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DBL™ Vinorelbine Injection Concentrate Name of the Medicine Vinorelbine Tartrate CAS No: 125317-39-7 the Chemical Structure of Vinorelbine Tartrate Is Shown Below

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DBL™ Vinorelbine Injection Concentrate Name of the Medicine Vinorelbine Tartrate CAS No: 125317-39-7 the Chemical Structure of Vinorelbine Tartrate Is Shown Below DBL™ Vinorelbine Injection Concentrate Name of the Medicine Vinorelbine Tartrate CAS No: 125317-39-7 The chemical structure of vinorelbine tartrate is shown below: Description Vinorelbine tartrate is a semi-synthetic vinca alkaloid with antitumour activity. The chemical name is 3’,4’-didehydro-4’-deoxy-C’- norvincaleukoblastine [R-(R*,R*)-2,3 dihydroxybutanedioate (1:2)(salt)]. Vinorelbine tartrate is a white to yellow or light brown amorphous powder with the molecular formula C45H54N4O8.2C4H6O6 and molecular weight of 1079.12. The aqueous solubility is > 1000 mg/mL in distilled water. DBL™ Vinorelbine Injection Concentrate is a clear colourless to pale yellow solution containing 10 mg vinorelbine per mL (present as 13.85 mg of vinorelbine tartrate), in water for injections. The pH of DBL™ Vinorelbine Injection Concentrate is approximately 3.0 to 4.0. Pharmacology Vinorelbine is a cytostatic antineoplastic drug. It is a semi-synthetic member of the vinca alkaloid family that interferes with microtubule assembly. The vinca alkaloids are structurally similar compounds comprised of two multiringed units, vindoline and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for vinorelbine. The antitumour activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. In intact tectal plates from mouse embryos, vinorelbine, vincristine, and vinblastine inhibited mitotic microtubule formation at the same concentration (2 micromolar), including a blockade of cells at metaphase. Vincristine produced depolymerisation of axonal tubules at 5 micromolar, but vinblastine and vinorelbine did not have this effect until concentrations of 30 micromolar and 40 micromolar respectively. These data suggest relative selectivity of vinorelbine for mitotic microtubules. Vinorelbine has an active metabolite, 17 deacetylvinorelbine, low levels of which are recovered in humans: its toxicity and activity are slightly higher than those of vinorelbine. Pharmacokinetics Following intravenous (IV) administration of vinorelbine tartrate to patients at 30 mg/m2, concentration in plasma decays in a triphasic manner. The initial rapid decline primarily represents distribution of the drug to peripheral compartments followed by metabolism and excretion of the drug during subsequent phases. The prolonged terminal phase is due to relatively slow efflux of vinorelbine from peripheral compartments. The terminal phase half life averages 27.7 to 43.6 hours and the mean clearance ranges from 0.6 to 1.3 L/h/Kg. Vinorelbine demonstrated high binding to human platelets and lymphocytes. The binding to plasma constituents in cancer patients ranged from 79.6% to 92.2%. Vinorelbine binding was not altered in the presence of cisplatin, fluorouracil, or doxorubicin. Penetration of vinorelbine into pulmonary tissue is significant with tissue/plasma concentration ratios of greater than 300 in a study involving surgical biopsy. Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in faeces after IV administration to humans. One active metabolite, deacetylvinorelbine, has been detected but not quantified in human plasma. The effects of renal or hepatic dysfunction on the disposition of vinorelbine have not been assessed, but based on experience with other anticancer vinca alkaloids, dose adjustments are recommended for patients with impaired hepatic function (see Dosage and Administration). Clinical Trials Advanced breast cancer The demonstration of vinorelbine activity as a single agent in the treatment of advanced breast cancer is based on eight phase II studies and one phase III study, totalling 577 patients. In the four trials where vinorelbine was used as first line treatment, the overall response rate ranged from 41% to 60%. Of the total 283 evaluable patients, 128 had objective responses, i.e. response rate of 45.2% (95%CI 39.4% to 51%), duration of response 8.7 months. In the three phase II studies of vinorelbine administered weekly in second or third line treatment of advanced breast cancer, the response rate ranged from 19.6% to 30.3%. Based on an intention to treat analysis of evaluable patients in the two studies which used the recommended dose of 30 mg/m2 weekly, the overall response rate was 24% and median duration 4.4 months. Results of the eighth phase II study are not presented here because of the different mode of administration used. In a randomised phase III study conducted to investigate efficacy in anthracycline refractory advanced breast cancer 115 patients received vinorelbine as a single agent versus 64 patients who received IV melphalan. The median dose, number of doses and duration of treatment for vinorelbine were 27.5 mg/m2, nine doses and 12 weeks, respectively; and for melphalan, 25 mg/m2, two doses and eight weeks, respectively. Of those receiving vinorelbine, 13 of 84 (15.5%) patients with measurable disease achieved an objective response compared with four of 46 (8.7%) receiving melphalan. Overall survival was 38 weeks for patients receiving vinorelbine compared with 31 weeks for those receiving melphalan (log-rank p=0.023). Neither treatment had an adverse effect on quality of life. Vinorelbine was also investigated in combination with other chemotherapy agents in advanced breast cancer. In a phase II study, a combination of vinorelbine plus doxorubicin resulted in an overall response rate of 74% (66 objective responses out of 89 evaluable patients), with an overall median duration of response of 12 months and a median time to progression of 13.2 months. The median survival of patients attaining complete response had not yet been reached with a median follow up of 30 months. The median survival of patients attaining a partial response was 22.4 months. The overall median survival was 27.5 months. In a phase II study of the combination of vinorelbine plus fluorouracil, an overall response rate of 64% was found (40 out of 63 evaluable patients), with an overall median duration of response of 12.3 months, median time to progression of 12.7 months and an overall median survival of 23 months (28.1 months for responding patients). Non-small cell lung cancer The activity of vinorelbine was investigated in a series of phase II trials. The overall response rate to vinorelbine single agent in NSCLC patients ranged from 8% to 33% in previously untreated patients. In the two major phase II trials with more than 60 evaluable patients, the overall response rate was over 30% in chemotherapy-naive patients. The high activity of vinorelbine as a single agent in non-small cell lung cancer which was observed in non-controlled phase II studies has also been confirmed in three randomised phase III trials. In one prospective randomised study with 216 stage IV patients, vinorelbine was compared to fluorouracil with calcium folinate (considered equivalent to best supportive care for the purposes of the study). The median survival time of patients who received vinorelbine was 30 weeks compared to 22 weeks for those on the fluorouracil/calcium folinate arm (log-rank p=0.03). The response rates were 12% for the vinorelbine arm and 3% for the fluorouracil/calcium folinate arm. The activity of vinorelbine in combination with cisplatin has been investigated in two randomised phase III trials in a total of 782 patients. In a two arm trial, vinorelbine was compared to vinorelbine with cisplatin. The overall response rate to vinorelbine as single agent was 16% while that of the combination vinorelbine/cisplatin was 43%. The median survival time for patients receiving vinorelbine as single agent was similar to that observed with vinorelbine and cisplatin. In a large European clinical trial, 612 patients with Stage III or IV non-small cell lung cancer, no prior chemotherapy and WHO performance Status of 0, 1 or 2 were randomised to treatment with single agent vinorelbine (30 mg/m2/week), vinorelbine (30 mg/m2/week) cisplatin (120 mg/m2 days 1 and 29 then every six weeks), and vindesine (3 mg/m2/week for seven weeks, then every second week) plus cisplatin (120 mg/m2 days 1 and 29 then every six weeks). Vinorelbine plus cisplatin produced longer survival times than vindesine plus cisplatin (median survival 40 weeks vs 32 weeks, p=0.03). The median survival time for patients receiving single agent vinorelbine was similar to that observed with vindesine plus cisplatin (31 weeks vs 32 weeks). The one year survival rates were 36% for vinorelbine plus cisplatin, 27% for vindesine plus cisplatin, and 30% for single agent vinorelbine. The overall objective response rate (all partial responses) was significantly higher in patients treated with vinorelbine plus cisplatin (28%) than in those treated with vindesine plus cisplatin (19%, p=0.03) and in those treated with single agent vinorelbine (14%, p<0.001). The response rates reported for vindesine plus cisplatin and single agent vinorelbine were not significantly different. Significantly, less nausea, vomiting, alopecia, and neurotoxicity were observed in patients receiving single agent vinorelbine compared to those receiving the combination of vindesine and cisplatin. Indications DBL™ Vinorelbine Injection Concentrate is indicated for the treatment of advanced breast cancer after failure of standard therapy, as a single agent or in combination; and as first line treatment for advanced non-small cell lung cancer, as a single agent or in combination. Contraindications DBL™ Vinorelbine
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