Vinorelbine, Concentrate

Vinorelbine injection USP is for intravenous administration. Each vial contains vinorelbine tartrate, USP equivalent to 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, USP is a semi-synthetic vinca alkaloid with antitumor activity. The chemical name is 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)]. Vinorelbine tartrate, USP has the following structure:

C45H54N4O8•2C4H6O6 M.W. 1079.12

Vinorelbine tartrate, USP is a white to yellow or light brown amorphous powder. The aqueous solubility is >1000 mg/mL in distilled water. The pH of vinorelbine injection USP is approximately 3.5.

Mechanism of Action

Vinorelbine is a vinca alkaloid that interferes with microtubule assembly. The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin.  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. Vinorelbine inhibited mitotic microtubule formation in intact mouse embryo tectal plates at a concentration of 2 μM inducing a blockade of cells at metaphase, but produced depolymerization of axonal microtubules at a concentration 40 μM, suggesting a modest selectivity of vinorelbine for mitotic microtubules.

Pharmacokinetics

The pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/m2 administered as 15- to 20-minute constant-rate infusions. Vinorelbine concentrations in plasma decay in a triphasic manner. 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.

Distribution

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 human plasma over a concentration range of 234 to 1169 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.

Metabolism

Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces. 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 vinorelbine is mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily.

Excretion

After intravenous administration of radioactive vinorelbine, approximately 18% and 46% of administered radioactivity was recovered in urine and feces, respectively. In a different study, 10.9% + 0.7% of a 30-mg/m2 intravenous dose was excreted as parent drug in urine.

Specific Populations

Elderly: Age has no effect on the pharmacokinetics (CL, VSS and t1/2) of vinorelbine.

Drug Interactions

The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of vinorelbine has not been studied. Vinorelbine has been shown to affect chromosome number and possibly structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice). It was not mutagenic in the Ames test and gave inconclusive results in the mouse lymphoma TK Locus assay.

Vinorelbine did not affect fertility to a statistically significant extent when administered to rats on either a once-weekly (9 mg/m2, approximately one third the human dose) or alternate-day schedule (4.2 mg/m2, approximately 0.14 times the human recommended dose) prior to and during mating. In male rats, administration of vinorelbine twice weekly for 13 or 26 weeks at dose levels of 2.1 and 7.2 mg/m2 (approximately 0.07 and 0.24 times the recommended human  dose), respectively, resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.

Combination Use with Cisplatin

The safety and efficacy of vinorelbine in combination with cisplatin was evaluated in two randomized, multicenter trials.

Cisplatin 100 mg/m2

Study 1 was a randomized, multicenter, open-label trial of vinorelbine plus cisplatin and cisplatin alone for the treatment of stage IV or stage IIIb NSCLC patients with malignant pleural effusion or multiple lesions in more than one lobe of the ipsilateral lung who had not received prior chemotherapy. A total of 432 patients were randomized 1:1 to receive either vinorelbine 25 mg/m2 on Day 1 then every week of each 28-day cycle with cisplatin 100 mg/m2 administered on Day 1 of each 28-day cycle (N=214) or cisplatin 100 mg/m2 on Day 1 of each 28-day cycle (N=218).

Patient demographics and disease characteristics were similar between arms. Of the overall study population, the median age was 64 (range 33 to 84), 66% were male, 80% were Caucasian, 92% had stage IV disease and 8% stage IIIB, 53% had adenocarcinoma, 21% squamous cell, 14% large cell histology. The major efficacy outcome measure was overall survival. The efficacy results are presented in Table 7 and Figure 1.

Table 7: Efficacy Results (Study 1)

Cisplatin 120 mg/m2

Study 2 was a randomized, 3-arm, open-label, multicenter trial of vinorelbine plus cisplatin, vindesine plus cisplatin and vinorelbine alone for the treatment of patients with stage III or IV NSCLC who had not received prior chemotherapy.  The study was conducted in Europe.  A total of 612 patients were randomized 1:1:1 to receive vinorelbine 30 mg/m2 every week of a 6-week cycle plus cisplatin 120 mg/m2 on Day 1 and Day 29, then every 6 weeks thereafter (N=206); and vindesine 3 mg/m2 for 6 weeks, then every other week thereafter plus cisplatin 120 mg/m2 on Days 1 and Day 29, then every 6 weeks thereafter (N=200) or vinorelbine 30 mg/m2 every week of a 6-week cycle (N=206). The main efficacy outcome measure was to compare overall survival between vinorelbine plus cisplatin and vindesine plus cisplatin.  The other efficacy outcome measure was to compare overall survival in the better of the two combination regimens to that of vinorelbine alone.

Patient demographics were in general similar between arms: the median age of the overall population was 60 years (range 30 to 75), 90% were male, 78% had WHO performance status of 0 or 1. Tumor characteristics were in general similar with the exception of histologic subtype of NSCLC. Adenocarcinoma was the histologic subtype in 32% of patients in the vinorelbine plus cisplatin arm, 40% of patients in vindesine plus cisplatin arm and 28% of patients on the vinorelbine alone arm. Ten percent of the patients had stage IIIA disease, 28% stage IIIB and 50% stage IV. Twelve percent of the patients had received prior surgery or radiotherapy.

The efficacy results of Study 2 are presented in Table 8.

Table 8: Efficacy Results (Study 2)

1n/a = not applicable

Single Agent

The safety and efficacy of vinorelbine as a single agent was evaluated in one randomized multi-center trial.

Study 3 was a randomized, open-label clinical trial of vinorelbine or 5-Fluorouracil (5-FU) plus leucovorin (LV) in patients with Stage IV NSCLC who had not received prior chemotherapy. A total of 211 patients were randomized 2:1 to receive vinorelbine 30 mg/m2 weekly of a 8-week cycle (N=143) or 5-FU 425 mg/m2 bolus intravenously plus LV 20 mg/m2 bolus intravenously daily for 5 days of a 4-weeks cycle (N=68).  

Patient demographics and disease characteristics were in general similar between arms.  In the overall population, the median age was 61 years (range 32 to 83), 74% were male, 88% were Caucasian, 46% had adenocarcinoma histology. Fifty percent of the patients had Karnofsky performance status ≥ 90 in the vinorelbine arm compared to 38% in the 5-FU and LV arm. 

The primary efficacy outcome of the study was overall survival. The median survival time was 30 weeks versus 22 weeks for patients receiving vinorelbine versus 5-FU/LV, respectively (P=0.06). Partial objective responses were observed in 11.1% (95% CI=6.2%, 17.9%) and 3.5% (95% CI=0.4%, 11.9%) of patients who received vinorelbine and 5-FU/LV, respectively.

Vinorelbine Injection USP 10 mg/mL, 1 mL Single-Use Vial, Carton Text

Vinorelbine

Injection USP

equivalent to vinorelbine

tartrate, USP

10 mg/mL

1 mL Single-Use Vial

FOR INTRAVENOUS USE ONLY

MUST BE DILUTED FOR

ADMINISTRATION

CAUTION: Cytotoxic Agent

TEVA