INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VINO RELBIN-VISTA (VINORELBIN-VISTA)

Composition:

Active substance: vinorelbine;

1 ml of concentrate contains 13.85 mg of vinorelbine tartrate, equivalent to 10 mg of vinorelbine;

Excipient: water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group. Antineoplastic agents. Plant alkaloids and other natural agents. Vinorelbine. ATC code L01CA04.

Pharmacological Properties

Pharmacodynamics

Vinorelbine is a cytostatic antineoplastic agent, a vinca alkaloid that acts on the dynamic equilibrium of tubulin in the microtubular apparatus of cells. It inhibits tubulin polymerization and predominantly binds to mitotic microtubules; at high doses, it also affects axonal microtubules. Vinorelbine has a greater effect on tubulin spiralization than vincristine. Vinorelbine blocks mitosis at the G2-M phase, leading to cell death either during interphase or upon continuation of mitosis.

The safety and efficacy of vinorelbine in children have not been established.

Pharmacokinetics

Distribution

The volume of distribution at steady state for 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 to platelets (78%), while only 4.8% binds to lymphocytes. The drug is extensively 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.

Metabolism
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 main 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 hepatic blood flow, with an average of 0.72 L•h⁻¹•kg⁻¹ (range: 0.32–1.26 L•h⁻¹•kg⁻¹). Less than 20% of the intravenous dose is excreted by the kidneys, primarily in unchanged form. The majority of the drug is eliminated via bile as unchanged vinorelbine and its metabolites.

Pharmacokinetics in Special Patient Populations

Patients with Renal or Hepatic Impairment

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

Hepatic Impairment

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

In a phase I dose-finding pharmacokinetic study, 6 oncology patients with moderate hepatic impairment (bilirubin levels no more than 2 times the upper limit of normal (ULN) and transaminase levels no more than 5 times ULN), receiving vinorelbine doses up to 25 mg/m² body surface area, and 8 oncology patients with severe hepatic impairment (bilirubin levels more than 2 times ULN and transaminase levels more than 5 times 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 involving elderly patients (aged 70 years and older) 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 advised when increasing vinorelbine doses.

Pharmacokinetic/Pharmacodynamic Relationship

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

Clinical characteristics.

Indications.

Monotherapy or as part of first-line therapy for non-small cell lung cancer stage 3 or 4.
Treatment of metastatic breast cancer stage 3 or 4, recurrent after anthracycline therapy or in cases where anthracycline therapy was ineffective.

Contraindications.

Intrathecal administration of the drug is prohibited.

Hypersensitivity to vinorelbine or to other vinca alkaloids.

Administration of yellow fever vaccine during vinorelbine treatment.

Neutrophil count < 1500/mm³ or severe infections (current or recent, within the last 2 weeks).

Platelet count < 100,000/mm³.

Breastfeeding period.

Special safety precautions.

The drug should be handled only by trained personnel. Adequate protection of the drug from environmental exposure and protection of personnel handling the drug must be ensured. Preparation of infusion solutions should be carried out in a specially designated area where eating, drinking, and smoking are prohibited. When working with vinorelbine, standard procedures for handling cytotoxic drugs must be followed, including mandatory use of long-sleeved gowns, protective masks, caps, protective eyewear, sterile disposable gloves, protective covering for work surfaces, and containers or bags for toxic waste.

Syringes and infusion sets must be carefully assembled to prevent leakage (use of Luer-lock connectors is recommended). Infusion vials, bags, and systems made of polyvinyl chloride or clear neutral glass do not absorb vinorelbine and do not interact with it. In case of spillage or splashing of vinorelbine solutions, the contaminated area must be wiped and rinsed immediately.

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

All necessary precautions must be taken to prevent vinorelbine solutions from entering the eyes. If this occurs, the eyes must be immediately rinsed with 0.9% sodium chloride solution. In case of irritation, an ophthalmologist should be consulted.

If vinorelbine solutions come into contact with the skin, the area must be thoroughly washed with large amounts of water.

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

Special care should be taken when handling patient excreta and vomit.

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.

Interactions with other medicinal products and other forms of interactions.

Concomitant use is contraindicated

Yellow fever vaccine. Administration of yellow fever vaccine is contraindicated during vinorelbine treatment due to the potential risk of developing fatal systemic vaccine disease (see section "Contraindications").

Not recommended combinations

Live attenuated vaccines. Other live attenuated vaccines should not be administered (especially to patients with immunodeficiency due to underlying disease) due to the potential risk of systemic, possibly fatal, disease. This risk is increased in patients who already have immunosuppression due to their underlying condition. Inactivated vaccines should be used if available (e.g., polio vaccine).

Phenytoin. Concomitant use of vinorelbine with phenytoin is contraindicated due to the risk of increased seizures resulting from reduced gastrointestinal absorption of phenytoin caused by the cytotoxic agent, or reduced efficacy of vinorelbine due to enhanced hepatic metabolism induced by phenytoin.

Itraconazole. Increased neurotoxicity of itraconazole due to reduced hepatic metabolism.

Interactions characteristic of vinorelbine

Cisplatin. There is no pharmacokinetic interaction when vinorelbine is used in combination with cisplatin over several treatment cycles. However, the incidence of granulocytopenia associated with the combination of vinorelbine and cisplatin is higher than with vinorelbine monotherapy.

Mitomycin C. When vinca alkaloids and mitomycin C are used concomitantly, the risk of bronchospasm and dyspnea may increase; interstitial pneumonia has been observed rarely.

Immunosuppressants (cyclosporine, tacrolimus). Excessive immunosuppression with a risk of lymphoproliferative disorders should be considered.

Vinorelbine is a substrate of P-glycoprotein; however, specific studies are lacking, so caution is advised when co-administering inhibitors or inducers of this transport protein.

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

Since the CYP3A4 isoenzyme plays a major role in vinorelbine metabolism, concomitant use of CYP3A4 inducers (e.g., phenytoin, rifampicin) or inhibitors (e.g., itraconazole, ketoconazole) may alter vinorelbine blood concentrations. Blood concentrations of vinorelbine increase with inhibitors and decrease with inducers.

In one phase I clinical study, it was suggested that concomitant administration of vinorelbine (intravenous, 3-week schedule with doses of 22.5 mg/m² on day 1 and day 8) and lapatinib (1000 mg daily) may increase the incidence of grade 3–4 neutropenia; therefore, treatment with this combination should be administered with caution.

Anticoagulant therapy

Due to the increased risk of thrombotic events in oncological patients, anticoagulants are frequently prescribed. Given the high intra-individual variability in coagulation capacity during illness, as well as the potential for interaction between oral anticoagulants and antineoplastic agents, international normalized ratio (INR) should be monitored more frequently.

Special precautions for use.

Treatment should be conducted under the supervision of a physician experienced in the use of antineoplastic agents.

Since myelosuppression is the main risk associated with vinorelbine use, careful hematological monitoring (determination of hemoglobin levels and counts of leukocytes, neutrophils, and platelets on the day of each new administration) should be performed during treatment.

The principal dose-limiting toxicity of vinorelbine therapy is neutropenia. It is non-cumulative. The lowest neutrophil count is typically observed 7–14 days after drug administration, after which values rapidly return to normal (within 5–7 days). Administration of vinorelbine should be delayed until hematological parameters have normalized if neutrophil counts fall below 1,500/mm³ or platelet counts drop below 100,000/mm³.

Patients should be promptly examined and appropriate treatment initiated if symptoms of infection develop.

Special warnings and precautions for use

Particular caution is required when treating patients with a history of ischemic heart disease.

The pharmacokinetics of vinorelbine are not altered in patients with moderate or severe hepatic impairment. For dose adjustments in this patient group, refer to the section "Dosage and administration".

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

Vinorelbine should not be administered in combination with radiotherapy to the liver area.

During vinorelbine therapy, live attenuated vaccines are generally not recommended. Vaccination against yellow fever is contraindicated (see section "Contraindications").

Potent inhibitors or inducers of the CYP3A4 isoenzyme may alter vinorelbine concentrations; therefore, caution is required when co-administering such agents (see section "Interaction with other medicinal products and other forms of interaction"). Combination of vinorelbine with phenytoin (as with all cytotoxic agents) and with itraconazole (as with all vinca alkaloids) is not recommended.

All necessary precautions should be taken to prevent vinorelbine from entering the eyes, as this may cause severe irritation or even corneal ulceration, especially if the drug is sprayed under pressure. If accidental exposure occurs, the eyes should be immediately irrigated with 0.9% sodium chloride solution and medical advice from an ophthalmologist should be sought.

Pulmonary toxicity has been reported, including severe acute bronchospasm, interstitial pneumonitis, and acute respiratory distress syndrome (ARDS) occurring after vinorelbine administration. The median time to onset of ARDS after vinorelbine administration was one week (range: 3 to 8 days).

Infusion should be immediately discontinued in patients who develop unexplained dyspnea or any signs suggestive of pulmonary toxicity.

Interstitial lung disease has been reported more frequently in the Japanese population. Particular attention should be paid to this patient group.

Use during pregnancy or breastfeeding

Pregnancy

There are insufficient data on the use of vinorelbine in pregnant women. However, animal studies have demonstrated embryotoxicity and teratogenicity. Given these findings and the pharmacological activity of the drug, there is a potential risk of embryofetal developmental abnormalities.

Vinorelbine should not be used during pregnancy except when the expected benefit clearly outweighs the potential risk.

If a patient becomes pregnant during vinorelbine therapy, she should be informed of the potential risks to the fetus and placed under close surveillance. In such cases, consultation with a genetics specialist is advisable.

Women of reproductive potential

Due to the genotoxicity of vinorelbine, women of reproductive age must use effective contraception during treatment and for 7 months after completion of therapy.

Contraception in men

Men should use effective contraception during treatment and for 4 months after treatment ends.

Since vinorelbine is a genotoxic agent, it is important that patients planning pregnancy after therapy receive counseling from an appropriate specialist.

Breastfeeding

It is unknown whether vinorelbine is excreted in human breast milk. Excretion of vinorelbine into breast milk has not been studied in animal models. The possibility of the drug passing into breast milk cannot be excluded; therefore, breastfeeding must be discontinued prior to starting therapy with this medicinal product.

Fertility

Men receiving vinorelbine should not plan fatherhood during treatment and for 4 months after therapy ends. Since vinorelbine treatment may cause irreversible infertility, men who wish to have children in the future are advised to undergo sperm cryopreservation prior to starting therapy.

Effect on ability to drive and use machines

Studies on the effect of vinorelbine on the ability to drive or operate machinery have not been conducted. However, based on its pharmacodynamic profile, vinorelbine is not expected to affect the ability to drive or use machinery. Nevertheless, caution should be exercised due to possible adverse reactions that may impair attention and reaction ability (e.g., nausea, fever, or pain).

Method of Administration and Dosage

The medicinal product may only be administered intravenously after prior dilution.

Intrathecal administration is not permitted, as it may be fatal.

Vinorelbine-Vista must be administered intravenously as an infusion only.

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

Method of Administration

Vinorelbine is recommended to be administered over 6–10 minutes after dilution in 50 mL of sodium chloride 9 mg/mL (0.9%) injection solution or 5% glucose injection solution.

The duration of infusion (6 to 10 minutes) must be strictly observed, as the risk of venous irritation increases with prolonged infusion time.

Prior to administering the vinorelbine solution, it must be confirmed that the needle is properly positioned within the vein.

Local irritation may occur if the drug leaks into surrounding tissues. In case of extravasation of Vinorelbine-Vista solution, administration must be immediately discontinued and the vein flushed with 0.9% sodium chloride solution. The remaining infusion solution should be administered through another vein.

Management of any extravasation should be carried out in accordance with local hospital guidelines and procedures.

After completion of drug administration, an additional infusion of at least 250 mL of 0.9% sodium chloride solution is required to flush residual drug from the vein.

Refer to the section "Special Precautions for Handling" for instructions for healthcare personnel.

Dosing in Adults

Non-small cell lung cancer and metastatic breast cancer

In monotherapy, vinorelbine is usually administered at a dose of 25–30 mg/m² body surface area once weekly. In combination chemotherapy, the administration schedule depends on the treatment protocol. The drug is typically administered at the same dose (25–30 mg/m² body surface area), but with longer intervals, for example on day 1 and day 5, or day 1 and day 8 of a 3-week treatment cycle.

Dosage in Special Patient Groups

Elderly Patients

No significant differences in treatment response have been observed in elderly patients. However, increased sensitivity in some of these patients cannot be ruled out. The pharmacokinetics of vinorelbine are not affected by patient 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, dose reduction to 20 mg/m² and careful monitoring of hematological parameters are recommended in patients with severe hepatic impairment.

Patients with Renal Impairment

Since renal excretion of vinorelbine is minimal, dosage adjustment is not required in patients with renal impairment.

Pediatric Patients

The safety and efficacy of the drug in children have not been established; therefore, the drug is not recommended for use in this age group.

Overdose

In cases of overdose due to administration of doses significantly exceeding the therapeutic range, suppression of the bone marrow may occur, manifesting as fever, infections, and paralytic ileus.

In the event of overdose, supportive therapy is indicated. In case of infection, treatment with broad-spectrum antibiotics is recommended. Transfusion of granulocyte concentrate and administration of granulopoiesis-stimulating agents may be required as needed. There is no known specific antidote for vinorelbine.

Adverse reactions.

The most commonly reported adverse reactions with vinorelbine are 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.

Criteria for assessing the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (frequency cannot be estimated from the available data).

Additional adverse reactions collected from post-marketing experience and clinical trials have been included according to MedDRA classification with a frequency of "frequency not known".

Detailed information:

Reactions are described according to WHO classification (Grade 1 = G1; Grade 2 = G2; Grade 3 = G3; Grade 4 = G4; Grade 1–4 = G1–4; Grade 1–2 = G1–2; Grade 3–4 = G3–4).

Infections and infestations

Common: bacterial, viral, or fungal infections of various localizations (respiratory system, urinary system, gastrointestinal tract), mild to moderate in severity and usually reversible with appropriate treatment.

Uncommon: severe sepsis with other visceral disturbances; septicemia.

Very rare: complicated septicemia, sometimes with fatal outcome.

Frequency not known: neutropenic sepsis (sometimes with fatal outcome), neutropenic infection G3–4.

Blood and lymphatic system disorders

Very common: bone marrow function suppression, predominantly manifested as neutropenia (G3: 24.3%; G4: 27.8%), reversible within 5–7 days and not cumulative over time; anemia (G3–4: 7.4%).

Common: thrombocytopenia may occur but is rarely severe (G3–4: 2.5%).

Frequency not known: febrile neutropenia, pancytopenia, leukopenia (G1–4).

Immune system disorders

Frequency not known: systemic allergic reactions, including anaphylaxis, anaphylactic shock, or anaphylactoid reactions.

Endocrine disorders

Frequency not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders

Rare: severe hyponatremia.

Frequency not known: anorexia.

Nervous system disorders

Very common: neurological disorders (G3–4: 2.7%), including decreased deep tendon reflexes. Weakness of the lower limbs has been reported after prolonged chemotherapy.

Uncommon: severe paresthesia with sensory and motor symptoms. These effects are usually reversible.

Frequency not known: headache, dizziness, ataxia, posterior reversible encephalopathy syndrome.

Cardiac disorders

Uncommon: arterial hypotension, arterial hypertension, sensation of flushing and cold extremities.

Rare: ischemic heart disease (angina, myocardial infarction, sometimes fatal), marked arterial hypotension, collapse.

Very rare: tachycardia, palpitations, cardiac rhythm disturbances.

Frequency not known: heart failure.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea, bronchospasm. These reactions may occur both with vinorelbine and other vinca alkaloids.

Rare: interstitial pneumonia, which may occasionally be fatal.

Frequency not known: pulmonary artery thromboembolism, acute respiratory distress syndrome (sometimes leading to fatal outcome), cough – G1–2.

Gastrointestinal disorders

Very common: constipation is the main symptom, which rarely progresses to intestinal obstruction both during monotherapy with vinorelbine (G3–4: 2.7%) and in combination with other chemotherapeutic agents (G3–4: 4.1%); nausea (G1–2: 30.4%) and vomiting (G3–4: 2.2%) (antiemetic therapy may reduce these effects), stomatitis (during monotherapy with vinorelbine G1–4: 15%), esophagitis, anorexia.

Common: diarrhea, usually mild or moderate in severity.

Rare: pancreatitis, paralytic ileus (treatment may be resumed after normalization of intestinal motility).

Frequency not known: gastrointestinal hemorrhage, severe diarrhea, abdominal pain.

Hepatobiliary disorders

Very common: abnormal liver function tests (G1–2) without clinical symptoms (AST in 27.6% and ALT in 29.3%).

Frequency not known: hepatic function disorders.

Skin and subcutaneous tissue disorders

Very common: alopecia, usually mild (G3–4: 4.1%), may occur during monotherapy with vinorelbine.

Rare: generalized skin reactions.

Frequency not known: palmar-plantar erythrodysesthesia, skin hyperpigmentation (serpentine supravenous hyperpigmentation).

Musculoskeletal and connective tissue disorders

Common: arthralgia, including jaw pain, and myalgia.

General disorders and administration site conditions

Very common: reactions at the injection site (erythema, burning, pain, color changes of the vein at the injection site, local phlebitis) during monotherapy with vinorelbine (G3–4: 3.7%).

Common: asthenia, increased fatigue, chills, pain of various localizations (including chest pain and tumor site pain).

Rare: soft tissue necrosis at the injection site (correct needle or intravenous catheter placement and bolus administration followed by vein flushing may minimize this effect).

Frequency not known: chills G1–2.

Investigations

Frequency not known: weight loss.

Additional adverse reactions reported with oral vinorelbine include: taste disturbances, visual disturbances, insomnia, dysphagia, esophagitis, weight gain, dysuria, and other genitourinary symptoms.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature of 2°C to 8°C. Use the contents of the vial immediately after opening. Keep out of the reach of children.

Incompatibilities.

Vinorelbine should only be diluted with sterile solutions specified in the section "Dosage and administration".

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

Packaging.

1 ml (10 mg), 5 ml (50 mg) in a vial; 1 vial per cardboard pack.

Prescription status. Prescription only.

Manufacturers.

Actavis Italia S.p.A.
Sindan Pharma S.R.L.

Manufacturers' addresses and locations of business operations.

Via Pasteur, 10 - 20014 Nerviano (Milan), Italy.
Bulevardul Ion Mihalache, 11, Sector 1, 011171, Bucharest, Romania.

Vinorelbine — vista