Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions in the form of a transparent colorless or light yellow liquid.
aflibercept 25 mg
Excipients: sodium dihydrogen phosphate monohydrate 0.5774 mg, sodium hydrogen phosphate heptahydrate 0.2188 mg, citric acid monohydrate 0.0443 mg sodium citrate dihydrate 1.4088 mg sodium chloride 5.84 mg 0.1M hydrochloric acid or 0.1M sodium hydroxide solution up to pH 5.9-6.5, sucrose - 200 mg, polysorbate 20 - 1 mg, water d / and - up to 1 ml.
4 ml - vials of colorless glass (type I) (1) - packs cardboard.
4 ml - vials of colorless glass (type I) (3) - packs cardboard.
8 ml - bottles of colorless glass (type I) (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
Antitumor drug. Aflicibercept is a recombinant fusion protein consisting of VEGF-binding portions of the extracellular domains of the VEGF 1 receptor and the VEGF 2 receptor coupled to the Fc domain of a human immunoglobulin G1 (IgG1) fragment.
Aflicibercept is produced using recombinant DNA technology using the expression system of Chinese hamster ovary (CHO) cells K-1. Aflicibercept 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 growth factor V (VEGF-B) and placental growth factor (P1GF) belong to the VEGF family of angiogenic factors that can act as strong mitogenic, chemotactic and vascular-permeabilizing factors for endothelial cells. The action of VEGF-A is via 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, in addition to the presence of endothelial cells on the surface, is also on the surface of leukocytes. Excessive activation of these VEGF-A receptors can lead to pathological neovascularization and increased vascular permeability. P1GF also has to do with the development of pathological neovascularization and tumor infiltration by inflammation cells.
Afleibercept acts as a soluble "receptor-trap", which binds to VEGF-A with greater affinity than native VEGF-A receptors; in addition, it also binds to the related VEGF-B and P1GF ligands. Aflicibercept binds to human VEGF-A, VEGF-B and P1GF to form 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 transmission of signals through these receptors.
Aflicibercept blocks the activation of VEGF receptors and the proliferation of endothelial cells, thereby suppressing the formation of new vessels supplying tumors with oxygen and nutrients.
Aflibercept binds to human VEGF-A (the equilibrium dissociation constant (Kd) is 0.5 pmol for VEGF-A165 and 0.36 pmoles for VEGF-A121), with human P1GF (Cd 39 pmol for P1GF-2), with human VEGF-B (Kd 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 had previously been treated with oxaliplatin-containing chemotherapy (with previous administration of bevacizumab or without previous administration of bevacizumab), the chemotherapeutic regimen Zaltrap В® / FOLFIRI [fluorouracil, irinotecan, calcium folinate] demonstrated a statistically significant increase in life expectancy compared with chemotherapeutic scheme FOLFIRI.
In preclinical studies conducted on tumor models, biologically active doses of afiberbertsept 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 stream of afiberceptse associated with VEGF. Concentrations circulating in the systemic blood stream of Vebf-associated aflibercept as its dose is increased are increased until most of the VEGF is bound. A further increase in the dose of aflibercept leads to a dose-dependent increase in the concentration of free aflibercept circulating in the systemic blood stream and only to a slight further increase in the concentration of the afebertcept associated with VEGF.
Zaltrap В® was administered to patients at a dose of 4 mg / kg body weight IV every 2 weeks during which there was an excess concentration of circulating free afiberbertsept relative to the concentration of aflibercept associated with VEGF.
At a recommended dose of 4 mg / kg of body weight, once every 2 weeks, concentrations of free afiberceptse close to C ss 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 the first administration ).
V d of free aflibercept in the equilibrium state is 8 liters.
Because aflibercept is a protein, there has been no research into its metabolism. It is expected that afiberbertsept will be split into small peptides and individual amino acids.
Circulating in the systemic circulation of free aflibercept, mainly binds to the VEGF-family with the formation of stable inactive complexes.
It is expected that, like other large proteins, bound to VEGF and free afiberceptse will be gradually removed from the systemic bloodstream due to other biological mechanisms, such as proteolytic catabolism.
At doses exceeding 2 mg / kg, the clearance of free afiberbertsept was 1 l / day with a finite T 1/2 - 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 afiberbertsept 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.
Pharmacokinetics in special clinical cases
With IV injection Zaltrap * at doses of 2 mg / kg, 2.5 mg / kg, 3 mg / kg every 2 weeks to 8 children with solid tumors (aged 5 to 17 years), medium T 1 / 2 free afiberceptse, determined after the first dose, was approximately 4 days (3 to 6 days).
Age does not affect the pharmacokinetics of aflibercept.
Despite differences in the clearance of free aflibercept and the values вЂ‹вЂ‹of V d in males and females, there were no gender-related differences in its systemic exposure when administered at a dose of 4 mg / kg body weight.
Body weight influenced the clearance of free aflibercept and its V d , so, in patients with a body weight> 100 kg, the systemic exposure of aflibercept increased by 29%.
Racial and ethnicity did not affect the pharmacokinetics of aflibercept.
Official studies on the use of Zaltrap В® in patients with hepatic insufficiency have not been conducted. In patients with mild (the concentration of total bilirubin in blood? 1.5? VGN for any values вЂ‹вЂ‹of ACT activity) and the mean (concentration of total bilirubin in blood> 1.5-3? VGN for any ACT activity), 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 insufficiency (concentration of total bilirubin in the blood> 3? VGN for any ACT activity).
Official studies on the use of Zaltrap В® in patients with renal insufficiency have not been conducted. There was no difference in the systemic exposure (AUC) of free afiberceptse in patients with renal insufficiency of varying degrees of severity with Zaltrap В® at a dose of 4 mg / kg body weight.
- metastatic colorectal cancer (MCRC) (in adult patients), resistant to oxaliplatin-containing chemotherapy or progressing after its use (ZaltrapВ® preparation in combination with irinotecan, fluorouracil, calcium folinate (FOLFIRI)).
ZaltrapВ® is administered iv in the form of infusion for 1 h, followed by the use of the chemotherapeutic regimen FOLFIRI.
The recommended dose of Zaltrap В® in combination with the chemotherapy regimen FOLFIRI is 4 mg / kg body weight.
Chemotherapy scheme FOLFIRI:
on the first day of the cycle, simultaneous IV infusion through irinotecan Y-shaped catheter at a dose of 180 mg / m 2 for 90 min and calcium folinate (left and right-handed racemates) at a dose of 400 mg / m 2 for 2 h, with followed by intravenous (bolus) administration of fluorouracil at a dose of 400 mg / m 2 , followed by a continuous iv infusion of fluorouracil at a dose of 2,400 mg / m 2 for 46 hours.
The cycles of chemotherapy are repeated every 2 weeks.
Treatment with Zaltrap В® should be continued until the disease progresses or the development of unacceptable toxicity.
Recommendations for correcting the dosing regimen / delaying treatment
Treatment with Zaltrap В® should be discontinued:
- with the development of severe bleeding;
- with the development of perforation of the gastrointestinal wall;
- with fistula formation;
- 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);
- if wound healing is disturbed, 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 В® should be temporarily stopped.
Postponement of chemotherapy Zaltrap В® / FOLFIRI
Neutropenia or thrombocytopenia The use of the chemotherapy regimen Zaltrap В® / FOLFIRI should be postponed until the amount of neutrophils in the peripheral blood increases to? 1.5 Г— 10 9 / L and / or the platelet count in peripheral blood does not increase to? 75 Г— 10 9 / L .
Mild 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, the use of GCS and / or antihistamines can be used to arrest the hypersensitivity reaction. In subsequent cycles, it may be necessary to consider pre-medication with SCS and / or antihistamines.
Severe hypersensitivity reactions (including bronchospasm, dyspnoea, angioedema, and anaphylaxis) The use of the Zaltrap В® / FOLFIRI chemotherapy regimen should be discontinued and therapy aimed at arresting the hypersensitivity reaction should be initiated.
Postponement of treatment with Zaltrap В® and correction of its dose
Increasing blood pressure Zaltrap В® should be suspended until control over the increase in blood pressure is achieved. With the repeated development of a marked increase in blood pressure, the drug should be suspended until control over the increase in blood pressure is reached and in subsequent cycles the dose of Zaltrap В® isreduced to 2 mg / kg.
Proteinuria The use of Zaltrap В® should be suspended with proteinuria? 2 g / day, the resumption of treatment is possible after a decrease in proteinuria to <2 g / day.With the second development of proteinuria? 2 g / day, the use of Zaltrap В® should be stopped until the proteinuria <2 g / day decreases, and in subsequent cycles it is reduced to 2 mg / kg.
Correction of doses of chemotherapy FOLFIRI in its use with the preparation Zaltrap В®
Severe stomatitis and syndrome of palmar-plantar erythrodysesthesia The bolus and infusion dose of fluorouracil should be reduced by 20%.
Severe diarrhea The dose of irinotecan should be reduced 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, the use of FOLFIRI should be discontinued. If necessary, it is possible to carry out treatment with antidiarrheal drugs and replenishment of fluid and electrolyte losses.
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 G-CSF may be considered.
For more information on the toxicity of irinotecan, fluorouracil and calcium folinate, see the appropriate instructions for use.
Use of the drug in specific patient groups
Safety and efficacy in pediatric patients are not established. In a study of safety and tolerability with increasing dose, 21 patients aged 2 to 21 years (mean age 12.9 years) with solid tumors received Zaltrap В® at doses of 2 to 3 mg / kg IV every two weeks. The pharmacokinetic parameters of free afiberbertsept were evaluated in 8 of these patients (aged 5 to 17 years). The maximum tolerated dose in the study was a dose of 2.5 mg / kg, which was below the safe and effective dose for adults with metastatic colorectal cancer.
Elderly patients are not required to adjust the dose of Zaltrap В® .
Official studies on the use of Zaltrap В® in patients with hepatic insufficiency have not been conducted. Based on clinical data, the systemic exposure of aflibercept in patients with mild and moderate hepatic insufficiency 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 insufficiency .
Official studies on the use of Zaltrap В® in patients with impaired renal function were 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 for correction of the initial dose of aflibercept in patients with mild to moderate renal failure . There is very little data on the use of the drug in patients with severe renal insufficiency , so when using the drug in these patients should be careful.
Rules for the preparation of solutions and infusion
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).
Zaltrap В® is not intended for administration to the vitreous.
As with all parenteral preparations, a diluted solution of Zaltrap В® must be visually inspected for undiluted particles or discoloration before administration.
Diluted solutions of the preparation Zaltrap В® should be administered with the help of sets for IV 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);
- polyethylene, covered from the inside PVC;
Sets for intravenous infusions should contain polyether sulfone filters with a pore diameter of 0.2 Ојm. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon.
Due to the lack of compatibility studies, Zaltrap В® 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
Infusion solution of the preparation Zaltrap В® should be prepared by a medical worker in aseptic conditions with observance of the procedures for the 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 there is a change in its color.
- Infusion tanks made of PVC containing DEHP or polyolefin (without PVC and DEHP) should be used.
- Only for intravenous infusion due to hyperosmolarity (1000 mOsm / kg) concentrate of Zaltrap В® preparation.
- The drug is not intended for injection into the vitreous body.
- Concentrate formulation Zaltrap В® should be diluted. It should extract the necessary amount of the drug concentrate Zaltrap В® and dilute it up to the required volume of 0.9% sodium chloride solution for injection or 5% dextrose for injection. Aflibercept concentration in the infusion solution after dilution of the concentrate formulation Zaltrap В® should be in the range 0.6-8 mg / ml.
- From the microbiological point of view of formulation the solution was diluted Zaltrap В® to be used immediately, its physical and chemical stability is maintained up to 24 hours at a temperature of from 2 В° to 8 В° C and up to 8 hours at a temperature of 25 В° C.
Vials Zaltrap preparation В® intended for single use. Any number of unused product remaining in the bottle, must be disposed of according to the relevant Russian requirements. Do not pierce the vial stopper needle again, after it had already introduced the needle.
The most frequently observed following undesirable reaction (HP) of all degrees of severity (with a frequency of? 20%), at least 2% more frequently with chemotherapeutic circuit Zaltpap В® / FOLFIRI, than with chemotherapeutic FOLFIRI scheme (in decreasing order of frequency of occurrence) : leukopenia, diarrhea, neutropenia, proteinuria, increased activity of ACT, stomatitis, fatigue, thrombocytopenia, increased ALT, increased blood pressure, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increasing conc ation serum creatinine, and headache.
The most frequently observed following HP 3-4 severity (with a frequency of? 5%), at least 2% more frequently with chemotherapeutic circuit Zaltpap В®/ FOLFIRI, than with chemotherapeutic FOLFIRI scheme (in decreasing order of frequency of occurrence): neutropenia, diarrhea, increased blood pressure, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.
In general, cessation of therapy due to the occurrence of adverse events (all severities) was observed in 26.8% of patients receiving chemotherapeutic circuit ZaltpapВ® / FOLFIRI compared with 12.1% of patients receiving chemotherapeutic circuit FOLFIRI.
The most frequent HP, which served as the reason for the failure of therapy in в‰Ґ1% of patients treated with chemotherapeutic regimens Zaltpap В® / FOLFIRI, were asthenia / fatigue, infections, diarrhea, dehydration, increased blood pressure, disease, venous thromboembolic events, neutropenia and proteinuria.
Correction dose preparation Zaltrap В® (dose reduction and / or the introduction of gaps) held at 16.7%. Delays subsequent treatment cycles exceeding 7 days, have been observed in 59.7% of patients receiving chemotherapeutic circuit Zaltpap В® / FOLFIRI compared with 42.6% of patients receiving chemotherapeutic circuit FOLFIRI.
Death from other causes, except for death from disease progression was observed within 30 days after the last cycle of chemotherapy study schemes has been fixed at 2.6% of patients receiving chemotherapeutic regimens Zaltrap В® / FOLFIRI, and in 1.0% of patients receiving chemotherapeutic regimens FOLFIRI. The cause of death of patients receiving chemotherapeutic regimens ZaltpapВ® / FOLFIRI, were infection (including neutropenic sepsis) in 4 patients; dehydration in 2 patients; hypovolemia 1 patient; Metabolic encephalopathy 1 patient; respiratory diseases (acute respiratory insufficiency, aspiration pneumonia, and pulmonary embolism), 3 patients; lesions of the gastrointestinal tract (bleeding from duodenal ulcers, inflammation of the gastrointestinal tract, complete bowel obstruction) in 3 patients; death from unknown causes in 2 patients.
Below are the HP and abnormal laboratory values observed in patients receiving chemotherapeutic circuit Zaltrap В® / FOLFIRI (according to MedDRA).
HP data is defined as any clinical adverse reactions or abnormal laboratory values, the frequency of which has been on? 2% higher (for HP all severities) Aflibercept in the treatment group compared with the placebo group in a study conducted in patients with EGFR. HP intensity was classified according to the NCI CTC (grading scale general criteria of the National Cancer Institute Common Toxicity United States) version 3.0.
Definition HP frequency (according to the WHO classification): very common (10%?), Often (1% - <10%?); infrequently (? 0.1% - <1%), rare (0.01% - <0.1%), very rare (<0.001%), the frequency is unknown - the available data to determine the frequency of occurrence is not possible.
Infectious and parasitic diseases:very often - infection (all severities), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, infection at the site of the catheter; dental infection; often - neutropenic infection / sepsis (all severities, and Grade 3?).
From the blood and lymphatic system: very often - leukopenia (all severities, and Grade 3?), Neutropenia (all severities, and Grade 3?), Thrombocytopenia (all severities); often - febrile neutropenia of all severities, and Grade 3;? thrombocytopenia? 3 severity.
Immune system: often - hypersensitivity reactions (all severities); rarely - hypersensitivity reactions Grade 3.
On the part of metabolism and food: very often - loss of appetite (all severities); often - dehydration (all severities, and Grade 3?); loss of appetite? 3 severity.
From the nervous system: very often - headache (all severities); ? often - headache Grade 3; infrequently - the SLDF.
Cardio-vascular system:very often - increased blood pressure (all severities) (? 54% of patients who experienced an increase in blood pressure 3 severity, increased blood pressure developed during the first two cycles of treatment); bleeding / hemorrhage (all severities), the most frequent bleeding view nosebleeds were small (1-2 severity); often - arterial thromboembolic complications (ATEO) (such as acute cerebral circulatory disorders, including transient cerebrovascular ischemic attack, angina, intracardiac thrombi, myocardial infarction, arterial thromboembolism and ischemic colitis) (all severities), venous thromboembolic events (VTEC) (thrombosis deep vein thrombosis and pulmonary embolism) of all degrees of severity, bleeding? Grade 3, sometimes fatal,including gastrointestinal bleeding, hematuria, bleeding after medical procedures; the frequency is unknown - in patients receiving ZaltrapВ® , reported the development of severe intracranial hemorrhage and pulmonary hemorrhage / hemoptysis, including and with a fatal outcome.
The respiratory system: very often - shortness of breath (all severities), epistaxis (all severities), dysphonia (all severities); often - pain in the oropharynx (all severities), rhinorrhea (runny nose was observed only 1-2 severity); rarely - shortness of Grade 3, epistaxis Grade 3, Grade 3 dysphonia, oropharyngeal pain in Grade 3????.
From the digestive system:very often - diarrhea (all severities, and Grade 3?), stomatitis (all severities, and Grade 3?), abdominal pain (all severities), pain in the upper abdomen (all severities); ? Often - 3 abdominal pain severity, pain in the upper abdomen Grade 3;? hemorrhoids (all severities); bleeding from the rectum (all severities); pain in the rectum (all severities); toothache (all severities); aphthous stomatitis (all severities); fistulas (anal, enteric-vesical, outer enteric [enteric-cutaneous], colonic, vaginal, mezhkishechnogo) (all severities); infrequently - the formation of gastrointestinal fistulas Grade 3, punching the walls of the digestive tract of all severities, and 3 degrees of severity?including fatal perforation of the digestive tract wall, bleeding from the rectum? Grade 3, aphthous stomatitis? 3 severity, pain in the rectum? 3 severity.
Skin and subcutaneous tissue disorders: very often - a syndrome of palmar-plantar eritrodizestezii (all severities); often - skin hyperpigmentation (all severities), palmar-plantar eritrodizestezii 3 severity of the syndrome.
From the urinary system: very often - proteinuria (by combined clinical and laboratory data) (all severities), an increase in the concentration of creatinine in serum (all severities); ? often - Grade 3 proteinuria; infrequently - nephrotic syndrome. One patient with proteinuria and increased blood pressure from 611 patients treated by chemotherapy scheme Zaltrap В® / FOLFIRI, was diagnosed thrombotic microangiopathy.
General reaction:very often - asthenic conditions (all severities); feeling of fatigue (and of all severities> Grade 3); often - asthenic conditions (Grade 3?); infrequently - a violation of the healing of wounds (wound dehiscence, anastomotic leak) (all severities, and Grade 3?).
Laboratory and instrumental data: very often - increasing the activity of ACT, ALT (all severities), weight loss (of all degrees of severity); often - ? improving ACT activity, ALT Grade 3, weight loss Grade 3?.
HP frequency in special patient groups
In elderly patients (? 65 years)the incidence of diarrhea, dizziness, fatigue, weight reduction, and dehydration was more than 5% higher than in younger patients. Elderly patients should be monitored carefully for the development of diarrhea and / or a possible dehydration.
In patients with mild impaired kidney function at the time of application of the drug Zaltrap В® HP occurrence frequency was comparable to that of patients without renal dysfunction at the time of application of the drug Zaltrap В® . In patients with moderate to severe renal dysfunctionHP no occurrence from kidneys was generally comparable to that of patients without renal failure, except for increasing the frequency of dehydration (all severities)> 10%.
As with all other protein drugs in aflibercept there is a potential risk of immunogenicity. In general, the results of all cancer clinical trials, none of the patients had high titer antibodies to aflibercept were found.
Post-marketing use of the drug
from the heart: the frequency is unknown - cardiac failure, reduced ejection fraction of the left ventricle.
On the part of the musculoskeletal system and connective tissue:the frequency is unknown - osteonecrosis of the jaw. In patients receiving aflibercept, reported cases of osteonecrosis of the jaw, especially in those patients who have certain risk factors for osteonecrosis of the jaw, such as the use of bisphosphonates and / or invasive dental procedures.
- increased sensitivity to Aflibercept or any of the excipients of the drug Zaltrap В® ;
- arterial hypertension, is not amenable to pharmacological correction;
- chronic heart failure class III-IV (according to NYHA classification);
- severe liver failure (no data on the application);
- ophthalmological application or administration into the vitreous body (due to the properties of the hyperosmotic preparation Zaltrap В® );
- the period of breastfeeding;
- child and adolescence to 18 years (due to lack of sufficient experience in the application).
Contraindications to the use of irinotecan, fluorouracil and calcium folinate cm. In the instructions for use.
- severe renal failure;
- arterial hypertension;
- clinically significant cardiovascular systems (CAD, chronic heart failure I-II class NYHA classification);
- elderly age;
- overall 2 points on a scale to assess the general state of the patient's ECOG (Eastern Cooperative Oncology Group)?.
PREGNANCY AND LACTATION
Data on the use of aflibercept in pregnant women are missing. In experimental studies revealed embryotoxic and teratogenic effects of aflibercept in animals. BecauseAngiogenesis is essential for embryo development, inhibition of angiogenesis when administered drug Zaltrap В® can cause effects which are unfavorable for the development of pregnancy. Application Zaltrap preparation В® pregnancy contraindicated.
Women of childbearing potential should be advised to avoid conception during treatment Zaltrap drug В® . They should be informed of the potential for adverse effects of the drug Zaltrap В® on the fetus.
Women of childbearing potential and fertile males must use effective methods of contraception during treatment and for at least for 6 months after the last dose of the drug.
There is a possibility of impaired fertility in men and women during treatment with aflibercept (based on data obtained from studies conducted on monkeys, males and females that aflibercept caused impaired fertility, fully reversible after 8-18 weeks).
Clinical studies to evaluate the effects of the drug Zaltrap В® on breast milk production, isolation aflibercept breast milk and influence of the drug on infants was conducted.
It is not known whether aflibercept excreted in breast milk in women. However, due to the fact that we can not yet rule out the possibility of penetration of aflibercept in breast milk, and because of the potential for serious adverse reactions that aflibercept can cause in infants, it is necessary or not to breastfeed, or do not use the drug Zaltrap В® ( depending on the importance of the drug to the mother).
APPLICATION FOR FUNCTIONS OF THE LIVER
Official studies on the use of the drug Zaltrap В® in patients with impaired renal function was conducted. Based on clinical data, systemic exposure of aflibercept in patients with renal insufficiency mild to moderate severity was similar to that in patients with normal renal function. Clinical evidence supports that do not require correction aflibercept initial dose in patients with renal insufficiency mild to moderate severity. There is very little data on the drug administration in patients with severe renal impairment, so caution should be exercised when using the drug in these patients
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Formal studies on the drug Zaltrap В® y with hepatic failure patients have been conducted. Based on clinical data, systemic exposure of aflibercept in patients with mild to moderate degrees