NAVELBINE 10

Indications

• Advanced breast cancer
• Advanced non-small cell lung cancer
• Cytotoxic responsive malignancy

Dosage

Children: Refer to BNF for Children for appropriate dosing information.

Adults: Initially, 60 mg/m2 once weekly for 3 weeks, then increased if tolerated to 80 mg/m2 once weekly (maximum dose 160 mg once weekly). Consult local protocol for specific dosing.

Mechanism of action

Vinorelbine tartrate acts as a mitotic spindle poison that interferes with chromosomal segregation during mitosis. It binds to tubulin, inhibiting its polymerization and leading to cell cycle arrest at the G2/M phases. This action prevents proper mitotic spindle formation, thereby stopping the division of cancer cells.

Pharmacodynamics

Vinorelbine exhibits a broad spectrum of anti-tumor activity and is characterized as a spindle poison. It disrupts the normal function of microtubules, essential for cell division, which is particularly relevant in rapidly dividing cancer cells. The selective binding of vinorelbine to mitotic microtubules rather than others may reduce the risk of neurotoxicity compared to other agents in its class.

Pharmacokinetics

Vinorelbine is administered intravenously and has a complex pharmacokinetic profile. It is metabolized primarily in the liver and has a half-life that varies based on the dosage and individual patient factors. The drug's efficacy and safety can be influenced by liver function, necessitating caution in patients with hepatic impairment.

Contra-indications

• Intrathecal injection contraindicated
• Severe neurotoxicity risk with inadvertent intrathecal administration

Adverse effects

• Neurotoxicity
• Peripheral neuropathy
• Autonomic neuropathy
• Myocardial ischemia
• Neutropenic sepsis
• Renal failure
• Thrombocytopenia
• Thrombocytosis
• Vomiting
• Visual impairment
• Tinnitus
• Vertigo
• Posterior reversible encephalopathy syndrome (PRES)

Interactions

• Mitotane: Moderate (decreases exposure)
• Rifampicin: Moderate (decreases exposure)
• St. John's Wort: Unknown (decreases exposure)

Precautions

• Caution in patients with cardiovascular disease
• QT-interval prolongation (avoid hypokalaemia)
• Hepatic impairment (consider dosage reduction)
• Renal impairment (consider dosage adjustment)

Pregnancy

Avoid unless essential due to teratogenicity and embryotoxicity reported in animal studies.

Breast-feeding

Discontinue breastfeeding.

Storage

Store at room temperature, protected from light. Keep out of reach of children.

Formulations

• Vinorelbine tartrate powder for solution for injection

Mechanism of action

Vinca alkaloids are structurally similar compounds composed of two multi-ringed units, _vindoline_, and _catharanthine_. _Vinorelbine tartrate_ is a vinca alkaloid in which the catharanthine component is the target of structural modification,. This structural modification contributes to unique pharmacologic properties.The antitumor activity of vinorelbine tartrate is believed to be owed to the inhibition of mitosis at metaphase via its interaction with tubulin. Vinorelbine is a mitotic spindle poison that interferes with chromosomal segregation during mitosis, also known as cell division. It pauses cells at the _G2/M_ phases, when present at concentrations close to the half maximal inhibitory concentration (IC50). Microtubules, which are derived from polymers of tubulin, are the main target of vinorelbine. The chemical modification used to produce vinorelbine allows for the opening of the eight-member catharanthine ring with the formation of both a covalent and reversible bond with tubulin. The relative contribution of different microtubule-associated proteins in the production of tubulin vary between neural tissue and proliferating cells and this has important functional implications. The ability of vinorelbine to bind specifically to mitotic rather than other microtubules has been shown and may suggest that neurotoxicity is less likely to be a problem than with the molecular mechanism of action. As with other anti-microtubule agents, vinorelbine is known to contribute apoptosis in malignant cells. The exact mechanisms by which this process occurs are complex and many details are yet to be elucidated. The disarray of the microtubule structure has a number of effects, including the induction of tumor suppressor gene _p53_ and activation/inactivation of a number of protein kinases involved in essential signaling pathways, including _p21 WAF1/CIP1_ and _Ras/Raf_, _PKC/PKA_. These molecular changes lead to phosphorylation and consequently inactivation of the apoptosis inhibitor _Bcl2_. This, in turn, results in a decrease in the formation of heterodimers between _Bcl2_ and the pro-apoptotic gene _BAX_, stimulating the sequence of cell apoptosis. Vinorelbine tartrate also possibly interferes with amino acid, cyclic AMP and glutathione metabolism, calmodulin-dependent Ca++-transport ATPase activity, cellular respiration, and nucleic acid and lipid biosynthesis. Vinorelbine is an antimicrotubule antineoplastic agent. Microtubules are organelles that exist in a state of dynamic equilibrium with their components, tubulin dimers. They form an essential part of the mitotic spindle, participate in intracellular transport, and contribute to the cell's shape, rigidity, and motility. Vinorelbine and other vinca alkaloids exert their cytotoxic effects by binding to tubulin, the protein subunit of the spindle microtubules. The formation of vinorelbine-tubulin complexes prevents the polymerization of the tubulin subunits into microtubules and induces depolymerization of microtubules resulting in inhibition of microtubule assembly and cellular metaphase arrest. In addition to the antineoplastic effects of antimicrotubule activity, vinca alkaloids interfere with the microtubule-mediated movement of neurotransmitter substances along neuronal axons resulting in dose-limiting neurotoxicity. Like other vinca alkaloids, vinorelbine reportedly also interferes with amino acid, cyclic AMP, and glutathione metabolism; calmodulin-dependent Ca2+-transport ATPase activity; cellular respiration; and nucleic acid and lipid biosynthesis. Vinflunine blocks mitosis at the metaphase/anaphase transition, leading to apoptosis. The mechanism of the mitotic block is not known. On the basis of results with purified microtubules and in living interphase cells, /investigators/ hypothesized that it involves suppression of spindle microtubule dynamics. The effects of the three Vinca alkaloids on dynamics of centromeres and spindle kinetochore-microtubules /were m

Pharmacodynamics

Vinorelbine is a semi-synthetic vinca-alkaloid with a wide spectrum of anti-tumor activity. The vinca-alkaloids are considered spindle poisons. They work by interfering with the polymerization of tubulin, a protein responsible for building the microtubule system which appears during cell division in proliferating cancer cells.