Navelbine (Vinorelbine) capsules 20 mg No. 1 - Instructions

Pharmacological properties of the drug Vinorelbine 'ebeve'

Pharmacodynamics. Vinorelbine belongs to the antineoplastic agents of the vinca alkaloid group. It influences at the molecular level the dynamic balance of tubulin/microtubules and prevents tubulin polymerization. Vinorelbine acts primarily on mitotic microtubules. The effect on axonal microtubules is observed at high concentrations of the drug. The effect of tubulin helicalization under the action of vinorelbine is less pronounced than under the action of vincristine. Vinorelbine inhibits mitosis in the G2/M phases of the cell cycle and causes cell death during interphase and during mitosis. Pharmacokinetics. After intravenous administration, a three-phase decrease in the concentration of vinorelbine in the blood plasma is observed. The duration of the terminal half-life from blood plasma is 40 hours. The total clearance of vinorelbine is high (1.3 l/h• kg). Vinorelbine is excreted mainly in bile, renal excretion is insignificant (18.5%). The volume of distribution of vinorelbine exceeds 40 l/kg. Vinorelbine is moderately bound to plasma proteins (13.5%) and significantly bound to platelets (78%). Vinorelbine penetrates very well into lung tissue (the ratio of vinorelbine concentrations in lung tissue and blood plasma exceeds 300). In human urine, vinorelbine is determined predominantly in unchanged form, as well as its metabolite deacetylvinorelbine in low concentrations.

Navelbine Vinorelbine _ _

Types of tumors » Medicines in this group »

Registration number: P No. 011707/01; LS-000704. Pharmacotherapeutic group: Antitumor agent, alkaloid. ATX code: L01CA04. Dosage form: Concentrate for the preparation of solution for infusion 10 mg/ml; capsules 20 mg, 30 mg.

Compound

Concentrate for solution for infusion 10 mg/ml

Capsules

Description

Concentrate: transparent solution from colorless to pale yellow. Capsules: soft gelatin capsules (oval, size 3) 20 mg, light brown, marked “N20” in red. The contents of the capsules are a viscous solution from light yellow to orange-yellow. Soft gelatin capsules (oblong, size 4) 30 mg, pink with “N30” written in red. The contents of the capsules are a viscous solution from light yellow to orange-yellow.

Pharmacological properties

Pharmacodynamics: Vinorelbine (vinca rosea alkaloid, obtained semi-synthetically) is an antitumor agent from the group of vinca alkaloids.

It disrupts the polymerization of tubulin during cell mitosis. Blocks mitosis in the G2-M phase and causes cell destruction in interphase or during subsequent mitosis. Acts primarily on mitotic microtubules; when used in high doses, it also affects axonal microtubules. The effect of tubulin helicalization caused by vinorelbine is less pronounced than that of vincristine.

Pharmacokinetics: After intravenous administration of the drug, three-phase kinetics can be observed. The average half-life in the final phase is 40 (27.7-43.6) hours. When taken orally, it is quickly absorbed from the gastrointestinal tract. Maximum concentrations are reached after 1.5-3 hours. Absolute bioavailability averages 40%. Food intake does not affect the degree of absorption.

Plasma protein binding is 13.5%. Intensively binds to blood cells and especially platelets (78%). Penetrates well into tissues and lingers in them for a long time. High concentrations are determined in the spleen, liver, kidneys, lungs and thymus gland, moderate concentrations in the heart and muscles, minimal concentrations in adipose tissue and bone marrow. Does not penetrate the blood-brain barrier. The concentration in the lungs is 300 times higher than the concentration in plasma. Metabolized in the liver, mainly under the action of the CYP 3A4 enzyme isoform, which belongs to the cytochrome P450 system. Forms a number of metabolites; one of the metabolites, diacetylvinorelbine, which is the main metabolite in the blood, retains antitumor activity. It is excreted primarily in bile.

The pharmacokinetics of Navelbine administered at a dose of 20 mg/m2 weekly in patients with moderate or severe hepatic impairment does not change. The pharmacokinetics of Navelbine does not depend on the age of patients.

Indications:

• non-small cell lung cancer;
• mammary cancer;
• prostate cancer resistant to hormone therapy (in combination with low doses of oral corticosteroids).

Contraindications:

• hypersensitivity to vinca alkaloids or other components of the drug;
• neutrophil content <1500 cells/μl of blood, platelet count <75,000 cells/μl of blood (with intravenous administration) and <100,000 cells/μl of blood (with oral administration);
• severe infectious diseases during the initiation of therapy or suffered during the last 2 weeks;
• severe liver dysfunction not associated with a tumor process;
• the need for constant oxygen therapy – in patients with a lung tumor;
• diseases and conditions leading to decreased absorption in the gastrointestinal tract (for Navelbine capsules);
• pregnancy and lactation period.

Use with caution in case of respiratory failure, suppression of bone marrow hematopoiesis (including after previous chemotherapy or radiation treatment), constipation or a history of intestinal obstruction, a history of neuropathy.

Directions for use and doses

Navelbine is used both as monotherapy and in combination with other anticancer drugs. When choosing a dose and mode of administration in each individual case, you should refer to specialized literature.

Navelbine concentrate is administered strictly intravenously in the form of a 6-10-minute infusion. The capsules are taken orally whole with water, without chewing or dissolving in the mouth. In monotherapy mode, the usual dose of the drug for intravenous administration is 25-30 mg/m2 of body surface once a week.

Navelbine is diluted in 0.9% sodium chloride solution or 5% dextrose solution to a concentration of 1.0-2.0 mg/ml (average 50 ml). After administering the drug, the vein should be rinsed by injecting an additional at least 250 ml of 0.9% sodium chloride solution or 5% dextrose solution.

For patients with a body surface area ≥2 m2, a single dose of Navelbine administered intravenously should not exceed 60 mg.

The recommended single initial dose of Navelbine for oral administration is 60 mg/m2 of body surface once a week. After the third dose, it is recommended to increase the dose to 80 mg/m2.

An increase in the dose from 60 mg/m2 to 80 mg/m2 can be carried out if during three weeks of taking Navelbine there was no grade 4 neutropenia (<500 cells/µl) or there was one episode of grade 3 neutropenia (<1000 cells/µl and ≥ 500 cells/µl) and the neutrophil content before the next dose is not lower than 1500 cells/µl.

If, when using Navelbine at a dose of 80 mg/m2, grade 4 neutropenia (<500 cells/μl) or 2 cases of grade 3 neutropenia (<1000 cells/μl and ≥500 cells/μl) is observed, in the next 3 doses it is necessary to reduce the dose of Navelbine with 80 to 60 mg/m2 per week.

If the neutrophil count did not decrease to less than 500 cells/μl or more than one decrease in the neutrophil count in the range of 500 to 1000 cells/μl was observed during three weeks of taking Navelbine at a dose of 60 mg/m2 (as recommended above), you can increase the dose again drug from 60 to 80 mg/m2 per week.

The recommended doses of Navelbine capsules based on the patient's body surface area (BSA) are given in the following table.

For patients with BSA≥2 m2, the total single dose of Navelbine taken orally should never exceed 120 mg per week when prescribed at a dose of 60 mg/m2 and 160 mg per week when prescribed at a dose of 80 mg/m2.

The use of Navelbine orally in doses of 60 mg/m2 and 80 mg/m2 corresponds to the intravenous administration of Navelbine in doses of 25 mg/m2 and 30 mg/m2.

During polychemotherapy, the dose and frequency of administration of Navelbine (both intravenously and orally) depend on the specific antitumor therapy program.

If the neutrophil count decreases <1500 cells/μl or thrombocytopenia <75,000 cells/μl of blood (with intravenous administration) or <100,000 cells/μl of blood (with oral administration), the next administration or oral administration of Navelbine is postponed for 1 week. If, due to hematological toxicity, it was necessary to refrain from 3 weekly administrations or doses of the drug, it is recommended to discontinue the use of Navelbine.

Correction of the Navelbine dosage regimen for liver failure : in patients with severe liver failure, Navelbine should be prescribed with caution, at a dose reduced by 33%.

Children : the safety and effectiveness of Navelbine in children has not been studied.

Elderly : There are no special instructions for the use of Navelbine in the elderly.

Side effects: Adverse reactions that occurred more often than in isolated cases are listed according to the following gradation: very often (>1/10), often (>1/100, <1/10), sometimes (>1/1000, <1/100), rare (>1/10000, <1/1000), extremely rare (<1/10000).

From the hematopoietic organs: very often - neutropenia, anemia, thrombocytopenia, secondary infections against the background of suppression of bone marrow hematopoiesis; often – fever (>38°C) accompanied by neutropenia; sometimes – sepsis, septicemia; extremely rarely - complicated septicemia, in some cases leading to death.

The lowest number of neutrophils is observed on days 7-10 from the start of therapy, recovery occurs in the next 5-7 days. No accumulation of hematotoxicity was observed.

From the immune system: rarely - anaphylactic shock or angioedema.

From the nervous system: very often - paresthesia, hyperesthesia, decrease or loss of deep tendon reflexes; often - weakness in the legs; sometimes - severe paresthesia with sensory and motor symptoms, usually reversible.

From the cardiovascular system: sometimes - increased or decreased blood pressure, hot flashes and cold extremities; rarely – coronary heart disease (angina pectoris, myocardial infarction), severe hypotension, collapse; extremely rarely - tachycardia, palpitations and cardiac arrhythmias.

From the respiratory system: sometimes - shortness of breath, bronchospasm; rarely – interstitial pneumonia (with combination therapy with mitomycin), acute respiratory distress syndrome.

From the digestive system: very often - nausea, vomiting, stomatitis, constipation, diarrhea, transient increase in liver function tests (ALT, AST); rarely - pancreatitis, increased bilirubin levels, intestinal paresis.

From the skin and skin appendages: often – alopecia; rarely - skin rashes.

Local reactions: often - pain/burning or redness at the injection site, discoloration of the vein, phlebitis; with extravasation - cellulite, possibly necrosis of surrounding tissues.

Other: often - increased fatigue, myalgia, arthralgia, fever, pain of various locations, including chest pain, pain in the lower jaw and in the area of ​​​​tumor formations; rarely - hyponatremia; very rarely - hemorrhagic cystitis and syndrome of inappropriate secretion of antidiuretic hormone.

Overdose: The main expected effects of overdose include suppression of bone marrow function and manifestations of neurotoxicity. A specific antidote is unknown. In case of overdose, the patient should be hospitalized and the functions of vital organs should be carefully monitored. Treatment is symptomatic.

Interaction with other drugs and other types of interactions

When used together with other cytostatics, mutual aggravation of side effects is possible, primarily myelosuppression.

When used together with mitomycin C, acute respiratory failure may develop.

When used in combination with paclitaxel, the risk of neurotoxicity increases. Use during radiation therapy leads to radiosensitization. The use of Navelbine after radiation therapy can lead to the reappearance of radiation reactions.

Concomitant use of the drug with inducers and inhibitors of cytochrome P450 may lead to changes in the pharmacokinetics of Navelbine.

special instructions

Treatment with Navelbine should be carried out under the supervision of a physician experienced in working with anticancer drugs.

Treatment with Navelbine is carried out under strict hematological control, determining the number of leukocytes, neutrophils, platelets and hemoglobin level before each injection or oral administration. If the neutrophil count is less than 1,500 cells/μl and/or platelet count is less than 75,000 cells/μl (with intravenous administration) and less than 100,000 cells/μl (with oral administration), the next dose should be postponed until normal levels are restored.

In case of severe impairment of liver function, the dose of Navelbine should be reduced by 33%.

If renal function is impaired, increased monitoring of the patient is necessary. If signs of neurotoxicity of grade 2 or more appear, the use of Navelbine should be discontinued.

If shortness of breath, cough or hypoxia of unknown etiology occurs, the patient should be examined to exclude pulmonary toxicity.

If extravasation occurs, the drug infusion should be stopped immediately and the remaining dose should be administered into another vein.

If nausea or vomiting occurs after taking Navelbine capsules, the same dose should not be taken.

Reliable contraception must be used during and for at least three months after discontinuation of therapy.

If the active substance gets into the oral cavity, it is recommended to rinse your mouth with water or any saline solution.

If Navelbine gets into your eyes, rinse them copiously and thoroughly with water.

Due to the presence of sorbitol, Navelbine should not be used in patients with hereditary fructose intolerance.

Release form: Concentrate for the preparation of a solution for infusion of 1 ml (10 mg) and 5 ml (50 mg) in colorless glass bottles, sealed with a stopper made of butyl or chlorobutyl rubber (elastomer), rolled with an aluminum cap with a plastic lid. 10 bottles each in a polystyrene foam package (thermal container) with attached instructions for use. One thermal container in a cardboard box.

Capsules of 20 mg, 30 mg in blisters made of PVC/PVDC and aluminum foil. One capsule in a blister. One blister with attached instructions for use in a cardboard box.

Storage conditions: List B.

Concentrate for preparing a solution for infusion: at a temperature of 2° to 8°C, in a place protected from light and out of reach of children.

Capsules: at a temperature of 2° to 8°C, out of the reach of children.

After additional dilution of the drug, its physical and chemical stability is maintained for 8 days at room temperature (20°±5°C) or in the refrigerator (at a temperature of 2° to 8°C).

From a microbiological point of view, the drug should be used immediately after dilution. If the drug is not administered immediately, the healthcare professional assumes responsibility for the conditions and duration of its storage prior to administration. Typically, such storage should not exceed 24 hours at a temperature of 2° to 8°C, unless dilution is carried out under controlled and validated aseptic conditions.

Shelf life: Concentrate – 3 years. After additional dilution of the drug with saline or glucose solution, the shelf life is 24 hours at room temperature. Capsules 20 and 30 mg – 2.5 years. Do not use after the expiration date stated on the packaging.

Dispensing conditions: By prescription.

Use of the drug Vinorelbine 'ebeve'

Intended for intravenous administration only. It is strictly forbidden to administer the drug intrathecally! Before administering the infusion solution, you must make sure that the needle is in the vein. If the drug gets into the tissue surrounding the vessel, significant irritation may occur. In case of extravasation, the drug should be stopped immediately and continued into another vein. Use in adults In monotherapy, vinorelbine is usually administered in doses of 25–30 mg/m2 of body surface area weekly. In the case of combination therapy, the drug can be administered in the same doses, but at longer intervals, for example on the 1st and 5th day or the 1st and 8th day of a course lasting 3 weeks. Vinorelbine can be administered by slow IV injection (duration 5–10 min) after dilution of 20–50 ml of 0.9% sodium chloride solution or by short IV infusion (duration 20–30 min) after dilution of 125 ml 0 .9% sodium chloride solution. After completing the administration of the drug, 0.9% sodium chloride solution is always administered to rinse the vein. Dose adjustment In case of severe liver dysfunction, the dose of vinorelbine should be reduced (usually the dose is reduced by a third or more). In case of severe renal impairment, there is no need to reduce the dose, since vinorelbine is excreted primarily in bile. During treatment with vinorelbine, peripheral blood patterns should be constantly monitored. The maximum single dose of the drug is 35 mg/m2 of body surface. The maximum course dose is 60 mg. Instructions for personnel The concentrate for the preparation of solution for infusion can be diluted with 0.9% sodium chloride solution or 5% glucose solution. The amount of solution required is determined by the method of administration (slow IV injection or fast IV infusion). From a microbiological point of view, the diluted solution should be used immediately. If the solution for infusion is not used immediately after preparation, the period and conditions of its storage are controlled by the responsible person. From a microbiological point of view, the storage period for the solution should usually not exceed 24 hours at a temperature of 2–8 °C, unless it has been diluted under controlled aseptic conditions. Infusion solutions prepared by diluting Vinorelbine "Ebewe" with 0.9% sodium chloride solution or 5% glucose solution are physically and chemically stable for 28 days if stored in the refrigerator or at room temperature, protected from light place. If stored at room temperature, away from light, infusion solutions remain stable for 4 days. Only transparent, colorless or light yellow solutions can be used. When working with Vinorelbine "Ebewe", as with other cytotoxic drugs, you should be careful and be sure to use gloves, masks and protective clothing. The preparation of solutions for infusions should be carried out by trained personnel in a specially designated area. The workplace must be covered with disposable sheets of absorbent paper with a film coating on the reverse side. Pregnant women are not allowed to work with the drug. Avoid contact of vinorelbine with the eyes as this may cause severe irritation, including the formation of corneal ulcers. If this does happen, you should immediately rinse your eyes with a large amount of 0.9% sodium chloride solution (rinse for 15 minutes). Unused solutions, instruments and materials that have come into contact with vinorelbine solutions should be destroyed according to procedures determined by local health authorities.

Navelbine (vinorelbine) in the treatment of lung cancer

Non-small cell lung cancer is now considered a tumor sensitive to chemotherapy due to the introduction into widespread clinical practice of modern drugs such as navelbine, paclitaxel, docetaxel, gemcitabine, and irinotecan. The standards of first-line chemotherapy for NSCLC include combinations based on platinum derivatives and one of the above drugs, which allows for an overall effect in 40–60% of patients and a one-year survival rate of 30–50%. Navelbine, a semisynthetic vinca alkaloid, inhibits the polymerization of microtubule tubulin. Already during phase I–II clinical trials, the effectiveness of Navelbine in patients with disseminated NSCLC was noted. In these studies, Navelbine was administered at a dose of 25–30 mg/m2 once a week for 2–3 months until toxicity occurred. The dose-limiting toxicity was grade III–IV neutropenia in 21% [1]. A low level of other side effects was noted: infection, nausea, vomiting, alopecia, peripheral neuropathy. Table 1 presents the results of phase II study of Navelbine in stage III–IV NSCLC. [2]. When studying Navelbine monotherapy in 76 patients with NSCLC in the chemotherapy department of the Russian Cancer Research Center named after. N.N. Blokhin, Russian Academy of Medical Sciences, the overall effect was noted in 30.2%, the median survival was 36 weeks [3]. The results obtained (overall effect 12–31.1%, survival 25–52.4 weeks) served as the basis for organizing and conducting large phase III clinical trials of Navelbine in patients with NSCLC, to study the effectiveness of Navelbine in combination with platinum derivatives, because . Previously, the standard combination for the treatment of NSCLC was cisplatin + etoposide. The effectiveness of combinations of Navelbine with cisplatin and carboplatin is presented in Tables 2 and 3.

In the chemotherapy department of the Russian Cancer Research Center named after. N.N. Blokhin Russian Academy of Medical Sciences, 44 patients with stage III–IV NSCLC received the combination of Navelbine + cisplatin in the 1st line of treatment. The regimen used was: Navelbine 25 mg/m2 on days 1, 8, 15, 22 + cisplatin 100 mg/m2 on day 1. The treatment cycle is 28 days. The overall effect was obtained in 43.2%, the complete effect was 2.3%, stabilization of the process was 22.7%. Median survival was 46 weeks, one-year survival rate was 38.6%. The main types of toxicity were neutropenia (grade III–IV 77.2%), anemia (grade III–IV 22.7%), neurotoxicity (grade I–II 4.5%) [2]. In recent years, multicomponent chemotherapy regimens based on cisplatin and new cytostatics have been actively studied in NSCLC in order to increase the effectiveness of treatment. Similar studies are being carried out with Navelbine (Table 4). Summary data on clinical trials with three cytostatics for NSCLC are presented in Table 5. As can be seen from the presented data, Navelbine is well combined with both platinum derivatives and other new drugs for the treatment of NSCLC and is not inferior to them in effectiveness. In the work of K. Takeda, 2002 [22], there were also no differences in effectiveness when comparing combinations of irinotecan + cisplatin, paclitaxel + cisplatin, gemcitabine + cisplatin, Navelbine + cisplatin (cooperative study of 602 patients). If it is impossible to use platinum derivatives in patients with NSCLC, many researchers use combinations that include Navelbine. For patients with NSCLC who have received 1 line of chemotherapy, an active search is underway for effective combinations among new drugs. According to Pectasides et al., [27] in the 2nd line, Navelbine in combination with irinotecan (Navelbine 25 mg/m2 on days 1.15 + irinotecan 150 mg/m2 on days 1.15, every 28 days) was effective in 14. 6% of patients with stabilization in 21.3% of patients and median survival of 7.8 months. The combination: gemcitabine 1000 mg/m2 + Navelbine 25 mg/m2 1.5 days every 28 days in the 2nd line (after paclitaxel and carboplatin) was effective in 11 out of 28 patients (partial effect), stabilization of the process in 9 out of 28 patients, median survival was 18 weeks (Table 6) [28]. Given its good tolerability, Navelbine is actively used in elderly patients, both in monotherapy and in combinations (Table 7). Monotherapy with Navelbine in the elderly provides an effect of 19.7–39.1% with a median survival of 29–53 weeks [29]. In recent years, neoadjuvant chemotherapy for NSCLC has been actively developing and this has been proven for stage III. diseases [35]. Naturally, as one of the new drugs active in NSCLC, Navelbine is being studied in adjuvant and neoadjuvant chemotherapy regimens. According to Martins et al. [36], with neoadjuvant use of the combination Navelbine + cisplatin, 27% of patients with stage III. NSCLC were operated on, 70% had a complete effect, 22.5% were alive for 3 years. Combination of cisplatin + epirubicin + Navelbine (3 courses before surgery) in elderly patients with stage IIIA NSCLC. allowed to obtain an overall effect in 55% and 66% of patients underwent surgery [37]. According to MOKOB data [38], with neoadjuvant use of 2 cycles of chemotherapy according to the regimen of cisplatin 100 mg/m2 on day 1 + Navelbine 25 mg/m2 on days 1 and 8, an objective effect was noted in 63%, stabilization in 28.6%, surgery was performed 89% of patients. Pathomorphosis of grade III–IV – in 31% of patients. When assessing long-term results after 24 months of observation, there was a significant increase in life expectancy of patients receiving chemotherapy compared with simply operated patients. Table 8 summarizes the data from all 9 comparative randomized clinical trials of phase III, which most fully characterize the place of Navelbine in chronic NSCLC. Summarizing the data from the above studies (more than 1750 patients), we can conclude that the combination of Navelbine + cisplatin in stage IIIB–IV NSCLC. provides: objective response in 25–44%, median survival 8–11.6 months, 1-year survival 33–48%. Thus, the combination of Navelbine + cisplatin is one of the optimal first-choice options for chronic NSCLC, and the doctor’s decision is made taking into account the individual characteristics of the patient, the toxicity profile of cytostatics and the cost of treatment. For many years, the feasibility of adjuvant (postoperative) chemotherapy in patients with early stages of NSCLC who have undergone radical surgery has remained a subject of debate. A significant contribution to the argument “for” comes from the results of a phase III study published at ASCO 2004 (Winton T. et al. Phase III randomized trial or adjuvant vinorelbine and cisplatin in completely resected stage IB and II nonsmall cell lung cancer. Proc.Am Soc. Clin. Oncol. 2004; Vol 23: abstr. 7018 - oral communication). It was shown that as a result of the use of x/t Navelbine 25 mg/m2 weekly. + cisplatin 50 mg/m2 D1, cycle 8 4 weeks, 4 cycles after radical surgery in patients with NSCLC achieved (compared to the control group): – increase in 5-year disease-free survival by 13% (61% vs48%) – increase 5– year overall survival by 15% (69% vs54%) The results are highly reliable. The combination of Navelbine with cisplatin, thus, provides a dramatic improvement in the results of treatment of early stages of NSCLC. Considering that the standard treatment for patients with inoperable stage III NSCLC is combined chemoradiotherapy, in recent years active research has been conducted on the use of new drugs, including Navelbine, in combination with various radiation regimens (hyperfractionation, combined use). When navelbine is used in combination with platinum derivatives and various irradiation regimens in inoperable patients with NSCLC, the overall effect can be obtained in 60–83% of cases [40,41,42]. Research continues. An oral form of Navelbine has been developed, which is equal in effectiveness to the intravenous form, is more convenient to use and is currently being actively studied in various combinations for NSCLC [43,44]. Standard regimen for oral Navelbine (monotherapy): 60 mg/m2 once a week for 3 injections, then 80 mg/m2 per week under the control of blood counts. In a few studies in small cell lung cancer (SCLC), the effectiveness of Navelbine in the 1st line is 27%, in the 2nd line – 12–16% with a remission duration of 10–17 weeks. The combination of Navelbine with Vepezid and cisplatin is effective in 77% in localized SCLC and 40% in disseminated SCLC [45]. One of the most actively studied areas in the treatment of NSCLC is the use of “targeted” drugs in combination with chemotherapy. Phase I of a clinical study of the combination Navelbine + Tarceva (an inhibitor of tyrosine kinase receptors of epidermal growth factor) in patients with HMSPL has begun [46]. When using cetuximab in combination with cisplatin and Navelbine in patients with NSCLC, the overall effect was observed in 59%, and in the group receiving only chemotherapy, the overall effect was 36% [47]. The research is ongoing. Thus, Navelbine is one of the effective drugs included in the standard treatment regimens for NSCLC, has moderate toxicity, is well combined with other drugs and radiation therapy, and can be used on an outpatient basis, as well as in elderly and debilitated patients.

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Oncol., 1996, v. 7, suppl. 5, p. 98, N464P. 16. Niho S., Kubota K., Araki K., et al. A phase P study of gemcitabine, vinorelbine and cisplatine in advanced NSCLC. ASCO, 2001, v. 20, p. 241b, N2716. 17. Friedman EL, Straus MI, Ambunder JM Vinorelbine, paclitaxel and carboplatin for adenocarcinoma of the lung. ASCO, 2000, v. 19, p. 512, N2004. 18. Bameto J., Sanchez RP, Noguer M., et al. Alteraant chemotherapy with cisplatin, vinorelbine and gemcitabine–paclitaxel as first–line treatment for advanced NSCLC. ASCO, 2001, v. 20, p. 241b, N2715. 19. Hosoe S., Komuta K., Shibata K., et al. Gemcitabine and vinorelbine followed by docetaxel in patients with advanced NSCLC: final results of phase II trial of sequential non-platinum triplet combination chemotherapy. Proc. ASCO, 2002, v. 21, 315a, N1259. 20. Buffani L., Dougiovanni D., Addeo A., et al. Sequential chemotherapy with cisplatin / vinorelbine followed by paclitaxel / gemcitabine in advanced NSCLC: a phase II study. Proc. ASCO, 2002, v. 21, p. 21 Ib, N2664. 21. Bum P., Kelly K., et al. Clinical Lung Cancer. 2000, 2 (suppl. 1), 23–8. 22. Takeda K., Negoro S., Ohashi Y., et al. Preliminary Results of Four Arm Cooperative Study for Advanced Non–Small Cell Lung Cancer in Japan. Lung Cancer, 2003, v. 41, suppl. 2, s. 64, N.0–219. 23. Katakami N., Nishimura T., Sugiura T., et al. Vinorelbine plus gemcitabine in the treatment of chemotherapy naive stage IIIB/IV NSCLC. ASCO, 2001, v.20, p.255b, N2773. 24. Westeel V., Breton J., Braun D., et al. Gemcitabine and vinorelbine – a phase II study of a weekly low-dose combination without rest in advanced NSCLC. ASCO, 2001, v. 20, p. 250b, N 2751. 25. Tsao A., Kirn ES, Nazario A., et al. Phase II study of vinorelbine and docetaxel in the treatment of advanced non–small cell lung cancer as front line and second line therapy. Proc. ASCO, 2003, v. 22, 691, N 2779. 26. Nagashima S., Nakamura Y., Kasai T., et al. Phase I study of vinorelbine and weekly irinotecan as first line chemotherapy in patients with advanced non–small cell lung cancer. Proc. ASCO, 2003, v. 22, 698, N 2808. A complete list of references can be found on the website https://www.rmj.ru 27. Pectasides DG, Fountzilas G., Rigopoulos A., et al. An outpatient second–line chemotherapy with irinotecan and vinorelbine in patients with NSCLC previously treated with cisplatin–based chemotherapy. Proc. ASCO, 2002, v. 21, p.327a, N1307. 28. Moutalar J., Lopez-Tendeno P., Diaz-Bedverdge R., et al. Gemcitabine–Vinorelbine as second line chemotherapy in advanced non–small cell lung cancer previously treated with Paclitaxel , Carboplatin. Lung Cancer, 2003, v.41, suppl.2, s.95, P–19. 29. Besova N.S. Chemotherapy of non-small cell lung cancer in the elderly. In: “New in Lung Cancer Therapy,” ed. Prof. N.I. Perevodchikova, 2003, pp. 133–143. 30. Lippe P., Imperatory I., Casadei V., et al. Weekly cisplatin and vinorelbine in advanced non small cell lung cancer elderly patients. A phase II study. Ann. Oncol., v. 11, suppl. 4, 2000, p. 73, N321. 31. Martins S., Perreira J., Ikari F., et al. Chemotherapy with cisplatin and vinorelbine for elderly non–small cell lung cancer patients. Proc. ASCO, 1999, v. 18, N1890. 32. Maestu I., Munoz J., Lorenzo GA, et al. Assessment of comorbidity, symptoms and functional status in advanced non small cell lung cancer elderly patients treated with gemcitabine and vinorelbine. Lung Cancer, 2003, v. 41, suppl. 2, s. 91, N. P–2. 33. Le Caer H, Delhoume JY, Thomas PA, et al. A multicenter phase II study of carboplatin / vinorelbine in advanced non–small cell lung cancer in elderly patients. Lung Cancer, 2003, v. 41, suppl. 2, s. 93, N.

Side effects of the drug Vinorelbine 'ebeve'

From the blood system The dose-limiting factor during vinorelbine therapy is neutropenia. It is reversible (indicators quickly (after 5–7 days) normalize) and non-cumulative. The following courses of treatment can be prescribed only after the granulocyte count has normalized. Anemia and thrombocytopenia also occur, but are rarely severe. On the part of the immune system Like other vinca alkaloids, vinorelbine in isolated cases can cause the development of shortness of breath and bronchospasm, and also extremely rarely - local and generalized skin reactions. From the nervous system: Peripheral neuropathy. Damage is usually limited to decreased or loss of deep tendon reflexes. Paresthesia is possible. These effects are dose-dependent and disappear after cessation of treatment. Autonomic neuropathy. Its main symptom is intestinal paresis, which causes constipation. In some cases, paralytic intestinal obstruction may develop. Treatment with vinorelbine can be continued after normal peristalsis has been restored. Vascular disorders: With repeated administration of vinorelbine, burning pain at the injection site and local phlebitis are possible. When vinorelbine is administered by bolus injections with further lavage of the vein with a large amount of 0.9% sodium chloride solution, this effect is less pronounced. In some cases, vinorelbine must be administered through a central venous catheter. From the gastrointestinal tract Constipation (see side effects from the nervous system), diarrhea, nausea/vomiting; To reduce the severity of these effects, antiemetic drugs are used. Skin and subcutaneous tissue disorders Alopecia (its severity may progressively increase with repeated courses of treatment). General side effects and local reactions Sometimes there is pain in the jaws. Paravenous administration can cause local reactions (in isolated cases, tissue necrosis). Apparently, vinorelbine has mutagenic properties, given its effect on the mitotic apparatus of the cell. With prolonged administration of vinorelbine to laboratory animals every 2 weeks, no carcinogenic effects were observed. Experiments on animals have demonstrated the embryo- and feto-lethal and teratogenic effects of vinorelbine.

Special instructions for the drug Vinorelbine 'ebeve'

During treatment with vinorelbine, hematological parameters should be constantly monitored (before each administration of the drug, the level of hemoglobin, the number of leukocytes, granulocytes and platelets should be determined). If the neutrophil granulocyte count decreases to ≤2000/mm3, administration of vinorelbine should be delayed until bone marrow function is restored and the patient should be under medical supervision. If symptoms of infectious processes appear, the patient must be immediately examined and appropriate treatment prescribed. In case of significant impairment of liver function, the dose of vinorelbine should be reduced. In case of impaired renal function, there is no need to reduce the dose of the drug, since renal excretion of vinorelbine is negligible. Vinorelbine should not be administered in combination with radiation therapy to the liver area. There are currently no data on the effectiveness and safety of treatment with vinorelbine in children. Vinorelbine should not be prescribed during pregnancy. Patients should use effective methods of contraception during treatment with the drug. If pregnancy occurs during vinorelbine therapy, a genetic specialist should be consulted regarding further actions. It is not known whether vinorelbine is excreted in breast milk, so breastfeeding should be discontinued before starting treatment with the drug. It is not known whether vinorelbine affects the ability to drive vehicles and use machines.

Navelbine (Vinorelbine) capsules 20 mg No. 1 - Instructions

Compound

The main functional substance is vinorelbine.
Other components: anhydrous ethanol, purified water, glycerin, macrogol 400.

Release form

The drug is in the form of capsules. Supplied in packages of one capsule each.

pharmachologic effect

The chemical compound in question belongs to a group of drugs from the group of vinca alkaloids, that is, organic compounds with a complex chemical structure. The anticancer drug is pink periwinkle alkaloid. This determines the pharmacodynamics of Navelbine, which is expressed in the ability of the drug to block indirect division of eukaryotic cells (mitosis) even during the G2-M metaphase. This influence causes cells to die during the interphase period when the cell is "quiescent", or during the next division.

Vinorelbine at the molecular level influences the dynamic features of the interaction between a group of cell microtubules and tubulin. In this case, the antitumor drug reduces tubulin polymerization, mainly due to contact with mitotic microtubules. If the drug is administered in a significant dose, and the concentration of the active substance in the patient’s body increases, then Navelbine begins to act on axonal microtubules.

In the case of coiled tubulin, this characteristic appears somewhat less frequently than when the patient's vincristine enters the body.

Pharmacokinetics

The bioavailability of vinorelbine when taken orally is 40%, regardless of food intake. The maximum concentration of the drug is achieved 1.5-3 hours after administration. The concentration increases with increasing dose until a dose of 100 mg/m2 is reached, above which no further increase in concentration is observed.

The component is widely distributed in tissues (mainly in the lungs), where it reaches concentrations 300 times higher than in blood serum. The degree of binding to plasma proteins is low and amounts to 13.5%, while the drug binds to blood cells to a much greater extent, especially platelets (78%).

Metabolized mainly by the enzyme CYP3A4. The main metabolite is 4-O-deacetylvinorelbine, which is probably formed by carboxylesterase and is the only pharmacologically active metabolite. Other metabolites are vinorelbine N-oxide, 20\'-hydroxyvinorelbine and 6\'-vinorelbine oxide. The drug is not conjugated with sulfuric or glucuronic acid.

The half-life is 40 hours, and the half-life of the active metabolite 4-O-deacetylvinorelbine is 168 hours. The drug is mainly excreted unchanged in feces (bile) and to a small extent in urine.

Indications for use

Navelbine is used in advanced non-small cell lung cancer (stages III and IV), as well as in the treatment of metastatic breast cancer (stage IV), when anthracycline and taxane therapy is ineffective or impossible.

Contraindications

A strict limitation is the presence of hypersensitivity to the constituent substances. The medication is also contraindicated in people who require long-term therapy and with diseases that may affect the absorption of the drug, as well as in patients after surgical removal of the stomach or small intestine.

Side effects

The following negative reactions may occur when taking the medicine:

• infections in different places;
• stomach disorders: diarrhea, constipation, abdominal pain, nausea, vomiting;
• inflammation of the oral mucosa;
• a decrease in the number of red blood cells, which can make the skin pale and cause weakness or shortness of breath;
• a decrease in the number of platelets in the blood may lead to an increased risk of bleeding or bruising;
• a decrease in the number of white blood cells, which may increase susceptibility to infections;
• weakness of some reflexes, sometimes impaired sensitivity;
• hair loss, usually mild;
• fatigue;
• heat;
• weight loss, loss of appetite.

Compatibility with other medications

It is not recommended to combine the drug with:

1. blood thinners;
2. anticonvulsants;
3. antifungal drugs;
4. anticancer drugs such as mitomycin C or lapatinib;
5. medications that weaken the immune system.

Taking Navelbine with other medications that damage bone marrow (causing changes in blood counts) may make some side effects worse.

St. John's wort (Hypericum perforatum) may increase the metabolism of vinorelbine, thereby reducing its blood concentration and reducing the effectiveness of its anticancer effect.

Application and dosage

The dose to be treated depends on body weight, comorbidities (eg, liver failure), neutrophil count, concomitant medications in the anticancer treatment regimen, etc.

Usual weekly doses for adults: 60–80 mg/m2 body surface area. Maximum doses of 120–160 mg/m2 body surface area should not be exceeded, even if the body surface area calculation yields a higher dose.

It is assumed that an oral dose of 80 mg/m2 body surface area corresponds to an intravenous dose of 30 mg/m2 body surface area, and an oral dose of 60 mg/m2 body surface area corresponds to an intravenous dose of 25 mg/m2 body surface area. This is important when alternating the oral and intravenous forms.

Overdose

Taking too much Navelbine may lead to bone marrow hypoplasia associated with symptoms such as fever, infections, paralytic ileus and liver dysfunction.

special instructions

The medicine should be prescribed with caution to patients with coronary heart disease and poor physical fitness.

If nausea and vomiting occur, prophylactic use of antiemetic drugs is recommended.

Use during pregnancy and breastfeeding

No appointment allowed.

Impact on the ability to drive vehicles and operate machinery

No special precautions are required.

Terms of sale

As prescribed by the doctor.

Storage conditions

In a temperature range of 2 to 8 degrees Celsius in a place with limited access for children.

Drug interactions Vinorelbine 'ebeve'

When used in combination with cisplatin, the pharmacokinetics of vinorelbine do not change. The concentrate for preparing a solution for infusions of Vinorelbine “Ebewe” cannot be diluted with alkaline solutions due to the risk of sedimentation. In the case of combination chemotherapy, Vinorelbine "Ebewe" cannot be mixed with other drugs. The concentrate for preparing a solution for infusions Vinorelbine “Ebewe” can be diluted only with the solutions specified in the APPLICATION section. Vinorelbine is not absorbed and does not interact with infusion systems made of polyvinyl chloride, polyethylene or neutral flint glass.