing age during treatment Avastinom® and at least 6 months after the end of treatment must use reliable methods of contraception.
Breastfeeding is not recommended for at least 6 months after the end of therapy Avastinom®.
AVASTIN: Special instructions
Treatment Avastinom® can be carried out only under the supervision of a physician, having experience of anticancer therapy.
Patients, receiving Avastin®, There is an increased risk of perforation of DIGESTIVE TRACT. Experienced severe cases of perforation of the INTESTINE etc.. fatal. The clinical picture of GASTROINTESTINAL perforation differed in severity and varied from signs of free gas with abdominal radiography, which disappeared without treatment, before perforation with abdominal and by lethal. In some cases occurred as a result of the inflammation's original intraabdominal gastric ulcer, Tumor Necrosis, diverticulitis or colitis, associated with chemotherapy. The relationship between the development of intra-abdominal inflammation and GASTROINTESTINAL perforation with receiving Avastin® not installed. However, caution must be exercised in the treatment of Avastinom® patients with signs of intra-abdominal inflammation. With the development of Avastinom treatment perforation® discontinue.
AVASTIN® may interfere with wound healing. Bevacizumabom treatment should start no earlier than 28 days after surgery or until complete healing of the surgical wound. With the development of complications during treatment, associated with wound healing, AVASTIN® you need to temporarily cancel until complete healing wounds. Receiving Avastin® It is also necessary to temporarily stop in case of elective surgery.
Patients, treated with Avastin®, There was an increased incidence of hypertension. Clinical safety data suggest, that the incidence of ad, probably, depends on the dose involving bevacizumab. AVASTIN® can only be assigned to patients with previously compensated arterial hypertension the further control of HELL.
In patients with hypertension, requiring drug therapy, It is recommended that you temporarily stop their therapy Avastinom® to achieve adequate control of HELL. Ad normalization is achieved using ACE inhibitors, diuretics and calcium channel blockers. Receiving Avastin® You must stop if there is no normalization of HELL, development gipertoniceski kriza or hypertensive encephalopathy.
The risk of developing proteinuria increased in patients with a history of hypertension. Maybe, Chto proteinuria 1 dependent on the dose of Avastin®. Prior to and during therapy Avastinom® It is recommended to carry out urine test for proteinuria. Proteinuria was not associated with impaired renal; proteinuria 4 degrees (nephrotic syndrome) arise seldom. With the development of proteinuria 4 degree of Avastin® should be abolished.
Patients, receiving Avastin®, increased risk of bleeding, particularly associated with tumor. AVASTIN® should be abolished if you experience bleeding 3 or 4 severity.
In patients with congenital bleeding diathesis, acquired coagulopathy or receiving full dose of anticoagulants on the thromboembolism, before prescribing Avastin® caution must be exercised in view of the lack of information about the safety of the drug in these patients. There was no increase in the frequency of hemorrhages 3 severity and higher in patients, treated with Avastin® and warfarin full dose due to venous thrombosis.
Patients with non-small cell lung cancer, receiving Avastin®, have an increased risk of serious, and in some cases, Fatal pulmonary hemorrhage/pneumorrhagia. Patients, had bleeding/hemoptysis (more 2.5 ml of blood) history, should not receive Avastin®. Reception protivorevmatičeskih/anti-inflammatory drugs, antykoahulyantov, prior radiotherapy, atherosclerosis, the central location of tumors, the formation of Caverns before or during treatment are possible risk factors for pulmonary hemorrhage/pneumorrhagia, while statistically reliable link these symptoms with the development of bleeding proved only for squamous lung cancer.
Rarely were seen bleeding in other types of tumors (hepatoma with metastatic CNS, thigh sarcoma with necrosis).
In patients with colorectal cancer GASTROINTESTINAL bleeding are possible, associated with tumor, incl. rectal bleeding and Melena.
In 20-40% patients experienced muco-cutaneous haemorrhage. The most commonly observed nasal bleeding, not exceeding 1 severity, of less than 5 m. Nosebleeds stopped without medical intervention and did not require treatment changes Avastinom®. Were less likely bleeding gums or vaginal bleeding.
Avastinom therapy® in combination with chemotherapy, the frequency of arterial thromboembolism, including stroke, transient ischemic attack and myocardial infarction was higher, than in appointing only chemotherapy. When an arterial embolism therapy Avastinom® must stop. Arterial thromboembolism in history or age 65 years are associated with increased risk of arterial thromboembolism during treatment Avastinom®. When treating such patients need to exercise caution.
During treatment Avastinom® There is an increased risk of venous thromboembolism (pulmonary embolism, deep vein thrombosis, tromboflebit). Avastinom Therapy® You must stop when an žizneugrožaûŝej of pulmonary thromboembolism (4 severity), and when the severity of ≤ 3 should be closely monitored.
Avastinom therapy® registered isolated cases of reversible lejkoèncefalopatii later. Diagnosis can be confirmed by the brain rendering methods. In the case of complications should appoint a simptomaticescuu therapy, carefully monitor ad and cancel bevacizumab. Security the reappointment of Avastin® in these patients is not installed.
Most cases of congestive heart failure occurred in patients with metastatic breast cancer., receiving therapy antratziklinami and/or radiation therapy to the chest area in history, as well as with other risk factors for congestive heart failure, such as ISCHEMIC HEART DISEASE or concomitant therapy kardiotoksičnaâ. Were observed as asymptomatic left ventricular ejection fraction reduction, and congestive heart failure, necessitating the therapy or hospitalization. Caution must be exercised when prescribing Avastin® patients with clinically significant cardiovascular disease or congestive heart failure in history.
Avastinom therapy® cases of fistula, including cases with fatal outcome. The most frequent GASTROINTESTINAL fistulas in patients with metastatic colorectal cancer, at least other tumor localizations. Rare cases of fistula other localizations (Broncho-pleural, urogenital, cirrhosis). Education fistula most commonly seen in the first 6 months of therapy Avastinom®, but can occur both through 1 week, and through 1 a year later after the start of therapy. Therapy should be repealed Avastinom® When an intraoperative tracheo-èzofageal′nogo fistula or fistula of any localization 4 severity. When an internal fistula, not penetrating into GI, the question of the abolition of Avastin® individually.
Avastinom therapy® in combination with mielotoksičnymi chemotherapy regimes, there was an increase in the incidence of severe neutropenia, febrile neutropenia or infections with severe neutropenia (including cases with fatal outcome).
When prescribing Avastin® older patients 65 years, there is an increased risk of arterial thromboembolism (including the development of stroke, transient ischemic attack, myocardial infarction), leukopenia 3-4 severity and thrombocytopenia, as well as neutropenia (all degrees of severity), diarrhea, nausea, headaches and fatigue. Increase the incidence of other adverse reactions, associated with the use of Avastin®, in elderly patients is not marked.
AVASTIN: overdose
Symptoms: When assigning involving bevacizumab in maximum dose 20 mg/kg/in several noted severe migraine patients.
Overdose may increase the above side effects.
Treatment: No specific antidote. Symptomatic therapy.
AVASTIN: drug interaction
Effect of anticancer agents on farmakokinetiku Avastin®
There were no clinically significant effect on the distribution of bevacizumab joint use with chemotherapy. Involving bevacizumab clearance was not different in patients, receiving only Avastin®, and patients, treated with Avastin® in combination with IPP RAS (in basal mode). The influence of other chemotherapeutic drugs (5-FU-LV, carboplatin-paclitaxel, Capecitabine or doxorubicin) on the ground involving bevacizumab is considered clinically insignificant.
Effect Of Avastin® the farmakokinetiku other anticancer drugs
AVASTIN® does not significantly affect the farmakokinetiku irinotekana and its active metabolite (SN38); involving Capecitabine and its metabolites, as well as Oxaliplatin (determined by the free and overall level of Platinum); Interferon alfa-2A; cisplatin.
Reliable data on the impact of Avastin® on gevetabina no farmakokinetiku.
The combined application of warfarin (Treatment of venous thrombosis) and Avastin® increase in the frequency of serious bleeding is not marked.
When applying the Avastin® (10 mg / kg 1 once every 2 of the week) in combination with sunitinib (50 mg, daily) in patients with metastatic renal cell carcinoma cases development mikroangiopaticescoy hemolytic anemia (MAGA). MAGA hemolytic anemias subgroup refers to, which may be erythrocyte fragmentation, anemia and thrombocytopenia. Some patients further observed neurological disorders, elevated creatinine, arterial hypertension, including hypertonic Kriz. These symptoms were reversible after cessation of therapy and bevacizumabom sunitinib.
The safety and efficacy of Avastin® in combination with radiation therapy is not installed.
Pharmaceutical interaction
Pharmaceutically compatible with solutions of dextrose.
AVASTIN: terms of dispensing from pharmacies
The drug is released under the prescription.
AVASTIN: terms and conditions of storage
The drug should be stored out of reach of children, dark place at a temperature of 2 ° to 8 ° C; Do not freeze. Shelf life – 2 year.
