Vinflunine

Vinflunine is a vinca alkaloid that binds to tubulin and prevents cancer cells from completing mitosis. Its antitumour effect depends on both the concentration of the drug and the duration of exposure.

Mechanism of Action

• Tubulin binding: vinflunine binds to tubulin at or near the vinca-binding sites and inhibits its polymerisation into microtubules. This suppresses microtubule treadmilling and disrupts microtubule dynamics, which results in mitotic arrest and apoptosis.
• Antitumour activity: in vivo, vinflunine showed significant activity against a broad range of human tumour xenografts in mice, with longer survival and slower tumour growth. In vitro it induces drug resistance less strongly than other vinca alkaloids.
• Active metabolite: 4-O-deacetylvinflunine (DVFL) is the only active metabolite.
• Exposure and toxicity: blood exposure (AUC) correlates significantly with the severity of leucopenia, neutropenia and fatigue.

Pharmacokinetics

• Absorption and dose range: pharmacokinetics is linear over the doses studied in cancer patients (30 to 400 mg/m²).
• Distribution: moderate binding to plasma proteins (67.2%), mainly to high-density lipoproteins and serum albumin, and not saturable at patient concentrations; binding to alpha-1 acid glycoprotein and to platelets is negligible. The plasma-to-whole-blood ratio is 0.80. The terminal volume of distribution is large (2,422 L, about 35 L/kg), indicating extensive tissue distribution.
• Metabolism: all metabolites are formed by CYP3A4 except DVFL, which is formed by multiple esterases and is the main metabolite in blood.
• Elimination: terminal half-life close to 40 hours; DVFL is formed slowly and eliminated more slowly (half-life about 120 hours). Excretion is two thirds in faeces and one third in urine. Total blood clearance is 40 L/h, with low variability between patients (25%) and within patients (8%).
• Hepatic impairment: pharmacokinetics of vinflunine and DVFL did not change in 25 patients with varying degrees of hepatic impairment, but dose adjustments are still recommended (see Administration and Dosage).

• Urothelial carcinoma: monotherapy in adults with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen.
• Efficacy and safety have not been studied in patients with a performance status of 2 or more.

• Hypersensitivity to vinflunine or to other vinca alkaloids.
• Recent (within 2 weeks) or current severe infection.
• Baseline neutrophil count below 1,500/mm³ for the first administration, or below 1,000/mm³ for later administrations.
• Platelet count below 100,000/mm³.
• Breastfeeding.

The most frequent treatment-related reactions in studies of 450 patients with urothelial carcinoma were blood disorders (mainly neutropenia and anaemia), gastrointestinal disorders (especially constipation, anorexia, nausea, stomatitis or mucositis, vomiting, abdominal pain and diarrhoea) and asthenia or fatigue. Neutropenia of any grade occurred in 79.6% of patients (grade 3–4 in 54.6%), anaemia in 92.8% (grade 3–4 in 17.3%), asthenia or fatigue in 55.3% (grade 3–4 in 15.8%) and constipation in 54.9%.

Very common (≥1/10): neutropenia, leucopenia, anaemia, thrombocytopenia; hyponatraemia, decreased appetite; peripheral sensory neuropathy; constipation, abdominal pain, vomiting, nausea, stomatitis, diarrhoea; alopecia; myalgia; asthenia or fatigue, injection-site reactions, pyrexia; weight loss.

Common (≥1/100 to <1/10): neutropenic infection, infections (viral, bacterial, fungal); febrile neutropenia; hypersensitivity; dehydration; insomnia; syncope, headache, dizziness, neuralgia, dysgeusia, neuropathy; ear pain; tachycardia; hypertension, venous thrombosis, phlebitis, hypotension; dyspnoea, cough; ileus, dysphagia, mouth disorders, dyspepsia; rash, urticaria, pruritus, hyperhidrosis; muscular weakness, arthralgia, back pain, jaw pain, pain in the extremities, bone pain, musculoskeletal pain; chest pain, chills, pain, oedema.

Uncommon (≥1/1,000 to <1/100): neutropenic sepsis; tumour pain; inappropriate antidiuretic hormone secretion (SIADH); motor peripheral neuropathy; visual disturbance; vertigo, tinnitus; myocardial ischaemia, myocardial infarction; acute respiratory distress syndrome, pharyngolaryngeal pain; odynophagia, gastric disorders, oesophagitis, gingival disorders; dry skin, erythema; renal failure; extravasation; increased transaminases, weight gain.

Rare (≥1/10,000 to <1/1,000): posterior reversible encephalopathy syndrome (PRES).

Important serious reactions: across all indications, 8 patients (0.6% of those treated) died of infection as a complication of neutropenia, and febrile neutropenia occurred in 5.2%. Grade 3/4 ileus occurred in 1.9% of patients and was reversible with medical treatment. Ischaemic cardiac events, PRES and severe hyponatraemia are described under Special Instructions.

• Potent CYP3A4 inhibitors (for example ritonavir, ketoconazole, itraconazole, grapefruit juice): ketoconazole raised exposure to vinflunine by 30% and to its metabolite DVFL by 50%. Avoid the combination.
• CYP3A4 inducers (for example rifampicin, St John’s wort): they may lower vinflunine and DVFL concentrations. Avoid the combination.
• QT-prolonging medicines: using two or more QT/QTc-prolonging substances together is not recommended and should be avoided.
• Cisplatin, carboplatin, capecitabine, gemcitabine: no pharmacokinetic interaction was seen.
• Doxorubicin: no pharmacokinetic interaction, but the combination carried a particularly high risk of blood toxicity.
• Pegylated or liposomal doxorubicin: vinflunine exposure rose by an apparent 15–30% and doxorubicin AUC fell 2 to 3-fold. Use this combination with caution.
• Paclitaxel and docetaxel: a laboratory study suggested a possible interaction (slight inhibition of vinflunine metabolism); no clinical studies have been done.
• Opioids: they can add to the risk of constipation.
• Other: vinflunine did not induce or inhibit the CYP enzymes tested in vitro, and it is a P-glycoprotein substrate with a lower affinity than other vinca alkaloids, so clinically significant interactions through that route are unlikely.

Treatment is started under the responsibility of a physician qualified in anticancer chemotherapy and is confined to units specialised in giving cytotoxic chemotherapy. Before each cycle a full blood count checks the neutrophil count, platelets and haemoglobin. Javlor must only be given intravenously.

Recommended Dose

• 320 mg/m² as a 20-minute intravenous infusion every 3 weeks.
• Start at 280 mg/m² in patients with WHO/ECOG performance status 1, or status 0 with prior pelvic irradiation. If the first cycle causes no blood toxicity leading to a delay or dose reduction, the dose is raised to 320 mg/m² every 3 weeks from the next cycle.
• To prevent constipation, laxatives and dietary measures including oral hydration are recommended from day 1 to day 5 or 7 after each infusion.

Delaying or Stopping Treatment

• Neutropenia (neutrophils below 1,000/mm³) or thrombocytopenia (platelets below 100,000/mm³) on day 1: delay until recovery (neutrophils at least 1,000/mm³ and platelets at least 100,000/mm³) and adjust the dose if necessary. Stop if recovery has not occurred within 2 weeks.
• Moderate, severe or life-threatening organ toxicity: delay until it is mild or gone, or back to baseline, and adjust the dose if necessary. Stop if recovery has not occurred within 2 weeks.
• Cardiac ischaemia in a patient with a prior myocardial infarction or angina pectoris: stop.

Dose Reductions for Toxicity

The triggers are grade 4 neutropenia (neutrophils below 500/mm³) lasting more than 7 days; febrile neutropenia (neutrophils below 1,000/mm³ with fever of 38.5 °C or more); mucositis or constipation of grade 2 lasting 5 days or more, or of grade 3 or higher for any time; and any other grade 3 or higher toxicity, except grade 3 nausea or vomiting.

• Starting at 320 mg/m²: first event 280 mg/m²; second consecutive event 250 mg/m²; third consecutive event, stop treatment.
• Starting at 280 mg/m²: first event 250 mg/m²; second consecutive event, stop treatment.
• Starting at 250 mg/m² (severe renal impairment, or age 80 years and over, see below): first event 225 mg/m²; second consecutive event, stop treatment.

Special Populations

• Hepatic impairment: no adjustment is needed when liver tests are only mildly raised within the limits set in the SmPC. The dose is 250 mg/m² every 3 weeks in mild impairment (Child-Pugh A) and 200 mg/m² every 3 weeks in moderate impairment (Child-Pugh B), with laboratory criteria (prothrombin time, bilirubin, transaminases, gamma-glutamyl transferase) given in the SmPC. Vinflunine has not been evaluated in severe impairment (Child-Pugh C).
• Renal impairment: patients with creatinine clearance above 60 mL/min were treated at the recommended dose. The dose is 280 mg/m² every 3 weeks at 40–60 mL/min and 250 mg/m² every 3 weeks at 20 to below 40 mL/min.
• Elderly: no adjustment below 75 years. From 75 to under 80 years the dose is 280 mg/m² every 3 weeks; from 80 years it is 250 mg/m² every 3 weeks.
• Children and adolescents: there is no relevant use of Javlor in the paediatric population.

Method of Administration

• Javlor is a single-use concentrate and must be diluted before use (see section 6.6 of the SmPC). It is given as a 20-minute infusion, not as a rapid bolus.
• A peripheral line or a central catheter can be used. Peripheral infusion can irritate the vein; a central catheter may be preferred with small or sclerosed veins, lymphoedema or a recent puncture of the same vein. Check that the needle is correctly placed before starting, to avoid extravasation.
• After the diluted solution, flush the vein with at least an equal volume of sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) solution for infusion.

Haematological Toxicity

Neutropenia, leucopenia, anaemia and thrombocytopenia are frequent. Blood counts are checked before each infusion. Starting vinflunine is contraindicated if the neutrophil count is below 1,500/mm³ or platelets are below 100,000/mm³; for later infusions the limits are neutrophils below 1,000/mm³ or platelets below 100,000/mm³. The dose is reduced for haematological toxicity.

Constipation and Gastrointestinal Toxicity

Grade 3 or higher constipation occurred in 15.3% of treated patients. It is reversible and can be prevented with oral hydration, fibre and laxatives (stimulant laxatives or faecal softeners) from day 1 to day 5 or 7 of each cycle. Patients at high risk (taking opiates, with peritoneal carcinomatosis or abdominal masses, or after major abdominal surgery) should take an osmotic laxative once a day in the morning before breakfast from day 1 to day 7. Constipation of grade 2 lasting 5 days or more, or of grade 3 or higher, any gastrointestinal toxicity of grade 3 or higher (except vomiting or nausea), and mucositis of the same severity call for a dose adjustment.

Cardiac Disorders

QT interval prolongation was seen in a few patients, which may raise the risk of ventricular arrhythmias, although none occurred. Use caution in patients with a higher proarrhythmic risk, such as congestive heart failure, a known history of QT prolongation or hypokalaemia. Ischaemic cardiac events may occur, especially in patients with underlying heart disease, and patients with prior myocardial infarction, ischaemia or angina need special attention and vigilant monitoring. Stopping treatment should be considered if cardiac ischaemia develops.

Posterior Reversible Encephalopathy Syndrome (PRES)

PRES has been observed. Typical features are headache, confusion, seizures and visual disorders, with high blood pressure, nausea and vomiting; scans show white matter abnormalities in the posterior brain. Blood pressure should be controlled and brain imaging is recommended to confirm the diagnosis. The features usually resolve rapidly without lasting effects after stopping, and discontinuation should be considered when neurological signs appear.

Hyponatraemia

Severe hyponatraemia, including cases due to SIADH, has occurred. Serum sodium should be checked regularly during treatment.

Venous Irritation and Intrathecal Risk

Intrathecal administration of Javlor may be fatal. When infused through a peripheral vein, vinflunine caused venous irritation of grade 1 in 22% of patients, grade 2 in 11.0% and grade 3 in 0.8%; all cases resolved rapidly without stopping treatment.

Contraception, Pregnancy, Breastfeeding and Fertility

• Contraception: because vinflunine is genotoxic, men and women with reproductive potential must use effective contraception during treatment and for up to 4 months (men) and 7 months (women) after the last dose.
• Pregnancy: there are no data in pregnant women; animal studies showed embryotoxicity and teratogenicity. Vinflunine should not be used in pregnancy unless strictly necessary. If pregnancy occurs, the patient must be told of the risk to the unborn child and monitored carefully, and genetic counselling should be considered; it is also advised for patients who wish to have children after treatment.
• Breastfeeding: contraindicated.
• Fertility: advice on conserving sperm should be sought before treatment, because irreversible infertility is possible.

Effect on Driving

No studies have been done, but fatigue, dizziness, vertigo, visual disturbance and syncope have been reported. Patients should be advised not to drive or use machines without the advice of a healthcare professional.

Store in a refrigerator at 2–8 °C, in the original package to protect from light. Javlor is a refrigerated product, so cold-chain handling at 2–8 °C applies from dispatch to the pharmacy. Storage after dilution is covered under Shelf Life. The colourless glass vials (2 mL, 4 mL and 10 mL) come in packs of 1 and 10 vials; not all pack sizes may be marketed.

• Unopened vial: 3 years.
• Diluted solution: protected from light in a polyethylene or polyvinylchloride infusion bag, up to 6 days in a refrigerator (2–8 °C) or up to 24 hours at 25 °C; exposed to light in a polyethylene or polyvinylchloride infusion set, up to 1 hour at 25 °C. From a microbiological point of view the product should be used immediately after dilution; otherwise the user is responsible for in-use times, which would normally not exceed 24 hours at 2–8 °C unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx), as a medicinal product subject to restricted medical prescription. Treatment is started under the responsibility of a physician qualified in anticancer chemotherapy and is confined to units specialised in cytotoxic chemotherapy. Vinflunine is infused in hospital, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.