Vinorelbine "ebewe"

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VINORELBINE «EBEWE» (VINORELBIN «EBEWE»)

Composition:

Active substance: vinorelbine;

1 ml of concentrate contains vinorelbine 10 mg (as vinorelbine tartrate 13.85 mg);

Excipient: water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear solution, colorless to pale yellow.

Pharmacotherapeutic group. Antineoplastic agents. Vinca alkaloids and their analogues.

ATC code L01C A04.

Pharmacological Properties

Pharmacodynamics

Vinorelbine is an antineoplastic agent belonging to the vinca alkaloid family; however, unlike other vinca alkaloids, the catharanthine moiety of the vinorelbine molecule is structurally modified. At the molecular level, vinorelbine affects the dynamic equilibrium of tubulin in the microtubular apparatus of the cell. Vinorelbine inhibits tubulin polymerization and binds predominantly to mitotic microtubules, while effects on axonal microtubules occur only at high drug concentrations. The induction of tubulin spiralization by vinorelbine is weaker than that observed with vincristine.

The drug blocks mitosis at the G2-M phase, leading to cell death during interphase or subsequent mitosis.

Pharmacokinetics

Distribution. The volume of distribution at steady state of vinorelbine is large, averaging 21.2 L/kg (range: 7.5–39.7 L/kg), indicating extensive tissue distribution throughout the body. Plasma protein binding is low (13.5%). However, vinorelbine binds well to blood cellular elements, particularly platelets (78%). It is significantly taken up by the lungs, where, according to surgical biopsy data, concentrations up to 300 times higher than in blood serum have been observed. Vinorelbine is not detected in central nervous system tissues. The pharmacokinetics of intravenously administered vinorelbine up to a dose of 45 mg/m² has been shown to be linear.

Biotransformation. All metabolites of vinorelbine are formed via the CYP3A4 isoenzyme of the cytochrome P450 system, except for 4-O-deacetylvinorelbine, which is formed via carboxylesterases. 4-O-deacetylvinorelbine is the only active metabolite and the primary metabolite detected in blood. Sulfate and glucuronide conjugates have not been identified.

Elimination. The mean terminal half-life is approximately 40 hours. Vinorelbine clearance is high, approaching the rate of hepatic blood flow, and averages 0.72 L/h/kg (range: 0.32–1.26 L/h/kg). Less than 20% of an intravenous dose is excreted by the kidneys, primarily in unchanged form. The majority of the drug is excreted in bile as unchanged vinorelbine and its metabolites.

Pharmacokinetics in Special Patient Populations

Patients with Impaired Renal or Hepatic Function

Pharmacokinetics of vinorelbine has not been studied in patients with renal impairment; however, dose reductions are not required in such patients due to the low renal excretion of vinorelbine.

Pharmacokinetic studies of vinorelbine in women with metastatic breast cancer involving the liver showed that changes in mean clearance occurred only when more than 75% of the liver was affected.

In a phase I dose-escalation pharmacokinetic study, six oncology patients with moderate hepatic impairment (bilirubin levels no more than 2 times above the upper limit of normal (ULN) and transaminase levels no more than 5 times above ULN), receiving vinorelbine doses up to 25 mg/m² body surface area, and eight oncology patients with severe hepatic impairment (bilirubin levels more than 2 times above ULN and transaminase levels more than 5 times above ULN), receiving vinorelbine doses up to 20 mg/m² body surface area, showed that mean total clearance of vinorelbine was comparable to that in patients with normal liver function. Thus, the pharmacokinetics of vinorelbine are not altered in patients with moderate or severe hepatic impairment. However, as a precautionary measure, it is recommended to reduce the dose to 20 mg/m² body surface area and to systematically monitor hematological parameters in patients with severe hepatic impairment.

Elderly Patients

A study in elderly patients (over 70 years of age) with non-small cell lung cancer showed that the pharmacokinetics of vinorelbine are not altered in older patients. However, due to the frailty of elderly patients, caution is required when increasing vinorelbine doses.

Pharmacokinetic/Pharmacodynamic Relationships

A strong relationship has been demonstrated between systemic exposure to vinorelbine and reductions in leukocyte or polymorphonuclear cell counts.

Clinical characteristics.

Indications.

• For the treatment of non-small cell lung cancer (stage 3–4).
• For the treatment of metastatic breast cancer (stage 4) as monotherapy, when anthracycline- or taxane-based therapies are ineffective or cannot be used.

Contraindications.

Intrathecal administration of the drug is strictly prohibited.

• Hypersensitivity to vinorelbine or to other vinca alkaloids, or to any of the excipients.
• Neutrophil count <1,500/mm³ (1.5×10⁹/L), or severe current or recently resolved infections (within the last 2 weeks).
• Platelet count less than 100,000/mm³ (100×10⁹/L).
• Concomitant use with yellow fever vaccine.
• Use in fertile women who are not using effective contraceptive methods.
• Breastfeeding period.

Special safety precautions.

Handling of the medicinal product must be performed only by trained personnel.

Protective clothing must be used (disposable gloves, masks, goggles, gowns, and caps or coveralls).

It is extremely important to avoid contact of the drug with the eyes: if the drug is aerosolized under pressure, there is a risk of severe irritation and even corneal ulceration. In case of contact with eyes, they must be immediately and thoroughly rinsed with 0.9% sodium chloride solution.

In case of spillage or splashing of vinorelbine solutions, the contaminated area should be wiped and cleaned.

After completing work with the drug, the work area must be thoroughly cleaned and hands and face washed.

Unused drug residues, as well as all instruments and materials that have come into contact with vinorelbine during preparation and administration of infusion solutions or during cleanup, must be disposed of according to approved procedures for cytotoxic waste disposal.

Excreta and vomit from patients should be handled with caution.

Pregnant healthcare workers must not handle the drug.

Interaction with other medicinal products and other forms of interaction.

Interactions typical for all cytotoxic agents.

In oncological diseases, the risk of thrombosis is increased, and patients are often prescribed anticoagulants. Due to high intra-individual variability in coagulation status in cancer patients, as well as the potential interaction between oral anticoagulants and anticancer agents, INR (International Normalized Ratio) should be monitored more frequently.

Contraindicated combinations.

Yellow fever vaccine: risk of developing fatal generalized infection.

Undesirable combinations.

Live attenuated vaccines: risk of generalized infection with potentially fatal outcome, especially in patients with immunodeficiency due to underlying disease. Inactivated vaccines should be used if available (e.g., poliomyelitis vaccine).

Phenytoin: risk of increased seizures, as anticancer agents reduce phenytoin absorption in the gastrointestinal tract, and also risk of increased toxicity or reduced efficacy of cytotoxic agents due to phenytoin-induced enhancement of hepatic metabolism.

Combinations requiring attention.

Cyclosporine and tacrolimus: possible excessive immunosuppression with risk of lymphoproliferative disorders.

Interactions typical for vinca alkaloids.

Undesirable combinations.

itraconazole: increased neurotoxicity of vinca alkaloids due to reduced hepatic metabolism.

Combinations requiring special precautions.

HIV protease inhibitors: possible increased toxicity of antimicrotubule agents due to reduced hepatic metabolism caused by protease inhibitors. In such cases, regular clinical monitoring of the patient is required and, if necessary, dose adjustment of antimicrotubule agents.

Combinations requiring attention.

mitomycin C: increased risk of pulmonary toxicity with mitomycin C and vinca alkaloids. Concurrent use of this combination may lead to bronchospasm and dyspnea; in rare cases, interstitial pneumonitis.

Since vinca alkaloids are substrates for P-glycoprotein, caution is required when co-administering strong inhibitors or inducers of this transport protein.

Interactions specific to vinorelbine.

When vinorelbine is used in combination with other myelosuppressive agents, bone marrow suppression may be enhanced.

Since the CYP3A4 isoenzyme plays a major role in vinorelbine metabolism, concomitant use of strong inhibitors of this isoenzyme (such as ketoconazole, itraconazole) may increase vinorelbine blood concentrations, while concomitant use of strong CYP3A4 inducers (such as rifampicin, phenytoin) may decrease them.

In combination chemotherapy with vinorelbine and cisplatin, no mutual pharmacokinetic interactions have been observed over several treatment cycles. However, the incidence of granulocytopenia is higher with this combination than with vinorelbine monotherapy.

In phase I clinical studies of intravenous vinorelbine administered in combination with lapatinib, an increased incidence of grade 3–4 neutropenia was observed. In this study, the recommended dose of intravenous vinorelbine on a 3-week schedule (days 1 and 8) was 22.5 mg/m² in combination with a daily dose of 1000 mg lapatinib. This combination should be used with caution.

Special precautions for use.

Special warnings.

Vinorelbine should be administered under the supervision of a physician experienced in the use of chemotherapy.

The medicinal product is intended for intravenous use only.

During treatment with vinorelbine, hematological parameters must be monitored regularly (prior to each administration, hemoglobin levels, leukocyte and platelet counts in peripheral blood should be determined). The dose of the drug is determined according to the hematological profile. The main dose-limiting adverse effect of vinorelbine therapy is neutropenia. It is non-cumulative in nature. The lowest neutrophil count occurs 7–14 days after drug administration, after which values rapidly normalize (within 5–7 days). Administration of vinorelbine should be postponed if neutrophil counts fall below 1,500/mm³ (1.5×10⁹/L) and platelet counts fall below 100,000/mm³ (100×10⁹/L), until hematological parameters return to normal.

If a patient presents signs or symptoms suggestive of infection, immediate investigation is required.

Precautionary measures.

Particular caution is recommended in patients with a history of ischemic heart disease.

The pharmacokinetics of vinorelbine are not altered in patients with moderate or severe hepatic insufficiency. Dose adjustment recommendations for these patient groups are provided in the section "Dosage and administration". Vinorelbine should not be administered concurrently with radiotherapy, or if the radiation field includes the liver.

Due to the minimal renal excretion of vinorelbine, there are no pharmacokinetic grounds for dose reduction in patients with impaired renal function.

This agent is specifically contraindicated for use with the yellow fever vaccine and is generally not recommended in combination with live attenuated vaccines.

Caution is required when co-administering strong inhibitors or inducers of the CYP3A4 isoenzyme of the cytochrome P450 system (see section "Interaction with other medicinal products and other forms of interaction"). Combined use of vinorelbine with drugs such as phenytoin (as with all cytotoxic agents) or itraconazole (as with all vinca alkaloids) is not recommended.

Contact of vinorelbine with the eyes should be avoided; there is a risk of severe irritation or even corneal ulceration if the drug is sprayed under pressure. In such cases, the eye should be immediately irrigated with 0.9% sodium chloride solution and an ophthalmologist should be consulted.

Interstitial lung disease has been more frequently reported in patients of Japanese ethnicity. Therefore, careful monitoring is required in this patient population.

Women of childbearing potential must use effective contraception throughout the entire treatment period and for at least 7 months after completion of therapy, and must immediately inform their physician if pregnancy occurs.

After dilution in 0.9% sodium chloride solution or 5% glucose solution, chemical and physical stability has been demonstrated at concentrations of 0.43 mg/mL and 2.68 mg/mL for 48 hours at 2–8°C in a light-protected environment. From a microbiological standpoint, the infusion solution should be administered immediately after preparation. If not used immediately, storage duration and conditions must be monitored by medical personnel. Generally, storage should not exceed 24 hours at 2–8°C, unless the solution was prepared under controlled and validated aseptic conditions.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of vinorelbine in pregnant women are insufficient. In reproductive studies in animals, vinorelbine was embryotoxic, fetotoxic, and teratogenic. Vinorelbine is contraindicated during pregnancy.

Vinorelbine may be used in pregnant women only under life-threatening circumstances, when the expected benefit to the mother outweighs the potential risk to the fetus.

The physician must inform the pregnant patient about the possible adverse effects of treatment and obtain her written consent for vinorelbine administration. Fetal development must be closely monitored during treatment.

Fertile women receiving vinorelbine should use effective contraceptive methods and inform their physician if pregnancy occurs. If pregnancy occurs during treatment, the patient should be informed about the risks to the unborn child and close monitoring should be established. Genetic counseling should also be considered.

Period of breastfeeding. It is unknown whether vinorelbine passes into breast milk. Excretion of vinorelbine into milk has not been studied in animal experiments. Breastfeeding must be discontinued prior to starting vinorelbine therapy.

Fertility. Vinorelbine may have genotoxic effects. Men receiving vinorelbine therapy are advised to avoid fathering a child during treatment and for at least 4 months after completion of therapy. Women of childbearing potential must use effective contraception throughout the entire treatment period and for at least 7 months after completion of therapy, and must immediately inform their physician if pregnancy occurs. Due to the potential for irreversible infertility caused by vinorelbine, consultation with a specialist regarding sperm cryopreservation is recommended.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of vinorelbine on the ability to drive or operate machinery have not been conducted; however, based on the pharmacodynamic profile of vinorelbine, such effects are not expected. Nevertheless, caution is advised during vinorelbine therapy due to the possible occurrence of certain adverse effects that may impair attention and reaction ability (e.g., nausea, fever, or pain).

Administration and Dosage.

Strictly intravenous administration after appropriate dilution.

Intrathecal administration of vinorelbine is not permitted (may be fatal).

Vinorelbine should be administered under the supervision of a physician experienced in the use of cytotoxic agents.

Prior to infusion, it must be confirmed that the needle is positioned within the vein.

For monotherapy, the usual dose for intravenous administration is 25–30 mg/m² body surface area once weekly.

In combination therapy, the dose and frequency depend on the treatment regimen.

Instructions for Administration and Handling.

Administration.

• Vinorelbine may be administered as a slow bolus injection (over 5–10 minutes) after dilution in 20–50 mL of 0.9% sodium chloride solution or 50 mg/mL (5%) glucose solution.
• After drug administration, an infusion of at least 250 mL of 0.9% sodium chloride solution should always be administered to flush the vein.

Non-small cell lung cancer: For monotherapy, the usual dose is 25–30 mg/m² body surface area once weekly. When used in combination with other anticancer agents, the dosing schedule depends on the treatment protocol. Typically, the drug should be administered at the same dose (25–30 mg/m²), but with shorter intervals, e.g., on days 1 and 5 or days 1 and 8 of each 3-week cycle according to the regimen.

Metastatic breast cancer: The usual dose is 25–30 mg/m² once weekly.

The maximum allowable single dose is 35.4 mg/m² body surface area. The maximum allowable total single dose is 60 mg.

Special Patient Groups.

Elderly patients (age over 70 years).

Clinical studies have not revealed any differences in treatment response rates among elderly patients, although increased sensitivity in some of these patients cannot be excluded. The pharmacokinetics of vinorelbine are not altered with age.

Patients with hepatic impairment.

The pharmacokinetics of vinorelbine are not altered in patients with moderate or severe hepatic impairment. However, as a precautionary measure, in patients with severe hepatic impairment, a reduced dose of 20 mg/m² is recommended, along with careful monitoring of hematological parameters.

Patients with renal impairment.

Given the minimal renal excretion of vinorelbine, there are no pharmacokinetic grounds for dose reduction in patients with impaired renal function.

Instructions for Personnel.

Preparation of infusion solutions must be performed by trained personnel in a specially designated area where eating, drinking, and smoking are prohibited.

When handling vinorelbine, standard procedures for cytotoxic agents must be followed, including the use of long-sleeved gowns, protective masks, caps, protective eyewear, sterile disposable gloves, protective surface covers, and containers or bags for toxic waste.

Pregnant healthcare workers should be warned that the drug is cytotoxic and should avoid handling it.

Prior to administration, the infusion solution should be visually inspected. Only clear, colorless or pale yellow solutions free of particulate matter should be administered.

Syringes and infusion sets should be securely connected to prevent leakage (Luer-Lock systems are recommended). Excreta and vomitus should be handled with care.

Spills and leaks should be wiped up immediately.

Contact with the eyes should be avoided as much as possible. In case of accidental eye exposure, the eyes should be immediately irrigated with physiological saline (9 mg/mL, 0.9%).

After solution preparation, all potentially contaminated surfaces should be thoroughly cleaned, and hands and face should be washed.

Compatibility of the drug has been demonstrated with glass vials, polyvinyl chloride or vinyl acetate infusion bags, and infusion systems with PVC tubing.

Vinorelbine may be administered slowly as an intravenous bolus injection (over 5–10 minutes) after dilution in 20–50 mL of 0.9% sodium chloride solution or 50 mg/mL (5%) glucose solution. After administration, the vein should always be flushed with at least 250 mL of 0.9% sodium chloride solution.

Since vinorelbine must be administered exclusively intravenously, the position of the needle in the vein must be confirmed prior to administration. Extravasation may cause significant tissue irritation. If extravasation occurs, administration should be stopped immediately, the vein flushed with 0.9% sodium chloride solution, and aspiration of the drug performed. The remaining infusion solution should be administered through another vein. Warm compresses may promote diffusion of extravasated drug and likely reduce the risk of cellulitis. Immediate intravenous administration of corticosteroids following extravasation may help reduce the risk of phlebitis.

Excreta and vomitus from patients should be handled with caution.

Any broken containers should be treated as hazardous waste, and appropriate precautions taken.

Toxic waste must be disposed of by incineration in specially marked rigid containers.

Children. There are no data on the efficacy and safety of vinorelbine in children; therefore, the drug should not be administered to this age group.

Overdose.

Symptoms: Overdose may cause bone marrow hypoplasia, sometimes accompanied by infections, fever, and paralytic ileus.

Treatment: Symptomatic and supportive therapy, including granulocyte transfusions, administration of granulopoiesis-stimulating agents, and broad-spectrum antibiotic therapy as determined by the physician.

There is no known specific antidote.

Adverse Reactions

The adverse reactions listed below are reported more frequently than isolated cases, organized by organ systems and frequency. Frequency categories are defined according to MedDRA: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Additional adverse reactions identified during post-marketing use are categorized as "not known" according to MedDRA.

The adverse reactions listed below are also described using the WHO toxicity grading classification (G).

The most commonly reported adverse reactions associated with the drug include bone marrow suppression with neutropenia, anemia, neurological disorders, gastrointestinal toxicity with nausea, vomiting, stomatitis, and constipation, transient elevations in liver function tests, alopecia, and local phlebitis.

Infections and infestations.
Common: Bacterial, viral, or fungal infections at various sites (respiratory tract, urinary tract, gastrointestinal tract), usually mild or moderate in severity and generally reversible with appropriate treatment.
Uncommon: Severe sepsis with multi-organ failure, septicemia.
Rare: Complicated and sometimes fatal septicemia.
Not known: Neutropenic sepsis.

Blood and lymphatic system disorders.
Very common: Bone marrow suppression, resulting primarily in neutropenia (G3: 24.3%; G4: 27.8%), reversible within 5–7 days and non-cumulative over time; anemia (G3–4: 7.4%).
Common: Thrombocytopenia may occur (G3–4: 2.5%), rarely severe.
Not known: Febrile neutropenia, pancytopenia, leukopenia (G1–4).

Immune system disorders.
Not known: Systemic allergic reactions, including anaphylaxis, anaphylactic shock, or anaphylactoid reactions.

Endocrine disorders.
Not known: Inadequate antidiuretic hormone secretion (SIADH).

Metabolic and nutritional disorders.
Uncommon: Severe hyponatremia.
Not known: Anorexia.

Nervous system disorders.
Very common: Neurological disorders, including loss of deep tendon reflexes; lower limb weakness has been reported after prolonged chemotherapy.
Uncommon: Severe paresthesia with sensory and motor symptoms.
Not known: Headache, dizziness, posterior reversible encephalopathy syndrome. These reactions are generally reversible.

Cardiac disorders.
Uncommon: Arterial hypotension, arterial hypertension, skin flushing, sensation of cold in peripheral body areas, hot flashes, and cold extremities.
Rare: Ischemic heart disease (angina, myocardial infarction, sometimes fatal), transient ECG changes, severe arterial hypotension, collapse.
Very rare: Tachycardia, palpitations, and cardiac arrhythmias.
Not known: Heart failure, pulmonary artery thromboembolism.

Respiratory, thoracic and mediastinal disorders.
Uncommon: Dyspnea and bronchospasm, as seen with other vinca alkaloids. These reactions may occur within minutes or several hours after drug administration.
Rare: Interstitial pneumopathy, particularly in patients treated with vinorelbine in combination with mitomycin.

Gastrointestinal disorders.
Very common: Stomatitis (G1–4: 15% when vinorelbine is used as single agent); nausea and vomiting (G1–2: 30.4%, G3–4: 2.2%), esophagitis, intestinal paresis. Antiemetic therapy may reduce their frequency; constipation is a prominent symptom (G3–4: 2.7% with vinorelbine monotherapy; G3–4: 4.1% when vinorelbine is combined with other chemotherapeutic agents), rarely progressing to paralytic ileus.
Common: Diarrhea, mild to moderate in severity.
Rare: Paralytic ileus; treatment may be resumed after normal bowel motility returns; pancreatitis has been reported.
Not known: Abdominal pain.

Hepatobiliary disorders.
Very common: Abnormal liver function tests (G1–2) (transient increases in total bilirubin, alkaline phosphatase, ALT (in 23%), AST (in 27.6%) without clinical symptoms.

Skin and subcutaneous tissue disorders.
Very common: Alopecia, usually mild (G3–4: 4.1% with vinorelbine monotherapy).
Rare: Generalized skin changes, skin reactions (rash, pruritus, urticaria, erythema of palms and soles).
Not known: Skin hyperpigmentation (serpentine supravenous hyperpigmentation).

Musculoskeletal and connective tissue disorders.
Common: Arthralgia, including jaw pain, and myalgia.

Renal and urinary disorders.
Uncommon: Increased creatinine levels.

General disorders and administration site conditions.
Very common: Reactions at the injection site, including erythema, burning pain, vein discoloration, and local phlebitis (G3–4: 3.7% with vinorelbine monotherapy).
Common: Patients receiving vinorelbine therapy have reported asthenia, increased fatigue, fever, pain in various locations including chest pain, tumor site pain, and malaise.
Rare: Local necrosis, cellulitis. Proper placement of the intravenous needle or catheter and bolus injection followed by adequate vein flushing may help minimize these effects.

Shelf life. 3 years.

Storage conditions.
Store in the original packaging, out of reach of children, at 2–8 °C.

Incompatibilities.
Vinorelbine may only be diluted with sterile diluents specified in the section "Administration and dosage."

Alkaline solutions must not be used for dilution, as precipitation may occur in alkaline environments.

Vinorelbine must not be mixed with other medicinal products in the same infusion bottle or syringe.

Packaging. 1 ml (10 mg) or 5 ml (50 mg) in a vial; 1 vial per carton.

Prescription category. Prescription only.

Manufacturer.
Pfizer Unterach GmbH
or
EBEWE Pharma Ges.m.b.H. Nfg. KG

Manufacturer's address.
Mondseestrasse 11, 4866 Unterach am Attersee, Austria
Mondseestrasse 11, 4866 Unterach am Attersee, Austria