JAVLOR CONCENTRATE FOR SOLUTION FOR INFUSION 25mg/ML FOR INTRAVENOUS USE

Product Information

Registration Status: Active

JAVLOR CONCENTRATE FOR SOLUTION FOR INFUSION 25mg/ML is approved to be sold in Singapore with effective from 2012-11-01. It is marketed by ORIENT EUROPHARMA PTE LTD, with the registration number of SIN14075P.

This product contains Vinflunine 25mg/mL in the form of INFUSION, SOLUTION CONCENTRATE. It is approved for INTRAVENOUS use.

This product is manufactured by Pierre Fabre Medicament Production in FRANCE.

It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.

Description

Vinflunine is a third-generation member of the vinca alkaloid family with anti-tumour actions. It was first described in 1998 at the Pierre Fabre research center in France. Like other vinca agents, vinflunine is an anti-mitotic agent that induces a cell cycle arrest at the G2/M phase and promotes cell death via apoptosis [L1396]. Vinflunine is a microtubule inhibitor that binds to tubulin at or near to the vinca binding sites to inhibits its polymerization into microtubules during cell proliferation [L1396]. In murine tumors and human tumor xenografts, vinflunine exhibits an antitumor efficacy than [DB00361], [DB00570], and [DB00541] [A31975]. Having an incidence of 429,700 new cases per year worldwide, urothelial carcinoma of the bladder is one of the most common malignancies that mostly affects individuals aged 50–79 years [A32626]. Some patients with advanced urothelial carcinoma experience inadequate therapeutic response from a prior platinum-containing regimen. While these patients have a median survival of approximately 4 months and a poor prognosis [L1396], there is currently no standard therapy in patients with advanced urothelial carcinoma [A32626]. In 2009, vinflunine was approved by the European Medicines Agency (EMA) as a second-line therapy of metastatic and advanced urothelial cancer after failure of platinum-based treatment [A32626]. Vinflunine ditartrate is an active ingredient in the EMA-authorised product Javlor for intravenous infusion. Efficacy and safety of vinflunine has not been studied in patients with performance status of 2 or less. The clinical use of vinflunine in other urologic malignancies, such as inoperable cancer of the penis, are currently have been investigated [A32626].

Indication

For use as a monotherapy in adults with advanced or transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing therapy [L2381].

Mechanism of Action

Microtubules are a major component of the cytoskeleton that have a critical role in maintenance of cell shape, mobility, adhesion and intracellular integrity. They also play a role in the formation of the mitotic spindle and chromosomal segregation to the daughter cells at mitosis [A32635]. Via GTP hydrolysis at the β-tubulin subunit and polymerization of tubulin into linear polymers, microtubules, or macromolecular filaments composed of tubulin heterodimers, are formed via a mechanism of nucleation-elongation [A32635]. At the onset of mitosis, the interphase microtubule network disassembles into the tubulin. The tubulin reassembles into a new population of mitotic spindle microtubules that further undergo rapid successions of lengthening and shortening until they are attached to the newly duplicated sister chromatids at their centromeres [A32635]. The dynamic behaviour of microtubules are characterized by two mechanical process: dynamic instability indicating repeated switches of growth and shortening at the ends, and microtubule treadmilling that involves the fast-growing (+) end of the microtubule accompanied by a net loss of the opposite slow-growing (-) end [A32635]. Microtubule treadmilling plays a critical role in mitosis by generating the forces for separation of the chromosomes in the mitotic spindle from centrosome and kinetochores. In both cancer and normal cells, vinflunine binds to tubulin at or near to the vinca binding sites at β-tubulin. It is proposed that in similarity to other vinca alkaloids, vinflunine is most likely to bind to β-tubulin subunit at the interdimer interface [A32635]. Via direct binding to tubulin, vinflunine inhibits microtubule polymerization and induces a G2+M arrest, or a mitotic arrest [A32626]. Vinflunine disrupts the dynamic function of microtubules by suppressing treadmilling and slowing the microtubule growth rate while increasing growth duration [A31982]. Ultimately, mitotic accumulation at the metaphase/anaphase transition results in cell apoptosis [A32626].

Pharmacokinetics

Absorption: Vinflunine displays a linear pharmacokinetic profile in the range of administered doses (from 30 mg/m^2 to 400 mg/m^2) in cancer patients [L2381].
Distribution: The terminal volume of distribution is large, 2422 ± 676 L (about 35 l/kg), suggesting extensive distribution into tissues. The ratio between plasma and whole blood concentrations of 0.80 ± 0.12 [L2381].
Metabolism: The metabolites of influnine are mostly cytochrome P450 3A4, but 4-O-deacetylvinflunine (DVFL) may be slowly formed by multiple esterases. DVFL is the main metabolite and is the only metabolite that retains pharmacological activity [L2381].
Elimination

Clearance

The total blood clearance was 40 L/h according to a population pharmacokinetic analysis in 372 patients. The inter- and intra-individual variability was low, with the coefficient of variation approximately 25% and 8%, respectively [L2381].

Toxicity

Overdose of vinflunine is associated with bone marrow suppression with a risk of severe infection. There is no known antidote for vinflunine overdose. In case of overdose, the vital functions of the patient should be closely monitored and other appropriate measures, such as blood transfusions and administration of antibiotics or growth factors, should be taken if necessary [L2381]. The severity of correlates with the AUC of, or overall exposure to, vinflunine [L2381]. In the _in vivo_ micronucleus test in rat, vinflunine was clastogenic that induced chromosome breakage. In a mouse lymphoma assay, vinflunine displayed mutagenic and clastogenic potential without any metabolic activation [L2381]. In the reproduction studies, vinflunine caused embryolethal and teratogenic effects in rabbits and teratogenic effects in rats. 2 cases of malformations of the uterus and vagina following vinflunine treatment were reported during the pre- and post-natal development study in rat [L2381].

Active Ingredient/Synonyms

Source of information: Drugbank (External Link). Last updated on: 3^rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.