Zaltrap^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Sanofi Winthrop Industrie (France)

Manufactured By

Sanofi-Aventis Deutschland, GmbH (Germany)

Contact Information

SANOFI

ATC Code

L01XX44 (Aflibercept)

Active Substance

Aflibercept (Rec.INN registered by WHO)

Dosage Form

Zaltrap®

Concentrate for solution for infusion 25 mg/1 ml: fl. 4 ml 1 or 3 pcs., 8 ml 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion in the form of a clear, colorless or pale yellow liquid.

Excipients: sodium dihydrogen phosphate monohydrate – 0.5774 mg, disodium 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 solution or 0.1M sodium hydroxide solution – to adjust pH to 5.9-6.5, sucrose – 200 mg, polysorbate 20 – 1 mg, water for injections – to 1 ml.

4 ml – colorless glass (type I) vials (1) – cardboard boxes.
4 ml – colorless glass (type I) vials (3) – cardboard boxes.
8 ml – colorless glass (type I) vials (1) – cardboard boxes.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent

Pharmacological Action

Aflibercept is a recombinant hybrid protein consisting of vascular endothelial growth factor (VEGF)-binding portions of the extracellular domains of human VEGF receptor 1 and VEGF receptor 2, fused to the Fc domain of human immunoglobulin G1 (IgG1).

Aflibercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) K-1 cell expression system. Aflibercept is a chimeric glycoprotein with a molecular mass of 97 kDa; glycosylation of the protein adds 15% to the total molecular mass, resulting in a total molecular mass for aflibercept of 115 kDa.

Vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic, and vascular permeability factors for endothelial cells. The action of VEGF-A is mediated through two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, which are expressed on the surface of endothelial cells. PlGF and VEGF-B bind only to the VEGFR-1 receptor tyrosine kinase, which is present not only on the surface of endothelial cells but also on the surface of leukocytes. Excessive activation of these VEGF-A receptors can lead to pathological neovascularization and increased vascular permeability. PlGF is also involved in the development of pathological neovascularization and tumor infiltration by inflammatory cells.

Aflibercept acts as a soluble “receptor trap” that binds to VEGF-A with greater affinity than native VEGF-A receptors; it also binds to the related ligands VEGF-B and PlGF. Aflibercept binds to human VEGF-A, VEGF-B, and PlGF to form stable, inert complexes that lack biological activity. By acting as a “trap” for ligands, aflibercept prevents the binding of endogenous ligands to their corresponding receptors, thereby blocking signaling through these receptors.

Aflibercept blocks the activation of VEGF receptors and the proliferation of endothelial cells, thereby inhibiting the formation of new vessels that supply tumors with oxygen and nutrients.

Aflibercept binds to human VEGF-A (equilibrium dissociation constant (Kd) – 0.5 pM for VEGF-A165 and 0.36 pM for VEGF-A121), to human PlGF (Kd 39 pM for PlGF-2), and to human VEGF-B (Kd 1.92 pM) to form a stable, inert complex lacking measurable biological activity.

Administration of aflibercept to mice with xenografted or allografted tumors resulted in inhibition of growth of various types of adenocarcinoma.

In patients with metastatic colorectal cancer who had previously received oxaliplatin-containing chemotherapy (with or without prior bevacizumab), the Zaltrap^®/FOLFIRI [fluorouracil, irinotecan, calcium folinate] chemotherapeutic regimen demonstrated a statistically significant increase in overall survival compared to the FOLFIRI chemotherapeutic regimen.

In a retrospective analysis of the VELOUR clinical trial, conducted in 482 out of 1226 patients (approximately 39%; 240 patients receiving the Zaltrap^®/FOLFIRI regimen; 242 patients receiving the placebo/FOLFIRI regimen) and based on RAS mutation status, no evidence of heterogeneity in treatment effect was observed (analysis of interaction variables).

In the analysis of overall survival (OS) among patients with wild-type RAS tumors (95% confidence interval (CI)) hazard ratio 0.696 (0.501-0.967), median OS in the Zaltrap^®/FOLFIRI group was 16 months (95% CI: 12.7-22.8) compared to the placebo/FOLFIRI group, where median OS was 11.7 months (10.1-15.9).

In the analysis of OS among patients with mutated RAS tumors (95% CI) hazard ratio 0.926 (0.698-1.23), median OS in the Zaltrap^®/FOLFIRI group was 12.6 months (95% CI: 10.7-14.5) compared to the placebo/FOLFIRI group, where median OS was 11.2 months (9.9-13.8).

Pharmacokinetics

Absorption

In preclinical studies conducted on tumor models, biologically active doses of aflibercept correlated with doses required to achieve circulating free aflibercept concentrations in the systemic bloodstream exceeding the concentrations of circulating VEGF-bound aflibercept. Concentrations of circulating VEGF-bound aflibercept increase with increasing dose until most of the VEGF is bound. Further increases in the aflibercept dose lead to a dose-dependent increase in the concentration of circulating free aflibercept and only a small further increase in the concentration of VEGF-bound aflibercept.

Zaltrap^® is administered to patients at a dose of 4 mg/kg body weight IV every 2 weeks, during which there is an excess of circulating free aflibercept concentration relative to the concentration of VEGF-bound aflibercept.

At the recommended dose of 4 mg/kg body weight once every 2 weeks, free aflibercept concentrations close to C_ss values were achieved by the second treatment cycle with virtually no accumulation (accumulation factor 1.2 at steady state, compared to the free aflibercept concentration at the first administration).

Distribution

The V_d of free aflibercept at steady state is 8 L.

Metabolism

Since Aflibercept is a protein, studies of its metabolism have not been conducted. Aflibercept is expected to be broken down into small peptides and individual amino acids.

Excretion

Circulating free Aflibercept in the systemic bloodstream primarily binds to the VEGF family to form stable inactive complexes.

As with other large proteins, VEGF-bound and free Aflibercept are expected to be gradually eliminated from the systemic bloodstream via other biological mechanisms, such as proteolytic catabolism.

At doses greater than 2 mg/kg, the clearance of free aflibercept was 1 L/day with a terminal T_1/2 of 6 days.

High molecular weight proteins are not excreted by the kidneys, so renal excretion of aflibercept is expected to be minimal.

Linearity/non-linearity of elimination

Due to the target binding of aflibercept to its “target” (endogenous VEGF), free Aflibercept at doses below 2 mg/kg showed a rapid (non-linear) decrease in its systemic concentrations, apparently related to its high-affinity binding to endogenous VEGF. In the dose range from 2 to 9 mg/kg, the clearance of free aflibercept becomes linear, apparently due to non-saturable biological elimination mechanisms, such as protein catabolism.

Pharmacokinetics in special patient groups

Following IV administration of Zaltrap^® at doses of 2 mg/kg, 2.5 mg/kg, 3 mg/kg every 2 weeks to 8 pediatric patients with solid tumors (aged 5 to 17 years), the mean T_1/2 of free aflibercept, determined after the first dose administration, was approximately 4 days (range 3 to 6 days).

Age does not affect the pharmacokinetics of aflibercept.

Despite differences in the clearance of free aflibercept and V_d values between men and women, no gender-related differences in its systemic exposure were observed when administered at a dose of 4 mg/kg body weight.

Body weight influenced the clearance of free aflibercept and its V_d, such that patients with a body weight ≥100 kg showed a 29% increase in systemic exposure to aflibercept.

Race and ethnicity did not affect the pharmacokinetics of aflibercept.

No formal studies have been conducted on the use of Zaltrap^® in patients with hepatic impairment. In patients with mild (total bilirubin concentration in blood ≤1.5×ULN at any AST value) and moderate (total bilirubin concentration in blood >1.5-3×ULN at any AST value) hepatic impairment, no change in aflibercept clearance was detected. There are no data on the pharmacokinetics of aflibercept in patients with severe hepatic impairment (total bilirubin concentration in blood >3×ULN at any AST value).

No formal studies have been conducted on the use of Zaltrap^® in patients with renal impairment. No differences in systemic exposure (AUC) of free aflibercept were found in patients with renal impairment of varying severity when using Zaltrap^® at a dose of 4 mg/kg body weight.

Indications

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

ICD codes

Dosage Regimen

Zaltrap^® is administered intravenously as an infusion over 1 hour followed by administration of the FOLFIRI chemotherapeutic regimen.

The recommended dose of Zaltrap^® in combination with the FOLFIRI chemotherapeutic regimen is 4 mg/kg body weight.

FOLFIRI chemotherapeutic regimen

On day 1 of the cycle – simultaneous IV infusion via a Y-site connector of irinotecan at a dose of 180 mg/m² over 90 minutes and calcium folinate (levo- and dextro-rotatory racemates) at a dose of 400 mg/m² over 2 hours, followed by IV (bolus) administration of fluorouracil at a dose of 400 mg/m², followed by continuous IV infusion of fluorouracil at a dose of 2400 mg/m² over 46 hours.

Chemotherapy cycles are repeated every 2 weeks.

Treatment with Zaltrap^® should be continued until disease progression or the development of unacceptable toxicity.

Recommendations for dosage regimen adjustment/treatment delay

Treatment with Zaltrap^® should be discontinued

• Upon development of severe bleeding;
• Upon development of gastrointestinal wall perforation;
• Upon fistula formation;
• Upon development of hypertensive crisis or hypertensive encephalopathy;
• Upon development of arterial thromboembolic complications;
• Upon development of nephrotic syndrome or thrombotic microangiopathy;
• Upon development of severe hypersensitivity reactions (including bronchospasm, dyspnea, angioedema, anaphylaxis);
• Upon impaired wound healing requiring medical intervention;
• Upon development of posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS).

Treatment with Zaltrap^® should be temporarily suspended at least 4 weeks prior to planned surgery.

For additional information on the toxicity of irinotecan, fluorouracil, and calcium folinate, refer to the respective prescribing information.

Use of the drug in special patient groups

Safety and efficacy in pediatric patients have not been established. In a safety and tolerability dose-escalation study, 21 patients aged 2 to 21 years (mean age 12.9 years) with solid tumors received Zaltrap^® at doses from 2 to 3 mg/kg IV every 2 weeks. Pharmacokinetic parameters of free aflibercept were assessed in 8 of these patients (aged 5 to 17 years). The maximum tolerated dose in the study was 2.5 mg/kg, which was lower than the safe and effective dose for adults with metastatic colorectal cancer.

No dose adjustment of Zaltrap^® is required for elderly patients.

No formal studies have been conducted on the use of Zaltrap^® in patients with hepatic impairment. Based on clinical data, the systemic exposure of aflibercept in patients with mild and moderate hepatic impairment was similar to that in patients with normal liver function. Clinical data suggest that no dose adjustment of aflibercept is required in patients with mild and moderate hepatic impairment. There are no data regarding the use of aflibercept in patients with severe hepatic impairment.

No formal studies have been conducted on the use of Zaltrap^® in patients with renal impairment. Based on clinical data, the systemic exposure of aflibercept in patients with mild and moderate renal impairment was similar to that in patients with normal renal function. Clinical data suggest that no initial dose adjustment of aflibercept is required in patients with mild and moderate renal impairment. There are very limited data on the use of the drug in patients with severe renal impairment, so caution should be exercised when using the drug in such patients.

Rules for solution preparation and infusion administration

The drug should be administered under the supervision of a physician experienced in the use of antineoplastic agents.

Do not administer the undiluted concentrate. Do not administer as an IV push (neither fast nor slow).

Zaltrap^® is not intended for intravitreal administration.

As with all parenteral drugs, the diluted solution of Zaltrap^® should be visually inspected for particulate matter or discoloration prior to administration.

Diluted solutions of Zaltrap^® should be administered using IV infusion sets made from the following materials

• Polyvinyl chloride (PVC) containing diethylhexyl phthalate (DEHP);
• Polyvinyl chloride not containing DEHP but containing trioctyl trimellitate (TOTM);
• Polypropylene;
• Polyethylene internally coated with PVC;
• Polyurethane.

Intravenous infusion sets should contain polyethersulfone filters with a pore diameter of 0.2 µm. Filters made of polyvinylidene fluoride (PVDF) or nylon must not be used.

Due to the lack of compatibility studies, Zaltrap^® must not be mixed with other medicinal products or solvents, except for 0.9% sodium chloride solution and 5% dextrose solution.

Preparation of the Infusion Solution and Handling of the Medicinal Product

The Zaltrap^® infusion solution must be prepared by a healthcare professional under aseptic conditions following safe handling procedures for the medicinal product.

Preparation of the Infusion Solution

• Do not use the vial if the concentrate solution contains undissolved particles or if there is a change in its color.
• Infusion containers made of PVC containing DEHP or polyolefin (without PVC and DEHP) should be used.
• For intravenous infusion only due to the hyperosmolarity (1000 mOsm/kg) of the Zaltrap^® concentrate.
• The medicinal product is not intended for intravitreal injection.
• The Zaltrap^® concentrate must be diluted. The required amount of Zaltrap^® concentrate should be withdrawn and diluted to the required volume with 0.9% sodium chloride injection or 5% dextrose injection. The concentration of aflibercept in the infusion solution after dilution of the Zaltrap^® concentrate should be in the range of 0.6-8 mg/ml.
• From a microbiological point of view, the diluted Zaltrap^® solution should be used immediately; its physical and chemical stability is maintained for up to 24 hours at a temperature of 2°C (35.6°F) to 8°C (46.4°F) and up to 8 hours at a temperature of 25°C (77°F).

Disposal

Zaltrap^® vials are intended for single use only. Any unused medicinal product remaining in the vial must be disposed of in accordance with relevant Russian requirements. Do not re-puncture the vial stopper with a needle after it has already been punctured.

Adverse Reactions

The most frequently occurring adverse reactions (AR) (all grades, with frequency ≥20%), observed at least 2% more often with the Zaltrap^®/FOLFIRI chemotherapy regimen than with the FOLFIRI chemotherapy regimen, were the following ARs (in order of decreasing frequency): leukopenia, diarrhea, neutropenia, proteinuria, increased AST activity, stomatitis, fatigue, thrombocytopenia, increased ALT activity, increased blood pressure, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine concentration, and headache.

The most frequently occurring grade 3-4 ARs (with frequency ≥5%), observed at least 2% more often with the Zaltrap^®/FOLFIRI chemotherapy regimen than with the FOLFIRI chemotherapy regimen, were the following ARs (in order of decreasing frequency): neutropenia, diarrhea, increased blood pressure, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.

Overall, discontinuation of therapy due to adverse events (all grades) was observed in 26.8% of patients receiving the Zaltrap^®/FOLFIRI chemotherapy regimen compared to 12.1% of patients receiving the FOLFIRI chemotherapy regimen. The most frequent ARs leading to therapy discontinuation in ≥1% of patients receiving the Zaltrap^®/FOLFIRI chemotherapy regimen were asthenia/fatigue, infections, diarrhea, dehydration, increased blood pressure, stomatitis, venous thromboembolic complications, neutropenia, and proteinuria.

Dose adjustment of Zaltrap^® (dose reduction and/or missed administration) was performed in 16.7%. Delays of subsequent therapy cycles exceeding 7 days were observed in 59.7% of patients receiving the Zaltrap^®/FOLFIRI chemotherapy regimen compared to 42.6% of patients receiving the FOLFIRI chemotherapy regimen.

Death from causes other than disease progression, observed within 30 days after the last cycle of the studied chemotherapy regimen, was recorded in 2.6% of patients receiving the Zaltrap^®/FOLFIRI chemotherapy regimen and in 1.0% of patients receiving the FOLFIRI chemotherapy regimen. Causes of death in patients receiving the Zaltrap^®/FOLFIRI chemotherapy regimen were: infection (including neutropenic sepsis) in 4 patients; dehydration in 2 patients; hypovolemia in 1 patient; metabolic encephalopathy in 1 patient; respiratory tract diseases (acute respiratory failure, aspiration pneumonia, and pulmonary embolism) in 3 patients; gastrointestinal lesions (duodenal ulcer bleeding, gastrointestinal inflammation, complete intestinal obstruction) in 3 patients; fatal outcome from unknown causes in 2 patients.

Below are the ARs and laboratory abnormalities observed in patients receiving the Zaltrap^®/FOLFIRI chemotherapy regimen, categorized by system organ class according to the MedDRA classification. The ARs listed below were defined as any adverse clinical reactions or laboratory abnormalities with a frequency ≥2% higher (for all-grade ARs) in the aflibercept treatment group compared to the placebo group in the study conducted in patients with metastatic colorectal cancer (mCRC). The intensity of ARs was classified according to the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0.

The frequency of ARs was determined according to the WHO classification as follows: very common (≥10%), common (≥1%-<10%); uncommon (≥0.1%-<1%), rare (≥0.01%-<0.1%), very rare (<0.001%), frequency not known (cannot be estimated from the available data).

Infections and infestations very common – infections (all grades), including urinary tract infections, nasopharyngitis, upper respiratory tract infections, pneumonia, catheter site infections; dental infections; common – neutropenic infections/sepsis (all grades and ≥ grade 3).

Blood and lymphatic system disorders very common – leukopenia (all grades and ≥ grade 3), neutropenia (all grades and ≥ grade 3), thrombocytopenia (all grades); common – febrile neutropenia all grades and ≥ grade 3, thrombocytopenia ≥ grade 3.

Immune system disorders common – hypersensitivity reactions (all grades); uncommon – hypersensitivity reactions ≥ grade 3.

Metabolism and nutrition disorders common – dehydration (all grades and ≥ grade 3).

Nervous system disorders very common – headache (all grades); common – headache ≥ grade 3; uncommon – RPLS (Reversible Posterior Leukoencephalopathy Syndrome).

Cardiac disorders very common – increased blood pressure (all grades) (in 54% of patients who experienced increased blood pressure ≥ grade 3, the increase developed within the first two treatment cycles); bleeding/hemorrhage (all grades), with the most frequent type of bleeding being minor epistaxis (grade 1-2); common – arterial thromboembolic events (ATE) (such as cerebrovascular accidents, including transient ischemic attacks, angina, intracardiac thrombus, myocardial infarction, arterial thromboembolism, and ischemic colitis) (all grades), venous thromboembolic events (VTE) (deep vein thrombosis and pulmonary embolism) all grades, bleeding ≥ grade 3, sometimes fatal, including gastrointestinal bleeding, hematuria, post-procedural bleeding; frequency not known – severe intracranial hemorrhages and pulmonary hemorrhage/hemoptysis, including fatal cases, have been reported in patients receiving Zaltrap^®.

Respiratory, thoracic and mediastinal disorders very common – dyspnea (all grades), epistaxis (all grades), dysphonia (all grades); common – oropharyngeal pain (all grades), rhinorrhea (only grade 1-2 rhinorrhea was observed); uncommon – dyspnea ≥ grade 3, epistaxis ≥ grade 3, dysphonia ≥ grade 3, oropharyngeal pain ≥ grade 3.

Gastrointestinal disorders very common – decreased appetite (all grades), diarrhea (all grades and ≥ grade 3), stomatitis (all grades and ≥ grade 3), abdominal pain (all grades), upper abdominal pain (all grades); common – decreased appetite ≥ grade 3, abdominal pain ≥ grade 3, upper abdominal pain ≥ grade 3, hemorrhoids (all grades), rectal bleeding (all grades), rectal pain (all grades), toothache (all grades), aphthous stomatitis (all grades), fistula formation (anal, enterovesical, external enteric [enterocutaneous], colovaginal, intestinal) (all grades); uncommon – gastrointestinal fistula ≥ grade 3, gastrointestinal perforation all grades and ≥ grade 3, including fatal gastrointestinal perforations, rectal bleeding ≥ grade 3, aphthous stomatitis ≥ grade 3, rectal pain ≥ grade 3.

Skin and subcutaneous tissue disorders very common – palmar-plantar erythrodysesthesia syndrome (all grades); common – skin hyperpigmentation (all grades), palmar-plantar erythrodysesthesia syndrome ≥ grade 3.

Renal and urinary disorders very common – proteinuria (combined clinical and laboratory data) (all grades), increased serum creatinine (all grades); common – proteinuria ≥ grade 3; uncommon – nephrotic syndrome. One patient with proteinuria and increased blood pressure out of 611 patients treated with the Zaltrap^®/FOLFIRI chemotherapy regimen was diagnosed with thrombotic microangiopathy.

General disorders and administration site conditions very common – asthenic conditions (all grades), feeling of tiredness (all grades and ≥ grade 3); common – asthenic conditions (≥ grade 3); uncommon – impaired wound healing (wound dehiscence, anastomotic insufficiency) (all grades and ≥ grade 3).

Investigations very common – increased AST, ALT activity (all grades), weight loss (all grades); common – increased AST, ALT activity ≥ grade 3, weight loss ≥ grade 3.

Frequency of ARs in Special Patient Groups

In elderly patients (≥65 years), the frequency 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.

In patients with mild renal impairment at the start of Zaltrap^® treatment, the frequency of ARs was comparable to that in patients without renal impairment at the start of Zaltrap^® treatment. In patients with moderate and severe renal impairment, the occurrence of non-renal ARs overall was comparable to that in patients without renal failure, except for an increased frequency of dehydration (all grades) by >10%.

Immunogenicity

As with all other protein medicinal products, aflibercept has a potential risk of immunogenicity. Overall, across all oncology clinical studies, no patient was found to have a high titer of antibodies to aflibercept.

Post-marketing Experience

Cardiac disorders frequency not known – cardiac failure, decreased left ventricular ejection fraction.

Musculoskeletal and connective tissue disorders frequency not known – osteonecrosis of the jaw. Cases of osteonecrosis of the jaw have been reported in patients taking Aflibercept, particularly in those who had certain risk factors for osteonecrosis of the jaw, such as the use of bisphosphonates and/or invasive dental procedures.

Contraindications

• Severe bleeding;
• Arterial hypertension not controlled by medication;
• Chronic heart failure class III-IV (according to NYHA classification);
• Severe hepatic impairment (no data on use);
• Ophthalmic use or intravitreal injection (due to the hyperosmotic properties of Zaltrap^®);
• Pregnancy;
• Breastfeeding period;
• Children and adolescents under 18 years of age (due to insufficient experience of use);
• Hypersensitivity to aflibercept or any of the excipients of the medicinal product.

For contraindications to the use of irinotecan, fluorouracil, and calcium folinate, refer to their respective prescribing information.

With caution

• Severe renal impairment;
• Arterial hypertension;
• Clinically significant cardiovascular diseases (coronary artery disease, chronic heart failure class I-II according to NYHA classification);
• Elderly age;
• General status ≥2 points on the ECOG (Eastern Cooperative Oncology Group) performance status scale.

Use in Pregnancy and Lactation

There are no data on the use of aflibercept in pregnant women. Experimental studies have revealed embryotoxic and teratogenic effects of aflibercept in animals. Since angiogenesis is important for embryonic development, inhibition of angiogenesis by Zaltrap^® administration may cause adverse effects on pregnancy outcome. The use of Zaltrap^® during pregnancy is contraindicated.

Women of childbearing potential should be advised to avoid becoming pregnant during treatment with Zaltrap^®. They should be informed about the potential adverse effects of Zaltrap^® on the fetus.

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

There is a possibility of impaired fertility in men and women during treatment with aflibercept (based on data from studies in monkeys, where Aflibercept caused fertility impairments in males and females, fully reversible after 8-18 weeks).

No clinical studies have been conducted to evaluate the effect of Zaltrap^® on breast milk production, the excretion of aflibercept in breast milk, or the effect of the medicinal product on breastfed infants.

It is not known whether Aflibercept is excreted in human milk. However, because the possibility of aflibercept passing into breast milk cannot be ruled out, and due to the potential for serious adverse reactions that Aflibercept may cause in breastfed infants, a decision must be made either to discontinue breastfeeding or not to use Zaltrap^® (depending on the importance of the drug to the mother).

Use in Hepatic Impairment

The use of the medicinal product is contraindicated in severe hepatic impairment (no data on use).

Clinical data suggest that no dose adjustment of aflibercept is required in patients with mild and moderate hepatic impairment.

Use in Renal Impairment

The medicinal product should be used with caution in patients with severe renal impairment.

Clinical data suggest that no initial dose adjustment of aflibercept is required in patients with mild and moderate renal impairment.

Pediatric Use

The use of the medicinal product is contraindicated in children and adolescents under 18 years of age (due to insufficient experience of use).

Geriatric Use

No dose adjustment of the medicinal product is required for elderly patients.

Elderly patients (≥65 years) have an increased risk of developing diarrhea, dizziness, asthenia, weight loss, and dehydration. To minimize the risk, such patients require careful medical monitoring for early detection and treatment of signs and symptoms of diarrhea and dehydration.

Special Precautions

Before starting treatment and before the start of each new cycle of aflibercept treatment, a complete blood count with differential is recommended.

Upon the first occurrence of neutropenia ≥ grade 3, therapeutic use of G-CSF should be considered; in addition, in patients who have an increased risk of neutropenic complications, prophylactic administration of G-CSF is recommended.

Patients should be continuously monitored for signs and symptoms of gastrointestinal and other severe bleeding. Aflibercept must not be administered to patients with severe bleeding.

Cases of cardiac failure and decreased left ventricular ejection fraction have been reported in patients treated with Zaltrap^®. Patients should be continuously monitored for signs and symptoms of cardiac failure and decreased left ventricular ejection fraction. In patients who develop cardiac failure or decreased left ventricular ejection fraction, the use of Zaltrap^® should be discontinued.

Patients should be monitored for signs and symptoms of gastrointestinal perforation. In case of gastrointestinal perforation, treatment with aflibercept should be discontinued.

If fistulae occur, treatment with aflibercept should be discontinued.

During treatment with aflibercept, blood pressure should be monitored every 2 weeks, including before aflibercept administration, or more frequently as clinically indicated during aflibercept treatment. If blood pressure increases during aflibercept treatment, appropriate antihypertensive therapy should be administered and blood pressure should be regularly monitored. If blood pressure is excessively elevated, aflibercept treatment should be suspended until blood pressure is reduced to target values, and in subsequent cycles the dose of aflibercept should be reduced to 2 mg/kg. In case of hypertensive crisis or hypertensive encephalopathy, administration of Aflibercept should be discontinued.

Caution should be exercised when administering Zaltrap^® to patients with clinically significant cardiovascular disease, such as coronary artery disease and heart failure. Clinical data on the administration of Zaltrap^® to patients with heart failure NYHA class III and IV are lacking.

In the event of a patient developing ATEO, treatment with aflibercept should be discontinued.

Before each administration of aflibercept, the level of proteinuria should be determined using a dipstick test or by measuring the urine protein/creatinine ratio to detect the development or increase of proteinuria. Patients with a urine protein/creatinine ratio >1 should undergo measurement of protein in a 24-hour urine collection.

If nephrotic syndrome or thrombotic microangiopathy develops, treatment with aflibercept should be discontinued.

In the event of a severe hypersensitivity reaction (including bronchospasm, dyspnea, angioedema, and anaphylaxis), treatment should be discontinued and appropriate therapy aimed at managing these reactions should be initiated.

In the event of a moderate hypersensitivity reaction to Aflibercept (including skin flushing, rash, urticaria, pruritus), treatment should be temporarily suspended until the reaction resolves. If clinically necessary, corticosteroids and/or antihistamines can be used to manage these reactions. In subsequent cycles, premedication with corticosteroids and/or antihistamines may be considered. Caution should be exercised when resuming treatment in patients who have previously experienced hypersensitivity reactions, as some patients have experienced recurrent hypersensitivity reactions despite prophylaxis, including the use of corticosteroids.

The use of aflibercept should be suspended for at least 4 weeks following major surgical procedures and until the surgical wound is fully healed. For minor surgical interventions, such as central venous catheter placement, biopsy, tooth extraction, treatment with aflibercept may be initiated/resumed after the surgical wound is fully healed. In patients with impaired wound healing requiring medical intervention, the use of aflibercept should be interrupted.

PRES may manifest as altered mental status, seizures, nausea, vomiting, headaches, and visual disturbances. The diagnosis of PRES is confirmed by brain MRI. In patients with PRES, the use of aflibercept should be discontinued.

Elderly patients (≥65 years) have an increased risk of developing diarrhea, dizziness, asthenia, weight loss, and dehydration. To minimize the risk, such patients require careful medical monitoring for the early detection and treatment of signs and symptoms of diarrhea and dehydration.

Patients with a performance status of ≥2 (on the five-point [0-4] ECOG [Eastern Cooperative Oncology Group] performance status scale) or those with serious comorbidities may have a higher risk of adverse clinical outcomes and require careful medical monitoring for the early detection of clinical deterioration.

Zaltrap^® is a hyperosmotic solution whose composition is incompatible with intraocular administration. Zaltrap^® must not be administered intravitreally.

Effect on the Ability to Drive and Use Machines

No studies on the effect of Zaltrap^® on the ability to drive vehicles or engage in other potentially hazardous activities have been conducted. If patients experience symptoms affecting vision, concentration, and slowing psychomotor reactions, patients should be advised to refrain from driving vehicles and other potentially hazardous activities.

Overdose

There is no safety data for Zaltrap^® at doses exceeding 7 mg/kg every 2 weeks or 9 mg/kg every 3 weeks. The most frequently reported adverse reactions observed with these dosing regimens were similar to the adverse reactions observed with the use of the drug at therapeutic doses.

Treatment There is no specific antidote. In case of overdose, patients require supportive care, specifically monitoring and treatment of arterial hypertension and proteinuria. The patient should be under close medical supervision to detect and manage any adverse reactions.

Drug Interactions

No formal drug interaction studies with Zaltrap^® have been conducted.

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

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

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature between 2°C (35.6°F) and 8°C (46.4°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.