Zaltrap concentrate solution for infusion 25 mg/ml, 8 ml

Pharmic action: Aflibercept is produced using recombinant DNA technology in Chinese hamster ovary (CHO) K-1 cells in a mammalian expression system.

Pharmgroup: Antitumor drugs.
Mechanism of action.
Vascular endothelial growth factors A and B (VEGF-A, VEGF-B) and placental growth factor (PGF) are members of the VEGF family of angiogenic factors that can function as potential mitogenic, chemotactic and vascular permeability factors for endothelial cells. FRES-A acts through two receptor tyrosine kinases, FRES receptor 1 and FRES receptor 2, present on the surface of endothelial cells. PFR and FRES-B bind only FRES receptor 1, which is also present on the surface of leukocytes. Hyperactivation of these receptors by FRES-A can lead to pathological neovascularization and increased vascular permeability. FRP is also associated with pathological neovascularization and inflammatory cell recruitment to tumors.
Aflibercept, also known in the scientific literature as FRPP trap, is a recombinant fusion protein composed of FRPP-binding fragments of the extracellular domains of human FRPP receptors 1 and 2 fused to the Fc-fragment of human immunoglobulin G1. Aflibercept is produced by recombinant DNA technology in Chinese hamster ovary (CHO) K-1 cells in a mammalian expression system. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and is glycosylated to form an additional 15% total molecular weight, resulting in a total molecular weight of 115 kDa.
Aflibercept acts as a soluble trap receptor that binds FRES-A with greater affinity than its native receptors as well as the related FRP and FRP-B ligands. Acting as a ligand trap, aflibercept prevents endogenous ligands from binding to their related receptors and thus blocks the receptor-mediated signaling pathway.
Aflibercept blocks activation of FRES receptors and endothelial cell proliferation, inhibiting the growth of new blood vessels that supply oxygen and nutrients to tumors.
Aflibercept binds human FRES-A (equilibrium dissociation constant KD of 0.5 pM for FRES-A165 and 0.36 pM for FRES-A121), with human PFR (KD of 39 pM for PFR-2) and with human FRES-B (KD of 1.92 pM), forming a stable, inert complex that shows no biological activity.
Pharmacodynamic effects.
Application of aflibercept in mice with xenograft or allograft tumors suppressed the growth of various forms of cancer.
Clinical efficacy and safety.
The efficacy and safety of Zaltrap were evaluated in a randomized, double-blind, placebo-controlled trial involving patients with metastatic colorectal cancer who had previously received oxaliplatin-containing treatment, with or without prior use of bevacizumab. A total of 1,226 patients (1:1) were randomized to receive either Zaltrap (N=612; 4 mg/kg as an intravenous infusion for 1 hour on day 1) or placebo (N=614) in combination with 5-fluorouracil plus irinotecan [FOLFIRI regimen included intravenous infusion of irinotecan 180 mg/m2 for 90 minutes and intravenous infusion of folinic acid (dl-(racemic)) 400 mg/m2 for 2 hours simultaneously on day 1 using a Y-port infusion system, followed by an intravenous bolus of 5-fluorouracil (5-FU) 400 mg/m2, followed by a continuous intravenous infusion of 5-FU 2 400 mg/m2 for 46 hours]. Treatment courses were repeated every 2 weeks. Patients did not receive treatment after disease progression or development of unacceptable toxicity. The main expected efficacy outcome was overall survival. Allocation into treatment groups was stratified by assessment of general status according to SBI criteria (0 versus 1 versus 2) and according to prior therapy with bevacizumab (yes or no).
Demographic data in treatment groups (age, race, general status according to SBI criteria, and bevacizumab use status) were balanced. Of the 1,226 patients randomized in the study, the mean age was 61 years, 58.6% were male, 97.8% had general status (GS) status according to SOG criteria 0 or 1 at baseline, and 2.2% had general status (GS) status according to SOG criteria 2 at baseline. Among the 1,226 randomized patients, 89.4% and 90.2% of patients who received placebo in combination with FOLFIRI and Zaltrap® in combination with FOLFIRI, respectively, had previously received combined oxaliplatin-containing chemotherapy for treatment of metastatic/progressive forms.
Approximately 10% of patients (10.4% and 9.8% of patients treated with placebo in combination with FOLFIRI and Zaltrap® in combination with FOLFIRI, respectively) had previously received adjuvant oxaliplatin-containing chemotherapy and had a positive trend by 6 months or no later than completion of adjuvant chemotherapy. Oxaliplatin-containing regimens were used in combination with bevacizumab in 373 patients (30.4%).
Overall survival (OS) and progression-free survival (PFS) by stratification factors were performed. A quantitatively lower treatment effect of Zaltrap in combination with FOLFIRI on the OV score was reported in patients with prior bevacizumab use compared with patients without prior bevacizumab exposure and no evidence of treatment effect heterogeneity (non-significant interaction test).
Analysis was also performed on the OV and VBP scores according to the general status according to SBI criteria. The hazard ratio (95% CI) of overall survival was 0.77 (0.64 to 0.93) for general status according to SBI criteria 0, and 0.87 (0.71 to 1.06) for general status according to SBI criteria 1. The hazard ratio (95% CI) of disease progression-free survival was 0.76 (0.63 to 0.91) for general status status under SBI criteria 0, and 0.75 (0.61 to 0.92) for general status under SBI criteria 1.
Other subgroup analyses of overall survival and progression-free survival according to age (In a subgroup analysis of overall survival, benefits comparable to the general population were observed in patients aged < 65 years and aged ≥65 years who received Zaltrap® in combination with FOLFIRI.
Pharmacokinetics: The pharmacokinetic properties described below are largely derived from a population pharmacokinetic analysis with data from 1,507 patients with various types of advanced malignancies.
Absorption.
In preclinical tumor models, biologically active doses of aflibercept were in line with those required to generate circulating concentrations of free aflibercept in excess of FRES-linked aflibercept (vascular endothelial growth factor).
Circulating concentrations of FRES-bound aflibercept increase with the dose of aflibercept until most of the FRES is bound. Further increases in the dose of aflibercept resulted in dose-dependent increases in circulating free aflibercept concentrations, but only small further increases in FRES-linked aflibercept.
In patients, Zaltrap® was administered at a dose of 4 mg/kg intravenously every two weeks, during which time there was an excess of free circulating aflibercept over FRES-linked aflibercept.
With the recommended dose regimen of 4 mg/kg every two weeks, by the second treatment cycle, free aflibercept concentrations were approaching steady state levels with virtually no cumulation (steady state accumulation ratio of 1.2 compared to the first application).
Distribution.
The volume of distribution of free aflibercept at equilibrium is approximately 8 liters.
Biotransformation.
No metabolic studies have been conducted with aflibercept because it is a protein. Aflibercept is thought to break down into small peptides and individual amino acids.
Excretion.
Free aflibercept is primarily excreted by binding to endogenous FRES, forming a stable, inert complex. As with other large proteins, both free and bound aflibercept are thought to be excreted more slowly by other biological mechanisms such as proteolytic catabolism.
At doses greater than 2 mg/kg, the clearance of free aflibercept was approximately 1.0 L/day with a final half-life of 6 days.
High molecular weight proteins are not excreted by the renal route, for this reason, excretion of aflibercept by the kidneys is assumed to be minimal.
Linearity/nonlinearity.
Because of the target organ-mediated distribution of the drug, free aflibercept exhibits faster (nonlinear) clearance at doses less than 2 mg/kg, most likely due to the high affinity of aflibercept binding to endogenous FRES. Linear clearance observed at doses ranging from 2 to 9 mg/kg is likely due to unsaturated biological mechanisms of excretion, such as protein catabolism.
Other special populations:
Older patients.
Age had no effect on free aflibercept pharmacokinetics.
Race.
Population analysis showed no differences in effects in patients of different races.
Gender.
Gender was the most significant covariate to explain variability in individual free aflibercept clearance values and clearance volume 15.5% greater and distribution volume 20.6% greater in men than in women. These differences did not affect exposure because of dose assignment based on weight and lack of dose modification based on sex.
Weight.
Weight had an effect on free aflibercept clearance and volume of distribution, leading to a 29% increase in aflibercept exposure in patients weighing ≥100 kg.
Impaired liver function.
No formal studies have been conducted with Zaltrap in patients with impaired liver function. In a population pharmacokinetic analysis with data from 1,507 patients with various types of advanced malignancies receiving Zaltrap® with or without chemotherapy, 63 patients with mild hepatic impairment (total bilirubin >1.0 x-1.5 x IUH (upper limit of normal) and any AST level) and 5 patients with moderate liver function impairment (total bilirubin >1.5 x-3 x IUH and any AST level) were treated with Zaltrap. In these patients with mild to moderate hepatic impairment, there was no effect on aflibercept clearance. No data are available for patients with severe hepatic impairment (total bilirubin >3 x HGH and any AST level).
Renal dysfunction.
No formal studies have been conducted with Zaltrap in patients with impaired renal function. A population pharmacokinetic analysis was performed using data from 1,507 patients with various types of advanced malignancies receiving Zaltrap® with or without chemotherapy. This population included: 549 patients with mild renal impairment (creatinine clearance (CLcr) between 50-80 ml/min), 96 patients with moderate renal impairment (CLcr between 30-50 ml/min), and 5 patients with severe renal impairment (CLcr

Indications

In combination with chemotherapy with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) is indicated in adults with metastatic colorectal cancer (MCDC) with resistance or signs of progression after an oxaliplatin-containing chemotherapy regimen.

Active ingredient

Composition

1 ml:
– aflibercept 4 mg
active ingredients: sodium phosphate monohydrate (E339), sodium hydrophosphate heptahydrate (E339), citric acid monohydrate (E330), sodium citrate dihydrate (E331), granulated sodium chloride, sucrose, Polysorbate 20 (E433), hydrochloric acid 36% (E507), sodium hydroxide (E524), water for injection.
Description. Liquid, colourless or pale yellow transparent liquid, free from mechanical impurities.

How to take, the dosage

The recommended dose of Zaltrap administered by intravenous infusion over 1 hour is 4 mg/kg body weight followed by the FOLFIRI regimen. Considered as a single course of treatment.
The FOLFIRI regimen includes an intravenous infusion of irinotecan 180 mg/m2 for 90 minutes and an intravenous infusion of folinic acid (dl-(racemic)) 400 mg/m2 for 2 hours simultaneously on day 1 using a Y-port infusion system, followed by an intravenous bolus of 5-fluorouracil (5-FU) 400 mg/m2, followed by a continuous intravenous infusion of 5-FU 2 400 mg/m2 for 46 hours.
The course of treatment is repeated every 2 weeks.
In case of disease progression or development of unacceptable toxicity, Zaltrap treatment should be discontinued.
Dose modification.
Zaltrap use should be discontinued for the following reasons (see “Special Indications”):
– severe bleeding
– gastrointestinal perforation
– fistula formation
– hypertension that is not sufficiently controlled by hypotensive therapy, the appearance of a hypertensive crisis or hypertensive encephalopathy
– arterial thromboembolic events – grade 4 venous thromboembolic events (including pulmonary embolism)
– nephrotic syndrome or thrombotic microangiopathy (TMA)
– severe hypersensitivity reactions (including bronchospasm, dyspnea, angioneurotic edema and anaphylaxis) (see “Contraindications and Special Indications)
– Wound healing disorders requiring medical intervention
– Reversible posterior encephalopathy syndrome (RPE) (also known as reversible posterior leukoencephalopathy syndrome (RPLES))
Zaltrap should be temporarily suspended for at least 4 weeks before elective surgical intervention (see “Special Indications”).

Suspension of Zaltrap in combination with FOLFIRI or dose modification

Neutropenia or thrombocytopenia (see “Special Guidelines. “

Treatment with Zaltrap in combination with FOLFIRI should be stopped until the neutrophil count is > 1.5 x 109/L, or the platelet count is > 75 x 109/L.

Febrile neutropenia or neutropenic sepsis

The irinotecan dose should be reduced by 15-20% for subsequent courses of treatment

. If relapsed, a further 20% reduction in 5-FU bolus and infusion doses should be considered on subsequent courses of treatment

If relapsed after reducing irinotecan and 5-FU doses, a reduction in the Zaltrap dose to 2 mg/kg may be considered.

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

Hypersensitivity reactions to Zaltrap of mild to moderate degree (including skin redness, rash, urticaria and pruritus) (see “Special Precautions”)

Until the reaction passes, the infusion should be temporarily suspended. If clinically indicated, corticosteroids and/or antihistamines may be prescribed.

In subsequent courses of treatment, pretreatment with corticosteroids and/or antihistamines may be considered.

Serious hypersensitivity reactions (including bronchospasm, dyspnea, angioedema and anaphylaxis) (see Contraindications and Special Precautions)

The treatment with Zaltrap in combination with FOLFIRI should be stopped and appropriate drug therapy applied.

Suspension of treatment with Zaltrap or dose modification

Hypertension (see “Special Precautions”)

The use of Zaltrap should be temporarily suspended until control of hypertension is achieved.

If significant or severe hypertension relapses despite optimal therapy, Zaltrap® should be suspended until hypertension control is achieved and the dose should be reduced to 2 mg/kg in subsequent courses of treatment.

Proteinuria (see Special Instructions)

The use of Zaltrap® should be suspended if proteinuria is > 2 grams within 24 hours, and resumed when proteinuria is < 2 grams within 24 hours.

In case of relapse, treatment should be suspended until levels are < 2 grams within 24 hours, and then doses should be reduced to 2 mg/kg.

FOLFIRI dose modification when treated in combination with Zaltrap

Severe stomatitis and palpebral erythrodysesthesia syndrome

The 5-FU bolus dose and the infusion dose should be reduced by 20%.

Severe diarrhea

The dose of irinotecan should be reduced by 15-20%.

If severe diarrhea recurs on a subsequent course of treatment, the 5-FU bolus dose and the infusion dose should be reduced by 20%.

If severe diarrhea persists when doses of both drugs are reduced, FOLFIRI treatment should be discontinued.

If necessary, antidiarrheal medications may be used and rehydration may be performed.

For information on toxicity associated with irinotecan, 5-FU, or folinic acid, see the relevant drug summary available.
Special Populations:
Elderly Patients.
In the baseline metastatic colorectal cancer (MCRC) study, 28.2% of patients were aged ≥65 years and < 75 years, and 5.4% of patients were aged ≥75 years. Dose adjustments of Zaltrap were not required in elderly patients.
Liver dysfunction.
No formal studies using Zaltrap involving patients with impaired liver function have been performed (see “Pharmacokinetics”). Clinical data suggest that there is no need to change the dose of aflibercept in patients with mild to moderate hepatic impairment. There are no data regarding the use of aflibercept in patients with severe hepatic impairment.
Renal dysfunction.
No formal studies have been conducted with Zaltrap in patients with impaired renal function (see “Pharmacokinetics”). Clinical data suggest that in patients with mild to moderate renal dysfunction the initial dose of aflibercept does not need to be changed. There are limited data regarding use in patients with severe renal dysfunction; therefore, these patients should be treated with caution.
Pediatric population.
There is no relevant experience with the use of Zaltrap for the indication of metastatic colorectal cancer in the pediatric population.

Method of administration.
Zaltrap® is intended for use only as an intravenous infusion for 1 hour. Due to the hyperosmolality (1,000 mOsmol/kg) of Zaltrap® concentrate, undiluted Zaltrap® concentrate is not administered as an intravenous stream or bolus. Zaltrap® is not used as an intravitreal injection (see “Contraindications” and “Special Indications”).
Each bottle of concentrate for preparation of solution for infusion is intended for single use only (single dose).
Diluted Zaltrap solutions should be administered by infusion sets with a 0.2 micron polyethersulfone filter.
Infusion sets should be made of the following materials:
– polyvinyl chloride (PVC) containing bis(2-ethylhexyl)phthalate (diethylhexyl phtholate DEGF)
– PVC without DEGF containing trioctyltrimellitrate (TOTM)
– polypropylene
– PVC-encapsulated polyethylene
– polyurethane
Filters made of polyvinylidene fluoride (PVDF) or nylon are not used.
Compatibility.
In the absence of compatibility studies, the drug should not be mixed with other drugs or solvents except those listed in “Precautions.”
Precautions taken prior to administration and handling
Zaltrap® is a sterile and apyrogenic concentrate without preservatives, therefore the infusion solution must be prepared by a healthcare professional using safe handling procedures and aseptic techniques.
Care should be taken when handling Zaltrap, including handling sealed products, the use of personal protective equipment (such as gloves) and during preparation procedures.
Preparation of infusion solution.
– Inspect the bottle of Zaltrap before use. The concentrate for solution preparation should be clear and should not contain solids.
– Based on the required dose for the patient take the required volume of Zaltrap® concentrate from the bottle. More than one bottle may be required for preparation of the solution for infusion.
– Dilute it with sodium chloride solution 9 mg/ml (0.9%) or 5% glucose solution for infusion to the volume required for injection. The concentration of the finished Zaltrap® solution for intravenous infusion should remain between 0.6 mg/ml and 8 mg/ml of aflibercept.
– Infusion bags of PVC containing DEGF or infusion bags of polyolefin are used.
– The diluted solution should be inspected for solids and color changes before use. If any discoloration or if solids are observed, the reconstituted solution should be discarded.
– The Zaltrap vial is intended for single use. Do not reinsert the needle into the vial after the initial puncture. Any unused concentrate must be discarded.
Disposal.
Any unused medication or waste must be disposed of according to local requirements.

Interaction

Pharmacokinetic analysis of the population and interstudy comparisons did not reveal any pharmacokinetic interaction between aflibercept and the FOLFIRI regimen.

Special Instructions

Aflibercept should not be used in patients with severe bleeding (see “Dosage and administration”).

Elevated risk of bleeding, including severe and sometimes fatal hemorrhagic events, reported in patients receiving aflibercept (see “Side effects”).
Patients should be monitored for signs and symptoms of gastrointestinal bleeding and other severe bleeding.
Thrombocytopenia has been reported in patients receiving Zaltrap® in combination with FOLFIRI.
Monitoring of total blood counts with platelet counts is recommended at baseline, before each course of treatment with aflibercept, and on clinical indications. Treatment with Zaltrap in combination with FOLFIRI should be withheld until the platelet count is > 75 x 109/L (see “Dosage and administration”).
Gastrointestinal perforation
Gastrointestinal perforation events have been reported in patients treated with aflibercept, including fatal gastrointestinal perforation (see “Side Effects”).
Patients should be monitored for signs and symptoms of gastrointestinal perforation. In patients with gastrointestinal perforation, treatment with aflibercept should be discontinued (see “Administration and Doses”).
Fistula formation.
Patients receiving aflibercept have developed fistulas, including gastrointestinal and non-gastrointestinal fistulas (see “Side Effects”).
In patients who have developed a fistula, treatment with aflibercept should be discontinued (see “Administration and Doses”). “Dosage and administration).
Hypertension.
An increased risk of grade 3-4 hypertension (including hypertension and one case of hypertension) has been observed in patients receiving Zaltrap® in combination with FOLFIRI (see “Side Effects”).
Prior to starting aflibercept, prior hypertension should be appropriately controlled. If hypertension cannot be adequately controlled, treatment with aflibercept should not be initiated. It is recommended that blood pressure be monitored every two weeks, including periods prior to each use of the medication or as clinically indicated during treatment with aflibercept. In the case of hypertension during treatment with aflibercept, blood pressure should be monitored with appropriate hypotensive therapy, and blood pressure should be monitored regularly. In cases of medically significant relapse or severe hypertension developing despite optimal therapy, treatment with aflibercept should be suspended until hypertension is controlled and in subsequent treatment cycles the dose of aflibercept should be reduced to 2 mg/kg. If hypertension cannot be properly controlled with appropriate hypotensive therapy, if a hypertensive crisis or hypertensive encephalopathy occurs, aflibercept should be discontinued completely (see Dosage and administration).
Hypertension may exacerbate an underlying cardiovascular disease. Caution should be exercised when treating patients with a history of clinically significant cardiovascular disease, such as coronary heart disease or chronic heart failure, with Zaltrap. Zaltrap should not be treated in patients with chronic heart failure functional class III or IV according to the New York Heart Association (NYHA) classification of chronic heart failure.

Thrombotic and embolic events:
Arterial thromboembolic events (ATS).
ATS (including transient ischemic attack, acute cerebral circulation disorder, angina, intracardiac thrombus, myocardial infarction, arterial embolism, and ischemic colitis) have been observed in patients treated with aflibercept (see “Side effects).
In patients who experience ATS, treatment with aflibercept should be discontinued (see “Administration and Doses”).
Venous thromboembolic events (VTE).
VTE, including deep vein thrombosis (DVT) and pulmonary embolism (rarely fatal), have been reported in patients treated with aflibercept (see “Dosage”). “Side effects).
In patients with life-threatening (grade 4) thromboembolic events (including pulmonary embolism), Zaltrap should be discontinued (see “Administration and Doses”). For clinical indications, patients with grade 3 DVT should be treated with anticoagulants, and treatment with aflibercept should be continued. In case of relapse, despite appropriate anticoagulation, treatment with aflibercept should be discontinued. Patients with thromboembolic events of grade 3 or lower should be closely monitored.
Proteinuria.
Severe proteinuria, nephrotic syndrome and thrombotic microangiopathy (TMA) have been observed in patients treated with aflibercept (see “Side effects).
Prior to each use of aflibercept, proteinuria should be monitored by urinalysis using test strips and/or protein/creatinine ratios for the course or worsening of proteinuria. In patients with a proteinuria test strip result ≥ 2+ or protein/creatinine ratio > 1, a daily (24-hour) urinalysis should be performed.
Aflibercept use should be suspended if proteinuria is ≥ 2 grams/24 hours and restarted if proteinuria is < 2 grams/24 hours. If relapsed, use should be suspended until < 2 grams/24 hours and the dose reduced to 2 mg/kg. In patients who develop nephrotic syndrome or TMA, treatment with aflibercept should be discontinued (see Administration and Doses).
Neutropenia and neutropenic complications.
A greater incidence of neutropenic complications (febrile neutropenia and neutropenic infection) has been observed in patients receiving Zaltrap® in combination with FOLFIRI (see “Side effects”).
Monitoring of general blood count with leukocyte counts is recommended at baseline and before each course of treatment with aflibercept. The use of Zaltrap treatment in combination with FOLFIRI should be stopped until the neutrophil count is > 1.5 x 109/L (see “Administration and Doses”). When neutropenia of grade ≥ 3 first appears in patients who may have an increased risk of neutropenic complications, therapeutic use of G-CSF and secondary prophylaxis may be considered.
Diarrhea and dehydration.
A greater incidence of severe diarrhea has been observed in patients receiving Zaltrap® in combination with FOLFIRI (see “Adverse Effects”).
If necessary, modification of the dose of FOLFIRI regimen (see “Dosage and administration”), use of anti-diarrheal medications and rehydration is performed.
Hypersensitivity reactions.
In a baseline study involving patients with MCRD, severe hypersensitivity reactions were reported in patients receiving Zaltrap® in combination with FOLFIRI (see “Side effects”). “
In case of severe hypersensitivity reactions (including bronchospasm, dyspnea, angioedema and anaphylaxis), aflibercept should be discontinued and appropriate therapeutic measures taken (see “Dosage and Administration. “
In case of hypersensitivity reactions to Zaltrap (mild to moderate, including skin redness, rash, urticaria, and itching), the use of aflibercept should be temporarily suspended until the reaction subsides.
Treatment with corticosteroids and/or antihistamines may be initiated if clinically indicated.
Prior treatment with corticosteroids and/or antihistamines may be considered for subsequent courses of treatment (see Administration and Doses). Caution should be exercised when re-treating patients with pre-existing hypersensitivity reactions because, despite prophylaxis including corticosteroids, recurrent hypersensitivity reactions have been observed in some patients.
Wound healing disorders.
In animal models, aflibercept slowed wound healing.
Aflibercept should be suspended at least 4 weeks prior to elective surgical intervention.
It is recommended that Aflibercept not be initiated for at least 4 weeks after extensive surgery and until the postoperative wound has completely healed. For minor surgical interventions, such as central venous access port, biopsy, and tooth extraction, aflibercept may be initiated/resumed as soon as the surgical wound is completely healed. In patients with impaired wound healing requiring medical intervention, aflibercept should be discontinued (see Dosage and Administration).
Reversible Posterior Encephalopathy Syndrome (RPE).
RPE may present as altered mental status, epileptic seizures, nausea, vomiting, headache or visual disturbance. The diagnosis of POPE is confirmed by magnetic resonance imaging (MRI).
Aflibercept should be discontinued in patients who develop POPE (see Contraindications).
Impaired renal function.
Very limited data are available for patients with severe impairment treated with aflibercept.
No dose adjustment of aflibercept is required (see “Dosage and administration,” “Side effects,” and “Pharmacokinetics”).
General condition and comorbidities.
Patients with an overall Eastern Cooperative Oncology Group (ECG) score of ≥ 2 or who have significant comorbidities may be at greater risk for non-significant clinical outcomes, such patients should be closely monitored for premature clinical deterioration.
Intravitreal Use Not Specified in Instructions for Medical Use of the Drug
Zaltrap® is a hyperosmotic solution not intended to interact with the intraocular medium. Zaltrap® should not be used as an intravitreal injection (see Contraindications).
Pediatric population.
Safety in children has not been established.
Other special populations:
Elderly patients.
In a baseline study of 611 MCRI patients receiving Zaltrap® in combination with FOLFIRI, 172 (28.2%) were aged ≥65 years and < 75 years, and 33 (5.4%) were aged ≥75 years. In all likelihood, older patients (aged ≥65 years) were more likely to develop adverse reactions. The incidence of diarrhea, dizziness, asthenia, weight loss, and dehydration was ≥5% higher in elderly patients compared with younger patients. Older patients should be monitored more closely for the development of diarrhea and potential dehydration (see Special Instructions).
Renal dysfunction.
In three placebo-controlled phase III clinical trials in patients with mild renal dysfunction at baseline (N = 352) receiving Zaltrap®, adverse reactions were comparable to patients without renal failure (N = 642). A limited number of patients with moderate/severe renal impairment at baseline (N = 49) were treated with Zaltrap. In these patients, nonrenal events were generally comparable between patients with impaired renal function and patients without impaired renal function, with the exception of a greater frequency of > 10% occurrence of dehydration events (all grades) (see “Special Instructions”).
Immunogenicity.
As with all therapeutic proteins, there is potential for immunogenicity with Zaltrap.
Overall, a similar incidence of low ATP titer (after baseline) was observed in all clinical oncology studies in the drug antibody (ATP) analysis in both patients receiving placebo and patients receiving Zaltrap® (3.3% and 3.8%, respectively). No patient had high titers of antibodies to aflibercept. Seventeen (17) patients receiving Zaltrap® (1.6%) and two (2) patients receiving placebo (0.2%) also showed a positive response in the neutralizing antibody assay. In the baseline study of patients with MCDR, positive responses in the ATP assay were observed at higher levels in patients receiving placebo in combination with FOLFIRI [18/526 (3.4%)] than when treated with Zaltrap in combination with FOLFIRI [8/521 (1.5%)]. In the baseline study of patients with MCDR, positive responses in the neutralizing antibody assay were also at higher levels in patients receiving placebo in combination with FOLFIRI [2/526 (0.38%)] than Zaltrap in combination with FOLFIRI [1/521 (0.19%)]. No effect on the pharmacokinetic profile of aflibercept was observed in patients who responded positively in the immunogenicity assay.
Given the similar results of the ATP assay in patients receiving placebo or Zaltrap®, the actual incidence of immunogenicity with Zaltrap appears to be overstated based on these assays.
Immunogenicity data is highly dependent on assay sensitivity and specificity. In addition, several factors, such as sample handling, timing of sample collection, concomitant medications, and underlying disease, may influence the observed frequency of antibody positivity in the assay. For these reasons, a comparison of the incidence of antibodies to Zaltrap with the incidence of antibodies to other drugs may not be reliable.
Women of childbearing age/contraception in men and women.
Women of childbearing age should be advised to avoid pregnancy while using Zaltrap and to inform them of the potential risk to the fetus. Women of childbearing age and fertile men should use effective contraception during treatment and for at least 6 months after the last dose.
Pregnancy.
There are no data on the use of aflibercept in pregnant women. Preclinical studies have shown reproductive toxicity. Because angiogenesis is critical to fetal development, delayed angiogenesis after administration of Zaltrap may result in adverse events in pregnancy.
Zaltrap® should be used only if, during pregnancy, the potential benefits justify the potential risks. If a patient becomes pregnant while using Zaltrap, she should be informed of the potential risk to the fetus.
Lactation.
No studies have been conducted to evaluate the effects of Zaltrap on milk production, its penetration into milk, or its effect on the infant during breastfeeding.
It is unknown whether aflibercept penetrates into human milk. The risk to newborns/infants cannot be ruled out. The decision as to whether to stop lactation or discontinue Zaltrap/stop treatment with Zaltrap must be made based on the benefit of breastfeeding for the child and the benefit of treatment for the woman.
Fertility.
Based on preclinical studies, male and female fertility are likely at risk during treatment with aflibercept.
Specific effects of the medication on driving or potentially dangerous machinery.
Zaltrap® has no or negligible effect on the ability to drive or operate machinery. If patients experience symptoms that affect vision, concentration or their ability to react, they should be advised not to drive or operate machinery (see “Side effects”).

Contraindications

Side effects

The most common adverse reactions (all grades, frequency of occurrence ≥20%) reported at least 2% more frequently in Zaltrap® in combination with FOLFIRI compared to placebo in combination with FOLFIRI were (in decreasing order of occurrence) Leukopenia, diarrhea, neutropenia, proteinuria, increased aspartate aminotransferase (AST), stomatitis, fatigue, thrombocytopenia, increased alanine aminotransferase (ALT), hypertension, weight loss, decreased appetite, nosebleed, abdominal pain, dysphonia, increased serum creatinine and headache (see Table 1).The safety of Zaltrap in combination with FOLFIRI was evaluated in 1,216 patients previously treated for metastatic colorectal cancer, of whom 611 patients were treated with Zaltrap 4 mg/kg every two weeks (one course of treatment) and 605 patients received placebo in combination with FOLFIRI.
Patients received an average of 9 courses of Zaltrap in combination with FOLFIRI.
The most common grade 3-4 reactions (incidence ≥ 5%) reported at least 2% more frequently in the Zaltrap® regimen in combination with FOLFIRI compared with placebo in combination with FOLFIRI were (in decreasing order of incidence): neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria and asthenia (see Table 1).
The most common adverse reactions leading to complete discontinuation of treatment in ≥1% of patients receiving Zaltrap® in combination with FOLFIRI were vascular disorders (3.8%), including hypertension (2.3%), infections (3.4%), asthenia/fatigue (1.6% 2.1%), diarrhea (2.3%), dehydration (1%), stomatitis (1.1%), neutropenia (1.1%), proteinuria (1.5%), and pulmonary embolism (1.1%).
Adverse reactions and abnormal laboratory parameters reported in patients receiving Zaltrap® in combination with FOLFIRI compared to patients receiving placebo in combination with FOLFIRI are listed in Table 1 according to the Medical Dictionary of Regulatory Activity organ system class and frequency categories. The adverse reactions in Table 1 are defined as either an adverse clinical reaction or a deviation from normal laboratory values occurring with a frequency ≥ 2% greater (all degrees) in the aflibercept treatment group compared to the placebo treatment group in the ICRD trials, including those reactions that do not meet this limit but were comparable to the class of drugs that block vascular endothelial growth factor inhibitor and were observed in any study with aflibercept. The severity of adverse reactions is categorized according to the National Cancer Research Institute Common Toxicity Criteria Assessment Scale, version 3.0 (grade ≥ 3 = G ≥ 3). Frequency of occurrence is based on all degrees and is defined as occurring: Very common (≥ 1/10); common (≥ 1/100 to Adverse reactions reported in patients receiving Zaltrap® in combination with FOLFIRI in the ICDR study
Table #1

Class of organ system

Unwanted reaction

Category of frequency of occurrence

/p>

All degrees

Degree ≥3

Infectious and parasitic diseases

Very common

Infection (1)/p>

Infection (1)

Often

Neutropenic infection/sepsis (1)

Urinary tract infection

/p>

Nasopharyngitis

Neutropenic infection/sepsis (1)

Infrequent

Urinary tract infection

/p>

Blood and lymphatic system disorders

Very common

Leukopenia (2)

Neutropenia (1), (2)

Thrombocytopenia (2)

Leukopenia (2)

Neutropenia (2)

Often

Febrile neutropenia

Febrile neutropenia

Thrombocytopenia (2)

Immune system disorders/p>

Often

Hypersensitivity (1)

Metabolic and nutritional disorders

Very often

/p>

Decreased appetite

Weight loss

Often

Dehydration (1)

Dehydration (1)

/p>

Decreased appetite

Weight loss

Nervous system disorders

Very often

Headache

Often

Headache

Infrequent

POPE (1), (4)

POPE (1), (4)

/p>

Vascular disorders

Very often

Hypertension (1)

Bleeding (1)

p> Hypertension

Often

Arterial thromboembolism (1)

Venous thromboembolism (1)

Arterial thromboembolism (1)

Venous thromboembolism (1)

bleeding (1)

Respiratory, chest and mediastinal disorders

Very common

Dyspnea

Nasal bleeding

Nasal bleeding/p>

Dysphonia

Oropharyngeal pain

Oropharyngeal pain

/p>

Rhinorrhea

Infrequent

Dyspnea

Nasal bleeding

Dysphonia

Oropharyngeal pain

Gastrointestinal tract disorders/p>

Very common

Diarrhea (1)

Stomatitis

Abdominal pain

Upper abdominal pain

Diarrhea (1)

Stomatitis

Often

Rectal bleeding

Fistula (1)

Aphthous stomatitis

Hemorrhoids

Proctalgia

Toothache

Abdominal pain

Upper abdominal pain

Infrequent

Gastrointestinal perforation (1)

Gastrointestinal perforation (1)

Rectal bleeding

Fistula (1)

Aphthous stomatitis

Proctalgia

Liver and biliary tract disorders

Very common

Elevated AST (2)

/p>

Elevated ALT (2)

Often

Elevated AST (2)

Elevated ALT (2)

p> Skin and subcutaneous tissue disorders

Very common

Palmodermal erythrodysesthesia syndrome/p>

Often

Hyperpigmentation of the skin

Personal palmar erythrodysaesthesia syndrome

Infrequent

p> Wound healing disorders (1)

Wound healing disorders (1)

River and urinary tract disorders/p>

Very common

Proteinuria (1), (3)

Increased serum creatinine

Frequently

p> Proteinuria (1), (3)

Infrequent

Nephrotic syndrome (1)

Thrombotic microangiopathy (1)

Nephrotic syndrome (1)

Thrombotic microangiopathy (1)

General disorders and disorders at the site of administration

/p>

Very common

Asthenic conditions

Asthenic conditions

Note: Adverse reactions are listed using the MEDDRA13 version of the Medical Dictionary of Regulatory Activity.1 and are graded according to the National Cancer Research Institute Common Toxicity Criteria Assessment Scale, version 3.0.

(1) See “Description of Individual Adverse Reactions” in this section

(2) Based on laboratory values (percentages are for patients who participated in laboratory studies)

(3) Clinical and laboratory data collection

(4) Not reported in the ICRR study; however, POPE was reported in patients from other studies treated with aflibercept in monotherapy and in combination with chemotherapy other than FOLFIRI.

In the baseline ICRR study, anemia, nausea, vomiting, constipation, alopecia, elevated alkaline phosphatase and hyperbilirubinemia occurred in ≥20% of patients. They were comparable between groups. The difference between groups for the Zaltrap® regimen in combination with FOLFIRI did not exceed an incidence of ≥ 2%.

Description of Individual Adverse Reactions:
Bleeding.
Patients receiving Zaltrap® have an increased risk of bleeding, including severe and sometimes fatal hemorrhagic events. In a baseline study of patients with MCDR, bleeding/bleeding episodes (all grades) were reported in 37.8% of patients receiving Zaltrap® in combination with FOLFIRI, compared to 19.0% of patients receiving placebo in combination with FOLFIRI. The most frequently reported bleeding event was minor (grade 1-2) nasal bleeding, occurring in 27.7% of patients receiving Zaltrap® in combination with FOLFIRI. Grade 3-4 bleeding, including gastrointestinal bleeding, hematuria, and postoperative bleeding was reported in 2.9% of patients receiving Zaltrap® in combination with FOLFIRI, compared with 1.7% of patients receiving placebo in combination with FOLFIRI. In other studies, severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis, including death, have occurred in patients receiving Zaltrap® (see “Special Indications”).
Gastrointestinal perforation.
Gastrointestinal perforation including fatal gastrointestinal perforation has been reported in patients receiving Zaltrap®. In a baseline study of patients with MCDR, gastrointestinal perforation (all grades) was reported in 3 of 611 patients (0.5%) receiving Zaltrap® in combination with FOLFIRI and in 3 of 605 patients (0.5%) receiving placebo in combination with FOLFIRI. Grade 3-4 gastrointestinal perforations occurred in all 3 patients (0.5%) receiving Zaltrap® in combination with FOLFIRI and in 2 patients (0.3%) receiving placebo in combination with FOLFIRI. In all three placebo-controlled phase III clinical trials (populations with colorectal cancer, pancreatic cancer, and lung cancer), the incidence of gastrointestinal perforation (all grades) was 0.8% in patients receiving Zaltrap® and 0.3% in patients receiving placebo. Grade 3-4 gastrointestinal perforation events occurred in 0.8% of patients receiving Zaltrap® and 0.2% of patients receiving placebo (see “Special Instructions”).
Fistula formation.
Fistula formation has occurred in patients receiving Zaltrap®, including gastrointestinal and non-gastrointestinal. In a baseline study of patients with ICPD, fistulas (anal, intestinal-ureteric, intestocutaneous, colorectal-vaginal, and intestinal fistulas) were reported in 9 of 611 patients (1.5%) receiving Zaltrap® in combination with FOLFIRI and in 3 of 605 patients (0.5%) receiving placebo in combination with FOLFIRI. Grade 3 gastrointestinal fistula occurred in 2 patients receiving Zaltrap® (0.3%) and 1 patient receiving placebo (0.2%). In all three placebo-controlled phase III clinical trials (populations with colorectal cancer, pancreatic cancer, and lung cancer), the incidence of fistula (all grades) was 1.1% in patients receiving Zaltrap® and 0.2% in patients receiving placebo. Grade 3-4 fistulas occurred in 0.2% of patients receiving Zaltrap® and 0.1% of patients receiving placebo (see “Special Instructions”).
Hypertension.
In a baseline study of patients with ICPD, hypertension (all grades) was reported in 41.2% of patients receiving Zaltrap® in combination with FOLFIRI and in 10.7% of patients receiving placebo in combination with FOLFIRI. An increased risk of grade 3-4 hypertension (including hypertension and one case of hypertension) was observed in patients receiving Zaltrap® in combination with FOLFIRI. Grade 3 hypertension (requiring correction of existing hypotensive therapy or treatment with more than one drug) was reported in 1.5% of patients receiving placebo in combination with FOLFIRI and 19.1% of patients receiving Zaltrap® in combination with FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with Zaltrap in combination with FOLFIRI.
Among patients receiving Zaltrap® in combination with FOLFIRI who developed grade 3-4 hypertension, 54% had hypertension within the first two courses of treatment (see “Special Instructions”).
Thrombotic and Embolic Events:
Arterial thromboembolic events (ATE).
In a baseline study of patients with MCDR, ATS (including transient ischemic attack, acute cerebral circulation disorder, angina, intracardiac thrombus, myocardial infarction, arterial embolism, and ischemic colitis) were reported in 2.6% of patients receiving Zaltrap® in combination with FOLFIRI and in 1.5% of patients receiving placebo in combination with FOLFIRI. Grade 3-4 events occurred in 11 patients (1.8%) receiving Zaltrap® in combination with FOLFIRI and in 3 patients (0.5%) receiving placebo in combination with FOLFIRI. In three placebo-controlled phase III clinical trials (populations with colorectal cancer, pancreatic cancer, and lung cancer), the incidence of ATS (all grades) was 2.3% in patients receiving Zaltrap® and 1.7% in patients receiving placebo. Grade 3-4 ATS occurred in 1.7% of patients receiving Zaltrap® and 1.0% of patients receiving placebo (see “Special Instructions”).
Venous thromboembolic events.
Venous thromboembolic events (VTE) include deep vein thrombosis and pulmonary embolism. In a baseline study of patients with MCDR, VTS of all degrees occurred in 9.3% of patients receiving Zaltrap® in combination with FOLFIRI and in 7.3% of patients receiving placebo in combination with FOLFIRI. Grade 3-4 VTS occurred in 7.9% of patients receiving Zaltrap® in combination with FOLFIRI and in 6.3% of patients receiving placebo in combination with FOLFIRI. Pulmonary embolism occurred in 4.6% of patients receiving Zaltrap® in combination with FOLFIRI and 3.5% of patients receiving placebo in combination with FOLFIRI. In three placebo-controlled phase III clinical trials (populations with colorectal cancer, pancreatic cancer and lung cancer), patients receiving Zaltrap® and patients receiving placebo had a 7.1% incidence of VTS (all grades).
Proteinuria.
In a baseline study of patients with ICPD, proteinuria (based on clinical and laboratory data) was reported in 62.2% of patients receiving Zaltrap® in combination with FOLFIRI, compared with 40.7% of patients receiving placebo in combination with FOLFIRI. Grade 3-4 proteinuria occurred in 7.9% of patients receiving Zaltrap® in combination with FOLFIRI compared to 1.2% of patients receiving placebo in combination with FOLFIRI. Nephrotic syndrome occurred in 2 patients (0.5%) receiving Zaltrap® in combination with FOLFIRI compared to none in patients receiving placebo in combination with FOLFIRI. One patient with manifestations of proteinuria and hypertension treated with Zaltrap in combination with FOLFIRI was diagnosed with thrombotic microangiopathy (TMA). In three placebo-controlled phase III clinical trials (populations with colorectal cancer, pancreatic cancer and lung cancer), the incidence of nephrotic syndrome was 0.5% in patients receiving Zaltrap® and 0.1% in patients receiving placebo (see “Special Instructions”).
Neutropenia and neutropenic complications.
In a baseline study of patients with MCDR, neutropenia (all grades) was reported in 67.8% of patients receiving Zaltrap® in combination with FOLFIRI and in 56.3% of patients receiving placebo in combination with FOLFIRI. Grade 3-4 neutropenia was observed in 36.7% of patients receiving Zaltrap® in combination with FOLFIRI compared to 29.5% of patients receiving placebo in combination with FOLFIRI. The most common grade 3-4 neutropenic complication in 4.3% of patients receiving Zaltrap® in combination with FOLFIRI was febrile neutropenia, compared to 1.7% of patients receiving placebo in combination with FOLFIRI. Neutropenic infections/sepsis of grade 3-4 occurred in 1.5% of patients receiving Zaltrap® in combination with FOLFIRI and 1.2% of patients receiving placebo in combination with FOLFIRI (see “Special Instructions”).
Infections.
Infections, including urinary tract infections, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and dental infections, occurred with greater frequency in patients receiving Zaltrap® in combination with FOLFIRI (46.2%, all grades; 12.3%, 3-4 degrees) than patients receiving placebo in combination with FOLFIRI (32.7%, all degrees; 6.9%, 3-4 degrees).
Diarrhea and dehydration.
In a baseline study of patients with MCDR, diarrhea (all degrees) was seen in 69.2% of patients receiving Zaltrap® in combination with FOLFIRI and 56.5% of patients receiving placebo in combination with FOLFIRI. Dehydration (all degrees) was observed in 9.0% of patients receiving Zaltrap® in combination with FOLFIRI and 3.0% of patients receiving placebo in combination with FOLFIRI. Grade 3-4 diarrhea was reported in 19.3% of patients receiving Zaltrap® in combination with FOLFIRI compared to 7.8% of patients receiving placebo in combination with FOLFIRI. Grade 3-4 dehydration was reported in 4.3% of patients receiving Zaltrap® in combination with FOLFIRI compared to 1.3% of patients receiving placebo in combination with FOLFIRI (see “Cautionary Note”).
Hypersensitivity reactions.
In a baseline study of patients with MCDR, severe hypersensitivity reactions were reported in 0.3% of patients receiving Zaltrap® in combination with FOLFIRI and in 0.5% of patients receiving placebo in combination with FOLFIRI (see “Special Instructions. “
Wound healing disorders.
Treatment with Zaltrap is associated with possible impairment of wound healing (wound dilation, anastomosis failure). In a baseline study of patients with MCDR, impaired wound healing was reported in 3 patients (0.5%) receiving Zaltrap® in combination with FOLFIRI and in 5 patients (0.8%) receiving placebo in combination with FOLFIRI. Grade 3 wound healing impairment was reported in 2 patients (0.3%) receiving Zaltrap® in combination with FOLFIRI and none in patients receiving placebo in combination with FOLFIRI. In three placebo-controlled phase III clinical trials (populations with colorectal cancer, pancreatic cancer and lung cancer) the incidence of wound healing impairment (all grades) was 0.5% in patients receiving Zaltrap® and 0.4% in patients receiving placebo.
Grade 3-4 wound healing impairment occurred in 0.2% of patients receiving Zaltrap® and was absent in patients receiving placebo (see “Special Indications”).
Reversible Posterior Encephalopathy Syndrome (RPE).
RPE was not reported in the baseline phase III study involving patients with ICPD. In other studies, POPE has been reported in patients receiving Zaltrap® in monotherapy (0.5%) and in combination with other chemotherapy (see “Special Indications”).
Additional adverse reactions and laboratory abnormalities reported with a difference of ≥ 5% (all grades) in patients receiving Zaltrap® in combination with FOLFIRI compared to placebo in combination with FOLFIRI
The following adverse reactions and abnormal laboratory parameters were reported with a difference of ≥ 5% (all degrees) in patients receiving Zaltrap® in combination with FOLFIRI compared to placebo in combination with FOLFIRI (in order of decreasing frequency of occurrence) Leukopenia (78.3% vs. 72.4% all degrees; 15.6% vs. 12.2% 3-4 degrees), AST elevation (57.5% vs. 50.2% all degrees; 3.1% vs. 1.7% 3-4 degrees), stomatitis (50.1% vs. 32.9% all degrees; 12.8% vs. 4.6% 3-4 degrees), fatigue (47.8% vs. 39.0% all degrees; 12.6% vs. 7.8% 3-4 degrees), thrombocytopenia (47.4% vs. 33.8% all degrees; 3.3% vs. 1.7% 3-4 degrees), elevated ALT levels (47.3% vs. 37.1% all degrees; 2.7% vs. 2.2% 3-4 degrees), decreased appetite (31.9% vs. 23.8% all degrees 3.4% vs. 1.8% 3-4 degrees), weight loss (31.9% vs. 14.4% all degrees; 2.6% vs. 0.8% 3-4 degrees), dysphonia (25.4% vs. 3.3% all degrees; 0.5% vs. 0 3-4 degrees), headache (22.3% vs. 8.8% all degrees; 1.6% vs. 0.3% 3-4 degrees), asthenia (18.3% vs. 13.2% all degrees 5.1% versus 3.0% to 3-4 degrees), palpebral erythrodysesthesia syndrome (11.0% versus 4.3% all degrees; 2.8% versus 0.5% 3-4 degrees), and skin hyperpigmentation (8.2% versus 2.8% all degrees; 0 versus 0 3-4 degrees).

Overdose

There is no specific antidote used for Zaltrap overdose. In cases of overdose, appropriate supportive measures should be used, in particular monitoring and treatment of hypertension and proteinuria. Patients should be closely monitored by a physician to monitor for any adverse reactions (see Adverse Effects).There is no information on the safety of aflibercept administered at doses greater than 7 mg/kg every 2 weeks or 9 mg/kg every 3 weeks. The most commonly observed adverse reactions at these doses were similar to those observed at the therapeutic dose.