What Is Javlor (Vinflunine Ditartrate)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA Approval: Not approved by the US Food and Drug Administration (FDA). Initial Approval Date: September 21, 2009 (European Medicines Agency, EMA)
• Brand Name: Javlor
• Active Ingredient: Vinflunine ditartrate
• Route of Administration: Intravenous infusion (into a vein)
• Class: Antineoplastic agent (vinca alkaloid derivative)
• Category: Chemotherapy medicine
• Manufacturer: Laboratoires Pierre Fabre (France)
• Availability in Turkey: Licensed in Turkey on August 9, 2017. The marketing authorization holder is Pierre Fabre İlaç A.Ş.
• Approved Cancer Indications: Advanced or metastatic urothelial carcinoma that does not respond to platinum-containing treatment

What Is Javlor? How Does It Work?

Javlor is a chemotherapy medicine containing vinflunine ditartrate, used particularly for advanced or metastatic urothelial (bladder) cancer. It belongs to the vinca alkaloid group, is a derivative of vinorelbine, and was approved by the European Medicines Agency (EMA) on September 21, 2009.

How Does It Work?

Vinflunine, the active ingredient in Javlor, targets microtubule structures involved in cell division. Specifically, it:

• Binds to β-tubulin and inhibits (blocks) microtubule polymerization,
• Thereby arrests cell division (mitosis) in the G2/M phase,
• And directs cancer cells that cannot divide toward apoptosis (programmed cell death).

As a result, tumor cell proliferation is inhibited and tumor growth slows.

FDA (US Food and Drug Administration) Approval History

Javlor, which contains vinflunine, is not approved by the US Food and Drug Administration (FDA). It therefore has no FDA approval date. However, it was approved by the European Medicines Agency (EMA) on September 21, 2009.

The principal reason given for the lack of FDA approval is that median overall survival (OS) with vinflunine in clinical trials was reported as 6.9 months. This duration did not meet the FDA's efficacy criteria for approval.

Licensing in Turkey

Javlor (vinflunine ditartrate) was licensed in Turkey on August 9, 2017. The marketing authorization holder is Pierre Fabre İlaç A.Ş.

Therapeutic Indications

Javlor is indicated for systemic treatment of patients with advanced, metastatic urothelial cancer that has progressed after first-line platinum-containing chemotherapy and an ECOG performance status of 0-1.

SGK Reimbursement Status

In Turkey, Javlor is reimbursed only for systemic treatment of metastatic urothelial cancer that has progressed after first-line platinum-containing chemotherapy in patients with an ECOG performance status of 0-1, when prescribed by a medical oncologist on the basis of a medical board report valid for no more than 6 months and issued by a board including at least one medical oncologist.

Price: As of May 2025, a Javlor 250 mg vial costs 36,908.04 Turkish lira

Mechanisms of Resistance

• Increased P-Glycoprotein (P-gp) Expression (MDR1 Gene): P-gp is a transporter protein in the cell membrane that pumps drugs out of the cell. Microtubule inhibitors such as vinflunine lose effectiveness when expelled by this pump. This may lead to multidrug resistance.
• Changes in β-Tubulin Isoforms: Vinflunine binds to the β-tubulin subunit of microtubules. Mutations or isoform changes in this subunit may reduce drug binding and lower its binding affinity.
• Increased Microtubule Dynamics: Some cancer cells may continue dividing by developing mechanisms that compensate for microtubule destabilization.
• Increased DNA Repair Mechanisms and Anti-Apoptotic Proteins: Cells may increase the expression of anti-apoptotic proteins, such as Bcl-2, to evade vinflunine-induced apoptosis. Their capacity to repair DNA damage may also increase.

Absorption

• Vinflunine is administered intravenously (IV), so oral absorption does not occur.
• Bioavailability after administration is 100% because it enters the systemic circulation directly.

Distribution

• Volume of distribution (Vd): Approximately 40 L/m², indicating extensive distribution into tissues.
• Plasma protein binding: High (>80%), particularly to albumin.
• High concentrations are reached particularly in the liver, kidneys, and tumor tissue.

Metabolism

• Vinflunine is metabolized in the liver, particularly by the cytochrome P450 3A4 (CYP3A4) enzyme.
• It has no active metabolites; its major metabolites are inactive.
• It should be used cautiously in patients with hepatic impairment.

Elimination

• Half-life (t½): Approximately 40 hours (long-acting).
• Principal elimination route: More than 70% through bile and feces (hepatobiliary elimination), and less than 10% through urine (limited renal elimination)
• Clearance: An average of 0.55 L per hour per m²

Dosing Schedule

• The standard recommended vinflunine dose is 320 mg/m² by intravenous infusion every 3 weeks.
• Starting at 280 mg/m² may be recommended in some patients, particularly older patients and those in poor general condition.
• Hepatic impairment: Cautious use is recommended with mild impairment. Use is not recommended or may be contraindicated in moderate-to-severe impairment.
• Severe neutropenia (Grade 3-4) may require dose reduction or longer intervals between treatments.
• Gastrointestinal toxicities, such as severe constipation: The dose should be reviewed if these persist despite supportive treatment.
• Every 21 days (a cycle every 3 weeks).
• Administration is generally by infusion over 20 minutes.
• Blood counts and liver function tests should be evaluated before starting treatment and before each cycle.
• Granulocyte colony-stimulating factor (G-CSF) may be recommended as supportive treatment to address the risk of neutropenia.

Drug Interactions

• Ketoconazole and itraconazole (antifungals), ritonavir and saquinavir (HIV protease inhibitors), clarithromycin and erythromycin (macrolide antibiotics), and grapefruit juice inhibit CYP3A4. These agents may increase plasma vinflunine levels, raising the risk of toxicity.
• Rifampicin, phenytoin, carbamazepine, phenobarbital (antiepileptics), and St. John's wort (Hypericum): These agents may lower vinflunine levels and reduce treatment effectiveness.
• Amiodarone, sotalol, haloperidol, chlorpromazine, cisapride, domperidone, and moxifloxacin (among certain antibiotics): Concomitant use may increase the risk of arrhythmia. Vinflunine may prolong the QT interval. ECG and electrolyte monitoring is recommended.
• Hematotoxic medicines, such as other chemotherapy agents: Their bone marrow-suppressing effects may increase.
• Constipating medicines, such as opioids: Vinflunine can cause constipation, and this effect may become more severe.
• Patients at risk of drug interactions should be monitored closely, with dose adjustment if necessary.

Precautions

• Hematological Toxicity (Neutropenia, Anemia, Thrombocytopenia): Neutropenia (a decrease in white blood cells) is the most common serious adverse effect during vinflunine treatment. Blood counts should be checked before each cycle. Neutropenia may require dose reduction or treatment delay. G-CSF, such as filgrastim, may be considered as supportive treatment.
• Constipation and Gastrointestinal Problems: Vinflunine may cause severe constipation, ileus, and abdominal pain. Concomitant use of constipating medicines should be avoided, and preventive measures such as laxatives and adequate fluid intake should be recommended.
• Hepatic Impairment: Vinflunine is metabolized in the liver and should therefore be used cautiously in patients with impaired hepatic function. It is generally contraindicated in moderate or severe hepatic impairment.
• Risk of QT Prolongation: Vinflunine may increase the risk of QT interval prolongation. ECG monitoring is needed, particularly when it is used with other medicines that prolong QT. Electrolyte disturbances, such as hypokalemia and hypomagnesemia, should be corrected.
• Renal Impairment: Most elimination occurs through the liver, but cautious use is recommended in severe renal impairment.
• Older Patients: Patients over 75 may experience more hematological and gastrointestinal adverse effects. Starting at a lower dose, such as 280 mg/m², may be recommended.
• Pregnancy and Breastfeeding: Vinflunine is fetotoxic and contraindicated during pregnancy. It should also not be used during breastfeeding; breastfeeding must be stopped throughout treatment.
• Before and during treatment, regular blood tests, liver function tests, ECG monitoring, and monitoring of gastrointestinal symptoms should be performed.

Adverse Effects

• Neutropenia (decreased white blood cells): 50–60%
• Anemia: 20–30%
• Thrombocytopenia (low platelets): 10–15%
• Febrile neutropenia (low white blood cells with fever): 5–10%
• Constipation: 40–50%
• Nausea: 30–40%
• Vomiting: 20–30%
• Decreased appetite (anorexia): 15–25%
• Fatigue (asthenia): 30–40%
• Peripheral neuropathy (numbness and tingling in the hands and feet): 10–20%
• Oral mucositis (mouth sores): 5–15%
• Alopecia (hair loss): 15–25%
• Diarrhea: 10–15%
• Abdominal pain: 10–20%
• Hypoesthesia (reduced sensation): 5–10%
• Fever: 10–15%
• Infection: Approximately 10%
• QT interval prolongation (ECG abnormality): Less than 1%
• Elevated liver enzymes (AST/ALT): 5–10%