Zaltrap® (Zaltrap®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAfleiberceptAfleibercept
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  • Zaltrap®
    solution d / infusion in / in 
    Sanofi-Aventis France     France
  • Eilea®
    solution c / cavity 
    Bayer AG     Germany
    • Dosage form: & nbspconcentrate for solution for infusion
    Composition:

    In 1 ml of concentrate for solution for infusion contains:

    active substance: aflibercept - 25.00 mg;

    Excipients: sodium dihydrogen phosphate monohydrate 0.5774 mg, sodium hydrogen phosphate heptahydrate 0.2188 mg, citric acid monohydrate 0.0444 mg sodium citrate dihydrate 1.4088 mg sodium chloride 5.84 mg 0.1M hydrochloric acid acid or 0.1 M sodium hydroxide solution to pH 5.9-6.5, sucrose - 200.00 mg, polysorbate 20 - 1.00 mg, water for injection up to 1 ml.

    Description:Transparent colorless or light yellow liquid.
    Pharmacotherapeutic group:Antitumor agent.
    ATX: & nbsp

    L.01.X.X   Other antineoplastic agents

    L.01.X.X.44   Afleibercept

    Pharmacodynamics:

    Aflicibercept is a recombinant fusion protein, consisting of binding to VEGF (endothelial vascular growth factors) parts of the extracellular domains of the receptor VEGF 1 and the receptor VEGF 2, connected to the domain Fc (fragment of a crystallizable) immunoglobulin G1 (IgGl) rights.

    Aflicibercept is produced using recombinant DNA technology using the expression system of Chinese hamster ovary (CHO) cells K-1. Afleibercept is a chimeric glycoprotein with a molecular mass of 97 kDa, glycosylation of the protein adds 15% to the total molecular weight, resulting in a total molecular weight of 115 kDa of aflibercept.

    Endothelial Vascular Growth Factor A (VEGF-A), endothelial vascular growth factor B (VEGF-B) and placental growth factor (P1GF) refer to VEGF-family of angiogenic factors that can act as strong mitogenic, chemotactic and vascular-permeabilizing factors for endothelial cells. Act VEGF-A is carried out through two receptor tyrosine kinases - VEGFR-1 and VEGFR-2, located on the surface of endothelial cells. P1GF and VEGF-B bind only to the receptor tyrosine kinase VEGFR-1, which, besides being on the surface of endothelial cells, is also present on the surface of leukocytes. Excessive activation of these receptors VEGF-A can lead to pathological neovascularization and increased vascular permeability. P1GF also relates to the development of pathological neovascularization and infiltration of the tumor by inflammation cells.

    Aflibercept acts as a soluble "receptor-trap", which binds to VEGF-A with greater affinity than native receptors VEGF-A, In addition, it also binds to related ligands VEGF-B and P1GF. Aflibercept binds to human VEGF-A, VEGF-B and P1GF with the formation of stable inert complexes that do not possess biological activity. Acting as a "trap" for ligands, aflibercept prevents the binding of endogenous ligands to their corresponding receptors, and thereby blocks the signaling through these receptors.

    Aflibercept inhibits receptor activation VEGF and proliferation of endothelial cells, thereby suppressing the formation of new vessels supplying tumors with oxygen and nutrients.

    Aflibercept is associated with VEGF-A (equilibrium dissociation constant (Cd) - 0.5 pmol for VEGF-A165 and 0.36 pmol for VEGF-A121), from P1GF rights (Cd 39 pmol for P1GF-2), from VEGF-B rights (Cd 1.92 pmol) to form a stable inert complex that does not have biological activity that can be determined. The use of aflibercept in mice with xenotransplanted or allotransplanted tumors inhibited the growth of various types of adenocarcinomas.

    In patients with metastatic colorectal cancer,who previously had oxaliplatin-containing chemotherapy (with previous administration of bevacizumab or without previous administration of bevacizumab), a chemotherapeutic regimen Zaltrap® /FOLFIRI [fluorouracil, irinotecan, calcium folinate] demonstrated statistically significant increase in life expectancy compared with the chemotherapeutic regimen FOLFIRI.

    Pharmacokinetics:

    Absorption

    In preclinical studies conducted on tumor models, biologically active doses of afiberbertsept were correlated with the doses necessary to create concentrations of circulating free aflibercept circulating in the systemic blood flow, exceeding the concentrations of circulating in the systemic blood flow of aflibercept, associated with VEGF. Concentrations of circulating in the systemic bloodstream associated with VEGF at increasing its dose increase until the majority of VEGF is not connected. A further increase in the dose of aflibercept leads to a dose-dependent increase in the concentration of free aflibercept circulating in the systemic circulation and only to a slight further increase in the concentration of the associated VEGF aflibercept.

    In patients, Zaltrap® is administered at a dose of 4 mg / kg body weight intravenously every 2 weeks during which there is an excess of circulating free aflibercept concentration above the concentration of aflibercept associated with VEGF.

    At a recommended dose of 4 mg / kg of body weight, biweekly concentrations of free aflibercept close to equilibrium concentrations were achieved during the second treatment cycle with little or no accumulation (accumulation factor 1.2 in the equilibrium state, compared with the concentration of free aflibercept at first introduction).

    Distribution

    The volume of distribution of free aflibercept in the equilibrium state is 8 liters.

    Metabolism

    As aflibercept is a protein, there has been no research into its metabolism. Expected that aflibercept will be split into small peptides and individual amino acids.

    Elimination

    Circulating in the systemic blood flow is free aflibercept, is mainly associated with VEGF-family with the formation of stable inactive complexes. It is expected that, like other large proteins associated with VEGF and free aflibercept will be gradually eliminated from the systemic blood flow due to other biological mechanisms, such as proteolytic catabolism.

    At doses exceeding 2 mg / kg, the clearance of free afiberbertsept was 1.0 L / day with a terminal half-life of 6 days.

    High-molecular proteins are not excreted by the kidneys, so it is expected that renal excretion of aflibercept will be minimal.

    Linearity / nonlinearity of elimination

    In connection with the target binding of aflibercept with its "target" (endogenous VEGF), free aflibercept at doses below 2 mg / kg showed a rapid (non-linear) decrease in its concentration in the systemic blood stream, apparently associated with its high affinity binding to endogenous VEGF. In the dose range of 2 to 9 mg / kg, the clearance of free aflibercept becomes linear, apparently due to unsaturated biological clearance mechanisms such as protein catabolism.

    Special patient groups

    Children

    The pharmacokinetic profile of aflibercept in children is not established.

    Elderly patients

    Age does not affect the pharmacokinetics of aflibercept.

    Gender identity

    Despite the differences in the clearance of free afiberceptse and the volume of distribution in men and women, there were no gender-related differences in its systemic exposure when administered at a dose of 4 mg / kg body weight.

    Body mass index

    Body weight influenced the clearance of free afiberbertsept and the volume of distribution, so in patients with a body weight> 100 kg, the systemic exposure of aflibercept increased by 29%.

    Race

    Racial and ethnicity did not affect the pharmacokinetics of aflibercept.

    Patients with hepatic insufficiency

    Official studies on the use of Zaltrap® in patients with liver failure have not been conducted.

    In patients with mild (the concentration of total bilirubin in the blood <1.5 VEN [upper limit of the norm] for any values ​​of activity of aspartate aminotransferase [ACT] and mean (the concentration of total bilirubin in the blood> 1.5-3 VEN at any activity values ACT) hepatic insufficiency did not reveal a change in the clearance of aflibercept. There are no data on the pharmacokinetics of aflibercept in patients with severe hepatic impairment (concentrationtotal bilirubin in the blood> 3 X VGN for any activity values ACT).

    Patients with renal insufficiency

    Official studies on the use of Zaltrap® in patients with renal insufficiency have not been carried out.

    There were no differences in systemic exposure (area under the pharmacokinetic curve "concentration-time" [AUC]) free afiberbertsept in patients with renal insufficiency of varying degrees of severity with the use of Zaltrap ® in a dose of 4 mg / kg body weight.

    Indications:

    Metastatic colorectal cancer (MCRC) (in adult patients), resistant to oxaliplatin-containing chemotherapy or progressing after its use (Zaltrap® preparation in combination with a regimen including irinotecan, fluorouracil, calcium folinate (FOLFIRI)).

    Contraindications:

    - Hypersensitivity to aflibercept or any of the auxiliaries of Zaltrap®.

    - Severe bleeding.

    - Arterial hypertension, not amenable to drug correction.

    - Chronic heart failure III-IV class (according to the classification NYHA).

    - Severe hepatic insufficiency (lack of application data).

    - Ophthalmic application or introduction to the vitreous (in connection with the hyperosmotic properties of the preparation Zaltrap®).

    - Pregnancy.

    - Breastfeeding period.

    - Children and adolescence up to 18 years (due to lack of sufficient experience of use).

    Contraindications to the use of irinotecan, fluorouracil and calcium folinate, see the instructions for their use.

    Carefully:

    - Severe degree of renal failure.

    - Arterial hypertension.

    - Clinically significant diseases of the cardiovascular system (ischemic heart disease, chronic heart failure I-II class by classification NYHA).

    - Elderly age.

    - General condition> 2 points on the scoring scale to assess the general condition of the patient ECOG (Eastern Joint Group of Oncologists).

    Pregnancy and lactation:

    Pregnancy

    Data on the use of aflibercept in pregnant women are absent. Studies conducted in animals revealed embryotoxic and teratogenic effects in aflibercept. Since angiogenesis is important for the development of the embryo, inhibition of angiogenesis with the administration of Zaltrap® can lead to adverse effects for the development of pregnancy.The use of Zaltrap® during pregnancy and in women who may have pregnancy is not recommended.

    Women of childbearing age should be advised to avoid pregnancy during treatment with Zaltrap®, and they should be informed of the potential for adverse effects of Zaltrap® on the fetus.

    Women of childbearing age and fertile men should use effective methods of contraception during treatment and, at least, for up to 6 months after the last dose of treatment.

    There is a possibility of impaired fertility in men and women during treatment with aflibercept (based on data obtained in studies conducted on monkeys, in males and females aflibercept caused fertility impairment, completely reversible after 8-18 weeks).

    Breastfeeding period

    Clinical studies to evaluate the effect of Zaltrap® on the production of breast milk, the isolation of aflibercept in breast milk and its effects on infants have not been conducted.

    It is not known whether aflibercept in women's breast milk.However, due to the fact that it is impossible to exclude the possibility of the penetration of aflibercept into breast milk, and also because of the possibility of developing serious undesirable reactions caused by aflibercept in infants, it is necessary either to give up breastfeeding or not to use Zaltrap® (depending on from the importance of the drug for the mother).

    Dosing and Administration:

    The preparation Zaltrap® is administered as a 1-hour intravenous infusion with the subsequent administration of a chemotherapeutic regimen FOLFIRI. The recommended dose of Zaltrap®, used in combination with chemotherapy regimens FOLFIRI, is 4 mg / kg body weight.

    Chemotherapy scheme FOLFIRI:

    on the first day of the cycle - simultaneous intravenous infusion through Yan irinotecan catheter in a dose of 180 mg / m2 for 90 min and calcium folinate (left and right-handed racemates) at a dose of 400 mg / m2 for 2 hours, followed by intravenous (bolus) administration of fluorouracil at a dose of 400 mg / m2, followed by a continuous intravenous infusion of fluorouracil at a dosage of 2,400 mg / m2 for 46 hours.

    The cycles of chemotherapy are repeated every 2 weeks.

    Treatment with Zaltrap® should continue until the disease progresses or the development of unacceptable toxicity.

    Recommendations for correcting the dosing regimen / delaying treatment

    Treatment with Zaltrap® should be discontinued:

    - with the development of severe bleeding;

    - with the development of perforation of the walls of the gastrointestinal tract (GIT);

    - when a fistula is formed;

    - with the development of hypertensive crisis or hypertensive encephalopathy;

    - with the development of arterial thromboembolic complications;

    - with the development of nephrotic syndrome or thrombotic microangiopathy;

    - with the development of severe hypersensitivity reactions (including bronchospasm, dyspnea, angioedema, anaphylaxis);

    - when wound healing is damaged, requiring medical intervention;

    - with the development of the syndrome of reversible posterior encephalopathy (SOSE), also known as reversible posterior leukoencephalopathy (COPD).

    At least 4 weeks before the scheduled operation, Zaltrap® should be temporarily stopped.

    Postponement of chemotherapy / FOLFIRI

    Neutropenia or thrombocytopenia

    Application of the chemotherapeutic regimen Zaltrap® /FOLFIRI should be postponed until the number of neutrophils in the peripheral blood is increased to> 1.5 x 109/ l and / or the number of platelets in the peripheral blood does not increase to> 75 x 109/ l

    Light or moderately expressed hypersensitivity reactions (including flushing of the skin, rash, hives and itching)

    It is necessary to temporarily suspend the treatment until the reaction stops. If necessary, glucocorticosteroids and / or antihistamines may be used to stop the hypersensitivity reaction.

    In subsequent cycles, the question of premedication with glucocorticosteroids and / or

    antihistamines.

    Severe hypersensitivity reactions (including bronchospasm, dyspnea, angioedema and anaphylaxis)

    The use of the chemotherapeutic regimen Zaltrap® /FOLFIRI and to conduct therapy aimed at arresting the hypersensitivity reaction.

    Postponement of treatment with Zaltrap® and correction of its dose

    Increased blood pressure

    It is necessary to temporarily suspend the use of Zaltrap ® until the control over the increase in blood pressure.

    With the repeated development of a pronounced increase in blood pressure, the use of the drug should be suspended until control over the increase in blood pressure is reached and in subsequent cyclesdose Zaltrap ® up to 2 mg / kg body weight.

    Proteinuria

    (see section "Special instructions")

    It is necessary to suspend the use of Zaltrap ® in proteinuria> 2 g / day, the resumption of treatment is possible after the reduction of proteinuria to <2 g / day.

    With the second development of proteinuria> 2 g / day, the use of Zaltrap® should be suspended until the proteinuria <2 g / day is reduced, and in subsequent cycles it is reduced to 2 mg / kg of body weight.

    Correction of doses of chemotherapy FOLFIRI when used with Zaltrap ®

    Heavy stomatitis and syndrome of palmar-plantar erythrodesisia

    It is necessary to reduce the bolus and infusion dose of fluorouracil by 20%.

    Severe diarrhea

    It is necessary to reduce the dose of irinotecan by 15-20%.

    If severe diarrhea develops repeatedly, the next cycle should additionally reduce the bolus and infusion dose of fluorouracil by 20%.

    If severe diarrhea persists with a decrease in the doses of both drugs, discontinue use FOLFIRI.

    If necessary, treatment with anti-diarrhea drugs and replenishment of fluid and electrolyte losses can be carried out.

    Febrile neutropenia and neutropenic sepsis

    In subsequent cycles, the dose of irinotecan should be reduced by 15-20%.

    In case of repeated development in subsequent cycles, the bolus and infusion dose of fluorouracil should be further reduced by 20%.

    The use of granulocyte colony-stimulating factor (G-CSF) can be considered.

    For more information on the toxicity of irinotecan, fluorouracil and calcium folinate, see the instructions for their use.

    Use of the drug in specific patient groups

    Children

    Safety and efficacy in pediatric patients are not established.

    Elderly patients

    Older patients are not required to adjust the dose of Zaltrap®.

    Patients with hepatic insufficiency

    Official studies on the use of Zaltrap® in patients with hepatic insufficiency was not performed. Based on clinical data, the systemic exposure of aflibercept in patients with mild to moderate hepatic impairment was similar to that in patients with normal liver function. Clinical evidence suggests that there is no need to adjust the dose of aflibercept in patients with mild or moderate hepatic impairment.There are no data on the use of aflibercept in patients with severe hepatic impairment.

    Patients with renal insufficiency

    Official studies on the use of Zaltrap® in patients with impaired renal function was not performed. Based on clinical data, the systemic exposure of aflibercept in patients with mild to moderate renal insufficiency was similar to that in patients with normal renal function. Clinical evidence suggests that there is no need to correct the initial dose of aflibercept in patients with mild and moderate renal failure. There is very little data on the use of the drug in patients with severe renal failure, so when using the drug in these patients should be careful.

    Recommendations for the preparation of solutions and their introduction

    The drug should be administered under the supervision of a doctor who has experience in the use of antitumor drugs.

    Do not administer undiluted concentrate. Do not inject intravenously (neither fast nor slow).

    The preparation Zaltrap® is not intended for intravitreal administration.

    As with all parenteral preparations, a diluted solution of Zaltrap® must be visually inspected for undiluted particles or discoloration before administration.

    Diluted solutions of the preparation Zaltrap® should be administered with the help of sets for intravenous infusions made of the following materials:

    - Polyvinyl chloride (PVC) containing diethyl hexyl phthalate (DEHP);

    - polyvinyl chloride, which does not contain DEHP, but contains trioctyltrimellitate (TOTM);

    - polypropylene;

    - polyethylene, covered from the inside PVC;

    - polyurethane.

    Sets for intravenous infusions should contain polyether sulfone filters with a pore diameter of 0.2 μm. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon.

    Due to the lack of compatibility studies, Zaltrap® should not be mixed with other drugs or solvents, with the exception of 0.9% sodium chloride solution and 5% dextrose solution.

    Preparation of the infusion solution and treatment of the drug

    Recommendations for the safe handling of the drug

    The infusion solution of Zaltrap® should be prepared by a medical professional in aseptic conditions, observing the procedures for safe handling of the drug.

    Preparation of a solution for infusions

    - Do not use the vial with the drug if there are undissolved particles in the concentrate solution or if there is a change in its color.

    - Use infusion containers made of PVC containing DEHP or polyolefin (without PVC and DEHP).

    - Only for intravenous infusion introduction due to hyperosmolarity (1000 mOsm / kg) of Zaltrap® concentrate.

    - The drug is not intended for injection into the vitreous.

    - Concentrate Zaltrap ® should be diluted. Extract the required amount of concentrate Zaltrap ® and dilute to the required volume of 0.9% solution of sodium chloride for injection or 5% solution of dextrose for injection. The concentration of aflibercept in the infusion solution after dilution of the concentrate of the preparation Zaltrap® should be in the range of 0.6-8 mg / ml.

    - From a microbiological point of view, the diluted solution of Zaltrap® should be used immediately, its physical and chemical stability is maintained for up to 24 hours at a temperature of 2-8 ° C and up to 8 hours at 25 ° C.

    Recycling

    The bottles of Zaltrap® are intended for single use.Any amount of unused product remaining in the vial must be disposed of in accordance with the relevant Russian requirements. Do not pierce the vial with a needle once the needle has been inserted into it.

    Side effects:

    The most common undesirable reactions (HP) (all degrees of severity, with a frequency> 20%), observed at least 2% more often with the use of the chemotherapeutic regimen Zaltrap ® /FOLFIRI, than with the use of a chemotherapeutic regimen FOLFIRI, were the following HP (in order of decreasing incidence): leukopenia, diarrhea, neutropenia, proteinuria, increased activity ACT, stomatitis, fatigue, thrombocytopenia, increased activity of alanine aminotransferase (ALT), increased blood pressure, weight loss, decreased appetite, nosebleeds, abdominal pain, dysphonia, increased serum creatinine and headache.

    The most common HP 3-4 degrees of severity (with a frequency> 5%), observed at least 2% more often with the use of the chemotherapeutic regimen Zaltrap® / FOLFIRI in comparison with the chemotherapeutic regimen FOLFIRI, were the following HP (in order of decreasing incidence): neutropenia, diarrhea, increased blood pressure, leukopenia, stomatitis, fatigue, proteinuria and asthenia.

    In general, discontinuation of therapy due to the occurrence of adverse events (all degrees of severity) was observed in 26.8% of patients receiving the chemotherapeutic regimen Zaltrap® / FOLFIRI compared with 12.1% of patients who received chemotherapeutic regimen FOLFIRI. The most common undesirable reactions that caused the refusal of therapy in> 1% of patients receiving the chemotherapeutic regimen Zaltrap® / FOLFIRI, asthenia / fatigue, infections, diarrhea, dehydration, increased blood pressure, stomatitis, venous thromboembolic complications, neutropenia and proteinuria.

    Correction of the dose of Zaltrap® (reduction of dose and / or omission of administration) was carried out in 16.7%. Delays in subsequent cycles of therapy exceeding 7 days were observed in 59.7% of patients who received the Zaltrap® / FOLFIRI chemotherapy regimen compared with 42.6% of patients receiving chemotherapeutic regimens FOLFIRI.

    Death from other causes, other than death from the progression of the disease,observed within 30 days after the last cycle of the studied chemotherapeutic regimen, was recorded in 2.6% of patients receiving the chemotherapeutic regimen Zaltrap® / FOLFIRI and 1.0% of patients receiving the chemotherapeutic regimen FOLFIRI. The cause of death of patients who received a chemotherapeutic regimen Zaltrap® /FOLFIRI, there was an infection (including neutropenic sepsis) in 4 patients; dehydration in 2 patients; hypovolemia in 1 patient; metabolic encephalopathy in 1 patient; respiratory diseases (acute respiratory failure, aspiration pneumonia, and pulmonary embolism) in 3 patients; disorders of the gastrointestinal tract (bleeding from duodenal ulcers, inflammation of the gastrointestinal tract, complete intestinal obstruction) in 3 patients; lethal outcome from unknown causes in 2 patients.

    Below are the HP and laboratory abnormalities observed in patients who received the Zaltrap® chemotherapy regimen / FOLFIRI with their division according to the system-organ classes in accordance with the classification of the Medical dictionary for normative-legal activity MedDRA. Submitted below HP were defined as any undesirable clinical reactions or deviations from the norm of laboratory indicators, having a> 2% higher frequency (for HP of all degrees of severity) in the group of treatment with aflibercept compared with the placebo group in a study conducted in patients with MCRC. Intensity HP classified according to NCI CTC (National Cancer Institute's Common Toxicity Criteria Assessment Scale) version 3.0.

    Frequency of occurrence HP was determined in accordance with the WHO classification as follows: very often:> 10%; often:> 1% - <10%; infrequently:> 0.1% - <1%; rarely:> 0.01 %-<0,1 %; very rarely: <0.001%, unknown frequency - it is not possible to determine the frequency of occurrence according to the available data.

    Infectious and parasitic diseases

    Often: infection (all degrees of severity), including urinary tract infections, nasopharyngitis of the upper respiratory tract infection; pneumonia, infection at the site of insertion of the catheter; dental infections.

    Often: neutropenic infections / sepsis (all degrees of severity and> 3 degrees of severity).

    Violations of the blood and lymphatic system

    Often: leukopenia (all degrees of severity and> 3 degrees of severity); neutropenia, (all degrees of severity and> 3 degrees of severity); thrombocytopenia (all degrees of severity).

    Often: febrile neutropenia of all degrees of severity and> 3 degrees of severity; thrombocytopenia> 3 degrees of severity.

    Immune system disorders

    Often: hypersensitivity reactions (all degrees of severity).

    Infrequently: hypersensitivity reactions> 3 degrees of severity.

    Disorders of metabolism and nutrition

    Often: decreased appetite (all degrees of severity).

    Often: dehydration (all degrees of severity and> 3 degrees of severity); decreased appetite> 3 degrees of severity.

    Disturbances from the nervous system

    Often: headache (all degrees of severity).

    Often: headache> 3 degrees of severity.

    Infrequently: syndrome of reversible posterior leukoencephalopathy (COPD).

    Vascular disorders

    Often: increased blood pressure (all degrees of severity) (in 54% of patients who had an increase in blood pressure> 3 degrees of severity, the increase in BP developed during the first two cycles of treatment); bleeding / hemorrhage (all degrees of severity), with the most frequent type of hemorrhage was small nosebleeds (1-2 degrees of severity).

    Often: arterial thromboembolic complications (ATEO) (such as acute disorders of cerebral circulation, including transient cerebrovascular ischemic attacks, angina, intracardiac thrombus, myocardial infarction, arterial thromboembolism and ischemic colitis) (all degrees of severity); venous thromboembolic complications (VTEO) (deep vein thrombosis and pulmonary embolism) all degrees of severity; bleeding> 3 degrees of severity, sometimes fatal, including gastrointestinal bleeding, hematuria, bleeding after medical procedures.

    Unknown frequency: patients receiving Zaltrap® received reports of severe intracranial hemorrhages and pulmonary hemorrhage / hemoptysis, including fatalities.

    Disturbances from the respiratory system, chest and mediastinal organs

    Often: shortness of breath (all degrees of severity), nosebleeds (all degrees of severity), dysphonia (all degrees of severity).

    Often: pain in the oropharynx (all degrees of severity), rhinorrhea (rhinorrhea only 1-2 degrees of severity was observed).

    Infrequently: dyspnea> 3 degrees of severity, nosebleed> 3 degrees of severity, dysphonia> 3 degrees of severity, pain in the oropharynx> 3 degrees of severity.

    Disorders from the digestive tract

    Often: Diarrhea (all degrees of severity and> 3 degrees of severity); stomatitis (all degrees of severity and> 3 degrees of severity), abdominal pain (all degrees of severity), pain in the upper abdomen (all degrees of severity).

    Often: abdominal pain> 3 degrees of severity, pain in the upper abdomen> 3 degrees of severity; hemorrhoids (of all degrees of severity); bleeding from the rectum (all degrees of severity); pain in the rectum (all degrees of severity); toothache (all degrees of gravity); aphthous stomatitis (all degrees of severity); the formation of fistulas (anal, small intestinal, external small intestinal, colonic-vaginal, intestinal) (all degrees of severity).

    Infrequently: formation of gastrointestinal fistula> 3 degrees of severity, perforation of the walls of the gastrointestinal tract of all degrees of severity and> 3 degrees of severity, including fatal perforations of the gastrointestinal wall; bleeding from the rectum> 3 degrees of severity; aphthous stomatitis> 3 degrees of severity; pain in the rectum> 3 degrees of severity.

    Disturbances from the skin and subcutaneous tissues

    Often: syndrome of palmar-plantar erythrodysesthesia (all degrees of severity).

    Often: hyperpigmentation of the skin (all degrees of severity), syndrome of palmar-plantar erythrodysesthesia> 3 degrees of severity.

    Disorders from the kidneys and urinary tract

    Often: proteinuria (by combined clinical and laboratory data) (all degrees of severity), increasing serum creatinine concentration (all degrees of severity).

    Often: proteinuria> 3 degrees of severity.

    Infrequently: nephrotic syndrome. One patient with proteinuria and an increase in blood pressure from 611 patients treated with the Zaltrap® chemotherapy regimen /FOLFIRI, was diagnosed with thrombotic microangiopathy.

    General disorders and disorders at the site of administration

    Often: asthenic conditions (all degrees of severity); feeling of fatigue (all degrees of severity and> 3 degrees of severity).

    Often: asthenic conditions (> 3 degrees of severity).

    Infrequently: violation of wound healing (divergence of wound edges, anastomosis failure) (all degrees of severity and> 3 degrees of severity).

    Laboratory and instrumental data

    Often: increased activity ACT, ALT (all degrees of severity), weight loss (all degrees of severity).

    Often: increased activity ACT, ALT> 3 degrees of severity, weight loss> 3 degrees of severity.

    Frequency HP in special patient groups

    Elderly patients

    In elderly patients (> 65 years), the incidence of diarrhea, dizziness, asthenia, weight loss and dehydration was more than 5% higher than in younger patients. Elderly patients should be closely monitored for the development of diarrhea and / or possible dehydration.

    Patients with renal insufficiency

    In patients with impaired renal function of mild degree at the time of starting the use of Zaltrap®, the incidence HP was comparable to that in patients without renal dysfunction at the time of application of Zaltrap®. In patients with moderate to severe renal impairment, the occurrence of HP not on the part of the kidneys as a whole was comparable to that in patients without renal failure, except for> 10% excess of the frequency of development of dehydration (all degrees of severity).

    Immunogenicity

    Like all other protein medications, afiberbertsept has a potential risk of immunogenicity. In general, according to the results of all oncological clinical studies, none of the patients had a high titer of antibodies to aflibercept.

    Overdose:

    Information on the safety of taking Zaltrap® in doses greater than 7 mg / kg once every 2 weeks or 9 mg / kg once every 3 weeks is not available. The most common HP, observed at these dosing regimes were similar to HP, observed with the use of the drug in therapeutic doses.

    There is no specific antidote for Zaltrap ®. In cases of overdose, patients require maintenance treatment, particularly monitoring and treatment of increased blood pressure and proteinuria. The patient should be under careful medical supervision to identify and control any HP (see section "Side effect").

    Interaction:

    There were no official studies on drug interaction with Zaltrap®.

    In comparative studies, the concentrations of free and bound aflibercept in combination with other drugs were similar to those of aflibercept in monotherapy, indicating that these combinationsoxaliplatinum, cisplatin, fluorouracil, irinotecan, docetaxel, pemetrexed, gemcitabine, and erlotinib) do not affect the pharmacokinetics of aflibercept.

    In its turn, aflibercept did not affect the pharmacokinetics of irinotecan, fluorouracil, oxaliplatin, cisplatin, docetaxel, pemetrexed, gemcitabine, and erlotinib.

    Special instructions:

    Before starting treatment and before every new cycle of treatment with aflibercept, it is recommended to perform a general blood test with the definition of the leukocyte formula. The first development of neutropenia> 3 severity should consider the therapeutic use of G-CSF, in addition, in patients who have an increased risk of developing neutropenic complications, the introduction of G-CSF is recommended for the prevention of neutropenia.

    Patients should be under constant observation for signs and symptoms of gastrointestinal and other severe bleeding. You can not enter aflibercept patients with severe bleeding.

    Patients should be monitored for signs and symptoms of perforation of the gastrointestinal wall.In the case of development of perforation of the walls of the digestive tract, treatment with aflibercept should be stopped.

    With the development of fistulas, treatment with aflibercept should be discontinued.

    During treatment with aflibercept it is recommended to monitor blood pressure every two weeks, including control of blood pressure before administration of aflibercept, or more often on clinical indications during treatment with aflibercept. In the case of increased blood pressure during treatment with aflibercept, appropriate antihypertensive therapy should be used and BP should be monitored regularly. In case of excessive increase in blood pressure, treatment with afibercept should be stopped until blood pressure drops to the target values, and in subsequent cycles the dose of aflibercept should be reduced to 2 mg / kg. In the case of hypertensive crisis or hypertensive encephalopathy, the administration of the drug aflibercept should be discontinued.

    Caution should be exercised when administering Zaltrap® to patients with clinically significant cardiovascular pathologies, such as ischemic heart disease and heart failure. Clinical studies on the administration of Zaltrap® to patients with heart failure III and IV of the functional class according to the classification NYHA are absent.

    If the patient develops ATEO, treatment with aflibercept should be stopped.

    Before each administration of aflibercept, proteinuria should be determined with the help of an indicator test strip or by determining the protein / creatinine ratio in urine to detect the development or increase of proteinuria. Patients with a protein / creatinine ratio in urine> 1 should determine the amount of protein in daily urine.

    When developing a nephrotic syndrome or thrombotic microangiopathy, treatment with aflibercept should be discontinued.

    In case of severe hypersensitivity reaction (including bronchospasm, dyspnea, angioedema and anaphylaxis), discontinue treatment and begin appropriate therapy aimed at stopping these reactions.

    If a mild hypersensitivity reaction develops aflibercept (including flushing of the skin, rash, hives, itching) should temporarily suspend treatment until the reaction is resolved. In case of clinical necessity, glucocorticosteroids and / or antihistamines can be used to stop these reactions.In subsequent cycles, you may consider premedication with glucocorticosteroids and / or antihistamines. When resuming treatment of patients with previous hypersensitivity reactions, care should be taken, as some patients experienced repeated development of hypersensitivity reactions, despite their prevention, including the use of glucocorticosteroids.

    The use of aflibercept should be suspended for at least 4 weeks after major surgical interventions and until the complete surgical wound heals. For small surgical interventions, such as the installation of a central venous catheter, biopsy, extraction of teeth, treatment with aflibercept can be started / resumed after complete healing of the wound. In patients with impaired wound healing, requiring medical intervention, the use of aflibercept should be discontinued.

    COPD can be manifested by a change in the mental state, epileptic seizures, nausea, vomiting, headaches and visual disorders.The diagnosis of COPD is confirmed by brain examination using magnetic resonance imaging (MRI).

    In patients with COPD, the use of aflibercept should be discontinued.

    Elderly patients

    In elderly patients (> 65 years) there is an increased risk of diarrhea, dizziness, asthenia, weight loss and dehydration. In order to minimize the risk, such patients need careful medical supervision for the early detection and treatment of signs and symptoms of diarrhea and dehydration.

    General condition and concomitant diseases

    Patients with an index of the general condition of the patient> 2 points (on a five-point [0-4 point] assessment scale ECOG [Eastern Joint Oncology Group]) or having significant co-morbidities may have a higher risk of adverse clinical outcome and need careful medical supervision for early detection of clinical deterioration.

    The drug Zaltrap ® is a hyperosmotic solution, whose composition is incompatible with the introduction into the intraocular space. Zaltrap ® should not be administered into the vitreous.

    Effect on the ability to drive transp. cf. and fur:

    There have been no studies on the effect of Zaltrap® on the ability to drive or engage in other potentially hazardous activities. If patients develop symptoms that affect their vision and ability to concentrate, and also slow psychomotor reactions, patients should be advised not to drive vehicles and not engage in other potentially hazardous activities.

    Form release / dosage:

    Concentrate for the preparation of a solution for infusions of 25 mg / ml.

    Packaging:

    To 4 ml of the drug in a bottle of colorless glass (type I), sealed with a cork made of bromobutyl rubber with an aluminum crimping cap with a stalling ring and a sealing disc. For 1 or 3 bottles together with instructions for use in a cardboard pack.

    For 8 ml of the drug in a bottle of colorless glass (type I), sealed with a cork made of bromobutyl rubber with an aluminum crimping cap with a stalling ring and a sealing disc. 1 bottle with instructions for use in a cardboard box.

    Storage conditions:

    Store in a dark place at a temperature of 2 ° C to 8 ° C.

    Keep out of the reach of children.

    Shelf life:3 years.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-002534
    Date of registration:15.07.2014
    The owner of the registration certificate:Sanofi-Aventis FranceSanofi-Aventis France France
    Manufacturer: & nbsp
    Representation: & nbspSanofi Russia, JSCSanofi Russia, JSCRussia
    Information update date: & nbsp15.07.2014
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