Vinorelbine accord

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VINOРЕLBIN ACCORD (VINORELBIN ACCORD)

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, free from visible particles.

Pharmacotherapeutic group. Antineoplastic agents. Plant alkaloids and other natural agents. Vinorelbine.

ATC code L01C A04.

Pharmacological Properties.

Pharmacodynamics.

Vinorelbine is an antitumor active substance belonging to the family of vinca alkaloids; however, unlike other vinca alkaloids, the catharanthine component of the vinorelbine molecule has been 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; at high doses, it also affects axonal microtubules. Induction of tubulin spiralization by vinorelbine is weaker compared to vincristine. Vinorelbine blocks mitosis at the G2-M phase, leading to cell death during interphase or subsequent mitosis.

The safety and efficacy of vinorelbine in children and adolescents have not been established. Phase II clinical trial data from intravenous administration of vinorelbine in 33 and 46 pediatric patients with recurrent solid tumors, including rhabdomyosarcoma, other soft tissue sarcomas, Ewing’s sarcoma, liposarcoma, synovial sarcoma, fibrosarcoma, central nervous system carcinoma, and neuroblastoma, at doses ranging from 30 to 33.75 mg/m² on D1 and D8 every 3 weeks or once weekly for 6 weeks every 8 weeks, did not show significant clinical benefit. The toxicity profile was similar to that observed in adult patients (see section "Method of administration and dosage").

Pharmacokinetics.

Pharmacokinetic parameters of vinorelbine were assessed in blood.

Distribution. The steady-state volume of distribution 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%), but vinorelbine binds well to blood cellular elements, particularly platelets (78%) and lymphocytes (4.8%). 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.

Biological transformation. 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 hepatic blood flow, and averages 0.72 L/h/kg (range: 0.32–1.26 L/h/kg). Less than 20% of the intravenous dose is excreted renally, primarily in unchanged form. Vinorelbine and its metabolites are mainly excreted via bile.

Pharmacokinetics in special patient populations.

Patients with impaired renal function.

The pharmacokinetics of vinorelbine in patients with impaired renal function have not been studied; however, dose reduction is not required in such patients due to the low renal excretion of vinorelbine.

Patients with impaired hepatic function.

An initial study reported the impact of hepatic dysfunction on the pharmacokinetics of vinorelbine. Results from a pharmacokinetic study in female patients with metastatic breast cancer and liver metastases showed that changes in mean vinorelbine clearance occurred only when more than 75% of the liver was affected.

In a phase I dose-escalation pharmacokinetic study involving 6 oncology patients with mild hepatic impairment (bilirubin levels no more than 2 times the upper limit of normal (ULN) and transaminase levels no more than 5 times ULN), who received vinorelbine up to 25 mg/m² body surface area, and 8 oncology patients with severe hepatic impairment (bilirubin levels more than 2 times ULN and/or transaminase levels more than 5 times ULN), who received vinorelbine up to 20 mg/m² body surface area, the 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 mild 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

Studies in elderly patients (aged 70 years and older) with non-small cell lung cancer showed that age does not affect the pharmacokinetics of vinorelbine. However, since elderly patients may be frail, 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.

Vinorelbine is indicated for use in adult patients:

• as a first-line treatment, either as monotherapy or in combination regimens, for stage III or IV non-small cell lung cancer;
• for the treatment of recurrent stage III or IV metastatic breast cancer following ineffective chemotherapy that included anthracyclines.

Contraindications.

• Intrathecal administration;
• Hypersensitivity to vinorelbine, other vinca alkaloids, or to any of the excipients;
• Neutrophil count less than 1500/mm³ or serious infections, present or occurring within the last 2 weeks;
• Platelet count less than 100,000/mm³;
• Breastfeeding period;
• The drug must not be administered to women of childbearing potential who are not using effective contraceptive methods;
• In combination with yellow fever vaccine.

Safety precautions.

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

Personnel must be provided with appropriate protective equipment (protective goggles, sterile disposable gloves, protective masks, disposable gowns). Syringes and infusion sets must be carefully prepared to prevent leakage (use of Luer-lock adapters is recommended).

All necessary precautions must be taken to avoid contact of vinorelbine solutions with the eyes. In case of accidental exposure, eyes must be immediately rinsed with 0.9% sodium chloride solution.

In the event of spillage or splashing of vinorelbine solutions, the contaminated area must be wiped and cleaned thoroughly.

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

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

Patient excreta and vomit must be handled with caution.

Pregnant healthcare workers must not handle the drug.

Interaction with other medicinal products and other forms of interaction.

Interactions common to all cytotoxic agents.

Patients with oncological diseases have an increased risk of thrombosis, thus anticoagulants are often prescribed. 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., polio vaccine).

Phenytoin: increased risk of seizures due to reduced gastrointestinal absorption of phenytoin caused by anticancer agents, as well as increased risk of toxicity or reduced efficacy of cytotoxic agents due to phenytoin-induced enhancement of hepatic metabolism.

Combinations requiring attention.

Cyclosporine, tacrolimus: excessive immunosuppression with risk of lymphoproliferative disorders.

Since vinca alkaloids are known substrates of P-glycoprotein, vinorelbine should be used with caution in combination with strong modulators of this membrane transporter in the absence of specific studies.

Interactions specific to vinca alkaloids.

Undesirable combinations.

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

Combinations requiring attention.

Mitomycin C: increased risk of pulmonary toxicity with both mitomycin C and vinca alkaloids. Concurrent use of this combination may lead to bronchospasm and dyspnea, and rarely, interstitial pneumonitis.

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

Concomitant use with P-glycoprotein inhibitors (e.g., ritonavir, clarithromycin, cyclosporine, verapamil, quinidine) or inducers (see list of CYP3A4 inducers) may affect vinorelbine blood concentrations.

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 with strong inhibitors of this isoenzyme (such as ketoconazole, itraconazole, erythromycin, clarithromycin, telithromycin, nefazodone, HIV protease inhibitors) may increase vinorelbine blood concentrations, while concomitant use with strong CYP3A4 inducers (such as rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s wort) may decrease its concentrations.

No mutual pharmacokinetic interaction has been observed during polychemotherapy with vinorelbine and cisplatin over several treatment cycles. However, the incidence of granulocytopenia with this combination therapy is higher than with vinorelbine monotherapy.

In phase I clinical trials of intravenous vinorelbine administered in combination with lapatinib, an increased incidence of grade 3–4 neutropenia was observed.

Within this study, the recommended dose of intravenous vinorelbine administered on days 1 and 8 of a 3-week schedule was 22.5 mg/m² in combination with a daily dose of 1000 mg lapatinib. This combination should be administered 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, platelet, and neutrophil counts in peripheral blood should be determined). The dose of the drug should be adjusted according to the hematological profile. The main dose-limiting adverse effect of vinorelbine therapy is neutropenia, which is non-cumulative. The lowest neutrophil count typically occurs 7–14 days after drug administration, after which values rapidly return to normal (within 5–7 days). Administration of vinorelbine should be postponed if neutrophil count falls below 1500/mm³ and/or platelet count drops below 100,000/mm³, until hematological parameters normalize.

If a patient presents signs or symptoms suggestive of infection, immediate investigation should be performed.

Precautionary measures.

Particular caution is required when prescribing the drug to patients with a history of ischemic heart disease.

The pharmacokinetics of vinorelbine are not altered in patients with moderate or severe hepatic impairment. Dose adjustment recommendations for these patient groups are provided in the section "Dosage and administration". Vinorelbine should not be used in combination with radiotherapy to the liver area or when the irradiated field includes the liver.

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

This medicinal product is contraindicated for concomitant use with the yellow fever vaccine. Concomitant administration with live attenuated vaccines is also not recommended.

Caution is required when vinorelbine is co-administered with 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"). Combination of vinorelbine with drugs such as phenytoin (and all other cytotoxic agents) or itraconazole (and all other 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 origin. Therefore, careful monitoring of patients belonging to this population group is required.

To minimize the risk of bronchospasm, particularly when used concomitantly with mitomycin, all appropriate preventive measures should be taken.

Outpatients should be advised to seek medical attention if dyspnea occurs.

Women of childbearing potential must use reliable contraceptive methods during treatment and for at least 3 months after its completion.

Safety preclinical data.

The dose-limiting toxic effect observed in animal studies is bone marrow suppression. In animal studies, vinorelbine induced the formation of aneuploids and polyploids. It can therefore be assumed that vinorelbine may also exert genotoxic effects (induction of aneuploidy and polyploidy) in humans.

Carcinogenicity studies in mice and rats yielded negative results, although only low doses were tested.

Reproductive function studies in animals showed effects after administration of subtherapeutic doses. Toxic effects on the embryo and fetus were observed, including restricted intrauterine development and delayed ossification.

Teratogenic effects (fused vertebrae, missing ribs) were observed at doses toxic to the mother. In addition, spermatogenesis and secretion from the seminal vesicles and prostate gland were reduced, although fertility in rats was not impaired.

Use during pregnancy or breastfeeding.

Pregnancy. There are insufficient data on the use of vinorelbine in pregnant women. Animal studies have demonstrated embryotoxicity and teratogenicity. Based on animal study results and the pharmacological action of vinorelbine, there is a potential risk that the drug may cause significant congenital malformations if used during pregnancy. Vinorelbine is contraindicated during pregnancy.

If there are life-threatening indications for the use of vinorelbine in pregnant women, consultation with a physician regarding the risk of adverse effects on the unborn child is necessary.

If pregnancy occurs during treatment, the patient should be informed of the potential risks to the fetus and closely monitored. Genetic counseling should also be considered.

Breastfeeding period. It is unknown whether vinorelbine is excreted in human breast milk. Excretion into milk has not been studied in animal models. Risk to the breastfed infant cannot be excluded. Breastfeeding must be discontinued prior to initiating vinorelbine therapy.

Fertility. Vinorelbine may exert genotoxic effects. Therefore, men undergoing vinorelbine therapy are advised to avoid fathering children during treatment and for at least 6 months (minimum 3 months) after treatment ends. Women of childbearing potential should use effective contraceptive methods during treatment and for at least 3 months after treatment. Due to the potential for irreversible infertility caused by vinorelbine, consultation with a specialist regarding sperm cryopreservation prior to starting therapy is recommended.

Ability to influence reaction speed when driving or operating machinery.

No studies have been conducted on the effects of vinorelbine on the ability to drive or operate machinery. However, based on its pharmacodynamic profile, such effects are not expected. Nevertheless, due to certain adverse reactions of the drug, patients undergoing vinorelbine therapy should exercise caution.

Administration and Dosage.

Intravenous use only 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 chemotherapeutic agents.

Prior to administration, ensure that the needle is within the vein.

If the drug infiltrates into surrounding tissues during administration, significant local irritation may occur. In such a case, administration must be stopped immediately, saline infusion should be initiated, and the remaining solution should be infused through another vein. In the event of extravasation, intravenous administration of glucocorticosteroids is recommended to reduce the risk of phlebitis.

Instructions for Use and Handling.

Administration.

• Vinorelbine may be administered as a slow bolus injection (over 6–10 minutes) after dilution in 20–50 mL of 0.9% sodium chloride solution or 50 mg/mL (5%) glucose solution, or as a short infusion (over 20–30 minutes) after dilution in 125 mL of physiological saline 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 and remove any residual drug.

Non-small cell lung cancer: in monotherapy, the usual dose is 25–30 mg/m² of body surface area once weekly. When used in combination with other antineoplastic agents, the same dose (25–30 mg/m²) should be administered, but the frequency of vinorelbine administration should be reduced, e.g., on days 1 and 5 every 3 weeks or on days 1 and 8 every 3 weeks, depending on the treatment regimen.

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

Maximum allowable single dose – 35.4 mg/m² of body surface area.

Maximum allowable total dose per single administration – 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. Age does not affect the pharmacokinetics of vinorelbine.

Patients with hepatic impairment.

The pharmacokinetics of vinorelbine are not altered in patients with moderate or severe hepatic dysfunction. However, as a precautionary measure, it is recommended to reduce the dose to 20 mg/m² of body surface area and to closely monitor hematological parameters in patients with severe hepatic impairment.

Patients with renal impairment.

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

Extravasation.

Significant irritation may occur if the drug leaks into extravascular space. If this occurs, administration should be stopped immediately, the vein should be flushed with 0.9% sodium chloride solution, and aspiration of the drug should be performed. The remaining infusion solution should be administered through another vein. In case of extravasation, immediate intravenous administration of corticosteroids helps reduce the risk of phlebitis.

Pediatric population. There are no data on the efficacy and safety of vinorelbine in children and adolescents; 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: general supportive therapy, including blood transfusions and administration of broad-spectrum antibiotics at the physician's discretion.

Specific antidote is unknown.

Adverse Reactions

The undesirable effects 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 (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

The adverse reactions listed below are also described according to the WHO classification, taking into account the toxicity criterion (G).

The most commonly reported adverse reactions associated 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.

Infections and infestations. Common: bacterial, viral, or fungal infections at various sites (respiratory tract, urinary tract, gastrointestinal tract), mild or moderate in severity, usually reversible with appropriate treatment. Uncommon: severe sepsis with multi-organ failure, septicemia. Rare: complicated and sometimes fatal septicemia. Frequency not known: neutropenic sepsis, neutropenic infection (G3-4).

Blood and lymphatic system disorders. Very common: bone marrow suppression, resulting primarily in neutropenia (G3: 24.3%; G4: 27.8%), which is reversible within 5–7 days and noncumulative over time; anemia (G3-4: 7.4%). Common: thrombocytopenia (G3-4: 2.5%) may occur, but is rarely severe. Frequency not known: febrile neutropenia, pancytopenia, leukopenia (G (1-4)).

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, including loss of deep tendon reflexes (G3-4: 2.7%); lower limb weakness has been reported after prolonged chemotherapy. Uncommon: severe paresthesias with sensory and motor symptoms. Frequency not known: headache, dizziness, posterior reversible encephalopathy syndrome.

These reactions are generally reversible.

Cardiac and vascular disorders. Uncommon: arterial hypotension, arterial hypertension, skin flushing, cold sensation 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. Rare: tachycardia, palpitations, and cardiac arrhythmias. Frequency not known: heart failure.

Respiratory, thoracic and mediastinal disorders. Uncommon: dyspnea and bronchospasm, as with other vinca alkaloids. Rare: interstitial pneumopathy, sometimes fatal. Frequency not known: cough (G 1-2), acute respiratory distress syndrome (ARDS), sometimes fatal, pulmonary embolism.

Gastrointestinal disorders. Very common: stomatitis (G1-4: 15% when vinorelbine is used as monotherapy); nausea and vomiting (G 1-2: 30.4% and G 3-4: 2.2%). Anti-emetic therapy may reduce their incidence; constipation is a prominent symptom (G 3-4: 2.7% with vinorelbine monotherapy and G3-4: 4.1% when vinorelbine is combined with other chemotherapeutic agents), which rarely progresses to paralytic ileus. Common: diarrhea, mild to moderate in severity, may occur. Rare: paralytic ileus; treatment may be resumed after normal bowel motility returns; pancreatitis has been reported. Frequency not known: gastrointestinal hemorrhage, severe diarrhea, abdominal pain.

Hepatobiliary disorders. Very common: abnormal liver function test results (G 1-2) (transient increases in total bilirubin, alkaline phosphatase, ALT (in 23%), AST (in 27.6%)) without clinical symptoms. Frequency not known: hepatic dysfunction.

Skin and subcutaneous tissue disorders. Very common: alopecia, usually mild (G3-4: 4.1% with vinorelbine monotherapy). Rare: generalized skin changes. Frequency not known: skin hyperpigmentation (serpentine supravenous hyperpigmentation), hand-foot syndrome (palmar-plantar erythrodysesthesia).

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

General disorders and administration site reactions. Very common: reactions at the infusion site, including erythema, burning pain, vein discoloration, and local phlebitis (G 3-4: 3.7% with vinorelbine monotherapy). Common: patients receiving vinorelbine therapy have reported asthenia, increased fatigue, fever, pain in various sites including chest pain, tumor site pain, and chills. Isolated cases: local necrosis has been observed. Proper placement of the intravenous needle or catheter and bolus injection followed by adequate flushing of the vein may minimize these effects.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Solution after dilution. Chemical and physical stability has been demonstrated for 24 hours at 25 °C.

From a microbiological standpoint (unless the vial has been opened and the solution reconstituted under aseptic conditions to prevent microbial contamination), the infusion solution should be used immediately after preparation. If not used immediately, the duration and conditions of storage are the responsibility of the user.

Storage conditions.

Store in the original packaging, protected from light.

Store in a refrigerator at 2 °C to 8 °C. Do not freeze.

Keep out of the reach of children.

Incompatibilities.

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

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

No incompatibility has been observed between Vinorelbine Accord and clear glass vials, polyvinyl chloride (PVC) or vinyl acetate bags, or infusion sets with PVC tubing.

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

Prescription category. Prescription only.

Manufacturer.

Accord Healthcare Polska Sp. z o.o. Importer's Address / Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address and location of operations.

ul. Lutomierska 50, Pabianice, 95-200, Poland / ul. Lutomierska 50, Pabianice, 95-200, Poland.