Vinorelbine

VINORELBINE — vinorelbine tartrate injection
Sagent Pharmaceutical, Inc.

Rx only

WARNING

Vinorelbine Injection, USP should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. This product is for intravenous (IV) use only. Intrathecal administration of other vinca alkaloids has resulted in death. Syringes containing this product should be labeled “WARNING — FOR IV USE ONLY. FATAL if given intrathecally.” Severe granulocytopenia resulting in increased susceptibility to infection may occur. Granulocyte counts should be ≥ 1,000 cells/mm3 prior to the administration of vinorelbine. The dosage should be adjusted according to complete blood counts with differentials obtained on the day of treatment. Caution — It is extremely important that the intravenous needle or catheter be properly positioned before vinorelbine is injected. Administration of vinorelbine may result in extravasation causing local tissue necrosis and/or thrombophlebitis (see DOSAGE AND ADMINISTRATION: Administration Precautions).

DESCRIPTION

Vinorelbine Injection, USP is for intravenous administration. Each vial contains 10 mg (1-mL vial) or 50 mg (5-mL vial) vinorelbine in Water for Injection. No preservatives or other additives are present. The aqueous solution is sterile and nonpyrogenic.

Vinorelbine tartrate is a semi-synthetic vinca alkaloid with antitumor activity. The chemical name is 3’4’-didehydro-4’-deoxy-C-8-norvincaleukoblastine [R-(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)].

Vinorelbine tartrate has the following structure:

c3b49c3a-figure-01
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Vinorelbine tartrate is a white to yellow or light brown amorphous powder with the molecular formula C45 H54 N4 O8 •2C4 H6 O6 and molecular weight of 1079.12. The aqueous solubility is >1,000 mg/mL in distilled water. The pH of Vinorelbine Injection, USP is approximately 3.5.

CLINICAL PHARMACOLOGY

Vinorelbine is a vinca alkaloid that interferes with microtubule assembly. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units, vindoline and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for vinorelbine. The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, vinorelbine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca++ -transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. In intact tectal plates from mouse embryos, vinorelbine, vincristine, and vinblastine inhibited mitotic microtubule formation at the same concentration (2 µM), inducing a blockade of cells at metaphase. Vincristine produced depolymerization of axonal microtubules at 5 µM, but vinblastine and vinorelbine did not have this effect until concentrations of 30 µM and 40 µM, respectively. These data suggest relative selectivity of vinorelbine for mitotic microtubules.

Pharmacokinetics:

The pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/m2 in 4 clinical trials. Doses were administered by 15- to 20-minute constant-rate infusions. Following intravenous administration, vinorelbine concentration in plasma decays in a triphasic manner. The initial rapid decline primarily represents distribution of 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 plasma clearance ranges from 0.97 to 1.26 L/hr/kg. Steady-state volume of distribution (Vss) values range from 25.4 to 40.1 L/kg.

Vinorelbine demonstrated high binding to human platelets and lymphocytes. The free fraction was approximately 0.11 in pooled human plasma over a concentration range of 234 to 1,169 ng/mL. The binding to plasma constituents in cancer patients ranged from 79.6% to 91.2%. Vinorelbine binding was not altered in the presence of cisplatin, 5-fluorouracil, or doxorubicin.

Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine. Therapeutic doses of vinorelbine (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes (see

PRECAUTIONS). 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).

The disposition of radiolabeled vinorelbine given intravenously was studied in a limited number of patients. Approximately 18% and 46% of the administered dose was recovered in the urine and in the feces, respectively. Incomplete recovery in humans is consistent with results in animals where recovery is incomplete, even after prolonged sampling times. A separate study of the urinary excretion of vinorelbine using specific chromatographic analytical methodology showed that 10.9% ± 0.7% of a 30-mg/m2 intravenous dose was excreted unchanged in the urine.

The influence of age on the pharmacokinetics of vinorelbine was examined using data from 44 cancer patients (average age, 56.7 ± 7.8 years; range, 41 to 74 years; with 12 patients ≥60 years and 6 patients ≥65 years) in 3 studies. CL (the mean plasma clearance), t1/2 (the terminal phase half-life), and VZ (the volume of distribution during terminal phase) were independent of age. A separate pharmacokinetic study was conducted in 10 elderly patients with metastatic breast cancer (age range, 66 to 81 years; 3 patients >75 years; normal liver function tests) receiving vinorelbine 30 mg/m2 intravenously. CL, Vss , and t1/2 were similar to those reported for younger adult patients in previous studies. No relationship between age, systemic exposure (AUC0-∞), and hematological toxicity was observed.

The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin with vinorelbine (see PRECAUTIONS: Drug Interactions).

Clinical Trials:

Data from 1 randomized clinical study (211 evaluable patients) with single-agent vinorelbine and 2 randomized clinical trials (1,044 patients) using vinorelbine combined with cisplatin support the use of vinorelbine in patients with advanced nonsmall cell lung cancer (NSCLC).

Single-Agent Vinorelbine Tartrate Injection:

Single-agent vinorelbine was studied in a North American, randomized clinical trial in which patients with Stage IV NSCLC, no prior chemotherapy, and Karnofsky Performance Status ≥70 were treated with vinorelbine (30 mg/m2) weekly or 5-fluorouracil (5-FU) (425 mg/m2 IV bolus) plus leucovorin (LV) (20 mg/m2 IV bolus) daily for 5 days every 4 weeks. A total of 211 patients were randomized at a 2:1 ratio to vinorelbine (143) or 5-FU/LV (68). Vinorelbine showed improved survival time compared to 5-FU/LV. In an intent-to-treat analysis, the median survival time was 30 weeks versus 22 weeks for patients receiving vinorelbine versus 5-FU/LV, respectively (P = 0.06). The 1-year survival rates were 24% (±4% SE) for vinorelbine and 16% (±5% SE) for the 5-FU/LV group, using the Kaplan-Meier product-limit estimates. The median survival time with 5-FU/LV was similar to or slightly better than that usually observed in untreated patients with advanced NSCLC, suggesting that the difference was not related to some unknown detrimental effect of 5-FU/LV therapy. The response rates (all partial responses) for vinorelbine and 5-FU/LV were 12% and 3%, respectively.

Vinorelbine in Combination with Cisplatin: Vinorelbine plus Cisplatin versus Single-Agent Cisplatin:

A Phase III open-label, randomized study was conducted which compared vinorelbine (25 mg/m2 per week) plus cisplatin (100 mg/m2 every 4 weeks) to single-agent cisplatin (100 mg/m2 every 4 weeks) in patients with Stage IV or Stage IIIb NSCLC patients with malignant pleural effusion or multiple lesions in more than one lobe who were not previously treated with chemotherapy. Patients included in the study had a performance status of 0 or 1, and 34% had received prior surgery and/or radiotherapy. Characteristics of the 432 randomized patients are provided in Table 1. Two hundred and twelve patients received vinorelbine plus cisplatin and 210 received single-agent cisplatin. The primary objective of this trial was to compare survival between the 2 treatment groups. Survival (Figure 1) for patients receiving vinorelbine plus cisplatin was significantly better compared to the patients who received single-agent cisplatin. The results of this trial are summarized in Table 1.

Vinorelbine plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine:

In a large European clinical trial, 612 patients with Stage III or IV NSCLC, no prior chemotherapy, and WHO Performance Status of 0, 1, or 2 were randomized to treatment with single-agent vinorelbine (30 mg/m2 per week), vinorelbine (30 mg/m2 per week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks), and vindesine (3 mg/m2 per week for 7 weeks, then every other week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks). Patient characteristics are provided in Table 1. Survival was longer in patients treated with vinorelbine plus cisplatin compared to those treated with vindesine plus cisplatin (Figure 2). Study results are summarized in Table 1.

Dose-Ranging Study:

A dose-ranging study of vinorelbine (20, 25, or 30 mg/m2 per week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks) in 32 patients with NSCLC demonstrated a median survival of 10.2 months. There were no responses at the lowest dose level; the response rate was 33% in the 21 patients treated at the 2 highest dose levels.

Table 1. Randomized Clinical Trials of Vinorelbine in Combination with Cisplatin in NSCLC
Vinorelbine/Cisplatin vs. Single-Agent Cisplatin Vinorelbine/Cisplatin vs. Vindesine/Cisplatin vs. Single-Agent Vinorelbine
Vinorelbine/Cisplatin Cisplatin Vinorelbine/Cisplatin Vindesine/Cisplatin Vinorelbine
Demographic
Number of patients214218206200206
Number of males146141182179188
Number of females6877242118
Median age (years)6364595960
Range (years)33-8437-8132-7531-7530-74
Stage of disease
Stage IIIANANA11%11%10%
Stage IIIB8%8%28%25%32%
Stage IV92%92%50%55%47%
Local recurrenceNANA2%3%3%
Metastatic after surgeryNANA9%8%9%
Histology
Adenocarcinoma54%52%32%40%28%
Squamous19%22%56%50%56%
Large cell14%14%13%11%16%
Unspecified13%13%NANANA
Results
Median survival (months)7.86.29.2* 7.47.2
P valueP = 0.01*P = 0.09 vs. vindesine/cisplatin = 0.05 vs. single-agent vinorelbine
12-Month survival rate38%22%35%27%30%
Overall response19%8%28%ठ19%14%
P valueP < 0.001 P = 0.03 vs. vindesine/cisplatin§ P<0.001 vs. single-agent vinorelbine

Figure 1. Overall Survival

Vinorelbine /Cisplatin versus Single-Agent Cisplatin

c3b49c3a-figure-02
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Figure 2. Overall Survival

Vinorelbine /Cisplatin versus Vindesine/Cisplatin versus Single-Agent Vinorelbine

c3b49c3a-figure-03
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