Source: Health Products Regulatory Authority (ZA) Publisher: Eurolab (Pty) Ltd., Woodmead Office Park, 3 Stirrup Lane, Van Reenens Avenue, Woodmead, 2144
A 26 Cytostatics
Pharmacotherapeutic group: Vinca alkaloids and analogues
ATC Code: L01CA04
Vinorelbine tartrate is a cytostatic antineoplastic medicine of the vinca alkaloid family; the catharanthine moiety has been structurally modified.
At the molecular level it acts on the dynamic equilibrium of tubulin in the microtubular apparatus of the cell. It inhibits tubulin polymerisation and binds preferentially to mitotic microtubules, affecting axonal microtubules at high concentrations only. Vinorelbine tartrate blocks mitosis at G2-M causing cell death in interphase or at the following mitosis. Vinorelbine may also interfere with amino acid, cyclic AMP and glutathione metabolism; calmodulin-dependent Ca2+ transport ATPase activity; cellular respiration; and nucleic acid and lipid biosynthesis.
Safety and efficacy of NAVILIN in paediatric patients have not been established.
Pharmacokinetic parameters of vinorelbine were evaluated in blood.
After oral administration, vinorelbine is rapidly absorbed and the Tmax is reached between 1,5 to 3 h with a blood concentration peak (Cmax) of approximately 130 ng/ml after a dose of 80 mg/m².
Absolute bioavailability is approximately 43% and a simultaneous intake of food does not alter the exposure to vinorelbine.
Oral vinorelbine at 60 and 80 mg/m² leads to blood exposure comparable to that achieved with intravenous vinorelbine at 25 and 30 mg/m², respectively.
The blood exposure to vinorelbine increases proportionally with the dose up to 100mg/m². Interindividual variability of the exposure is similar after administration by intravenous and oral routes.
The steady-state volume of distribution is large, on average 21,2 l.kg-1 (range: 11-21 l.kg-1), which indicates extensive tissue distribution.
Binding to plasma proteins is weak (13,5%), vinorelbine binds strongly to blood cells and especially to platelets (78%).
There is a significant uptake of vinorelbine in lungs, as assessed by pulmonary surgical biopsies which showed a mean ratio of tissue/plasma concentration greater than 300. Vinorelbine is not found in the central nervous system.
All metabolites of vinorelbine are formed by CYP3A4 isoform of cytochromes P450, except 4-O-deacetylvinorelbine likely to be formed by carboxylesterases. 4-O-deacetylvinorelbine is the only active metabolite and the main one observed in blood. Neither sulfate nor glucuronide conjugates are found.
The mean terminal half-life of vinorelbine is 35 to 40 hours. Blood clearance is high, approaching hepatic blood flow, and is 0,72 l.h-1.kg-1 (range: 0,32-1,26 l.h-1.kg-1).
Renal elimination is low (<5% of the dose administered) and consists mostly in parent compound. Biliary excretion is the predominant elimination route of both unchanged vinorelbine, which is the main recovered compound, and its metabolites.
The effects of renal dysfunction on the pharmacokinetics of vinorelbine have not been studied. However, dose reduction in case of reduced renal function is not indicated with vinorelbine due to the low level of renal elimination.
Total clearance of vinorelbine is neither modified between mild and moderate impairment nor is it altered in hepatically impaired patients when compared with clearance in patients with normal liver function.
No data is available for patients with severe liver impairment therefore, NAVILIN is contraindicated in these patients: see sections 4.2, 4.3 and 4.4.
Since elderly patients are frail, caution should be exercised when increasing the dose of NAVILIN soft capsule: see section 4.2.
A strong relationship is evident between blood exposure and depletion of leucocytes or PMNs.
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