Consumer medicine information

Javlor 25 mg/mL Concentrated Injection

Vinflunine

BRAND INFORMATION

Brand name

Javlor

Active ingredient

Vinflunine

Schedule

What is in this leaflet

This leaflet answers some common questions about Javlor.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Javlor against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Javlor is used for

Javlor is used to treat cancer of the bladder and urinary tract at an advanced stage. Javlor is given if previous therapy with a platinum-containing medicine has failed.

Javlor belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these medicines being called chemotherapy.

Javlor contains the medicine, vinflunine which belongs to a family of medicines called vinca alkaloids. Javlor works by stopping cancer cells from growing and multiplying causing the cells to die.

Your doctor may have prescribed Javlor for another purpose.

Ask your doctor if you have any questions about why Javlor has been prescribed for you.

This medicine is available only with a doctor’s prescription.

Before you are given Javlor

When you must not be given it

Do not take Javlor if you have an allergy to the active substance, vinflunine or to the other vinca alkaloids, (vinblastine, vincristine, vindesine, vinorelbine).

Symptoms of an allergic reaction to Javlor may include:

shortness of breath
wheezing, difficulty breathing or a tight feeling in your chest
swelling of the face, lips, tongue or other parts of the body
rash, itching, hives or flushed, red skin.

Do not take Javlor if you have or have had (within the last two weeks), a severe infection. Tell your doctor if you have or have had a severe infection in the last two weeks. Your doctor may decide to delay your treatment until the infection has gone.

Do not breastfeed while being treated with Javlor. Javlor may pass into breastmilk and therefore there is a possibility that the breast-fed baby may be affected.

Do not have Javlor after the expiry date printed on the pack. The expiry date refers to the last day of that month. If you have this medicine after the expiry date has passed, it may not work as well.

Do not have Javlor if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start having Javlor, talk to your doctor.

Before you are given it

Javlor is a potent cytotoxic drug that results in a decrease in blood cells. Your blood count will be carefully monitored before and during your treatment.

Tell your doctor if you have allergies to:

any other medicines;
any other substances, such as foods, preservatives or dyes.

Tell your doctor if you have or have had any medical conditions, especially the following:

heart problems including chest pain and heart attack)
liver problems.
kidney problems.
a low white blood cell count which you may notice as signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers.
constipation
stomach problems (including surgery on your stomach)
cancer of the peritoneum (the membrane lining the stomach wall, covering the liver, stomach, spleen, gallbladder and intestines.

Tell your doctor if you are pregnant or intend to become pregnant. Like most medicines used to treat cancer, Javlor is not recommended for use in pregnancy unless it is strictly necessary. Javlor may affect your developing baby if you take it during pregnancy. If there is a need to consider Javlor during your pregnancy, your doctor will discuss with you the benefits and risks of using it. Genetic counselling is also recommended.

If you are a fertile man or woman, you should use an effective method of contraception during your treatment with Javlor and for three months after your last dose of Javlor.

Tell your doctor if you wish to have children after your therapy with Javlor. It is recommended that you seek genetic counselling if you wish to have children after your therapy with Javlor.

If you intend to father a child, seek advice on sperm storage before starting your therapy because of the possibility that Javlor may cause permanent infertility.

Tell your doctor if you are breast-feeding or plan to breast-feed. You should not breast-feed while you are being treated with Javlor.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Tell your doctor if you are taking medicines for pain called opiates. If you are taking opiates at the same time as having Javlor, you may need treatment to avoid constipation.

Some medicines and Javlor may interfere with each other.

These include:

ketoconazole and itraconazole, medicines used to treat fungal infections;
retonavir, a medicine used to treat HIV and AIDS;
pegylated doxorubicin a medicine used to treat cancer;
rifampicin, a medicine used to treat tuberculosis or meningitis;
a herbal treatment for depression called St John’s wort or hypericum perforatum.

These medicines may be affected by Javlor or may affect how well it works. You may need to take different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or to avoid while taking Javlor.

You should also tell your doctor if you are drinking grapefruit juice. Grapefruit juice can also interfere with the effectiveness of Javlor.

If you have not told your doctor about any of the above, do so before you begin treatment with Javlor.

How Javlor is given

How much is given

Your doctor will decide what dose you will receive. This depends on your body surface area, your age, your condition and factors such as your liver and kidney function and whether you have had prior irradiation of the pelvis.

Your doctor may adjust your dose during treatment.

Javlor reduces the number of white blood cells in the body. Your doctor will check these levels regularly. Further doses of Javlor may be delayed until your blood cell numbers return to acceptable levels.

How it is given

Javlor is first diluted before it is given by intravenous infusion, i.e. a slow injection into your veins, lasting 20 minutes. The treatment is repeated every 3 weeks.

Before receiving Javlor, you may be given laxatives and other treatments to prevent constipation and antiemetic medicines to prevent vomiting.

Javlor must only be given by a doctor or nurse experienced in the use of chemotherapy medicines.

How long it is given

Your doctor will decide how many doses you will need.

If you miss a dose

Tell your doctor as soon as possible if you realize that you have missed an appointment for receiving your dose of Javlor.

If you have problems remembering when your next dose is due, use a diary or calendar or ask a friend to remind you.

Overdose

As Javlor is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience any side effects while or after being given Javlor, tell your doctor, nurse or pharmacist.

Symptoms of a Javlor overdose include the side effects listed below in the “Side Effects” section, but are usually of a more severe nature.

While you are being given Javlor

Things you must do

Tell your doctor or nurse immediately if you feel any pain or discomfort during the injection.

Tell your doctor or nurse if you experience any neurological symptoms such as headaches, loss of energy, fatigue, confusion, convulsions or altered consciousness.

Keep all follow-up appointments with your doctor. It is important to have your follow-up doses of Javlor at the appropriate times to get the best effects from your treatment.

Your doctor will also need to do some blood and other tests from time to time to check on your progress and monitor any unwanted side effects.

Tell any other doctors, dentists and pharmacists who are treating you that you are receiving treatment with Javlor.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are receiving treatment with Javlor.

If you become pregnant while taking Javlor, tell your doctor immediately. Taking Javlor during pregnancy is not recommended. Your doctor will discuss with you the risks and benefits of using Javlor when pregnant and decide whether or not treatment should be continued.

Things to be careful of

Be careful driving or operating machinery until you know how Javlor affects you. If you experience symptoms that affect your ability to concentrate and react, do not drive a car or operate machinery. Dizziness and fainting are common side effects of Javlor.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are taking Javlor. Like other medicines that treat cancer, Javlor can cause side effects, some of which may be serious. You may need medical treatment if you get some of these side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor, nurse or pharmacist if you notice any of the following and they worry you:

constipation;
diarrhea;
nausea;
vomiting;
weight loss;
weight gain;
loss of appetite;
muscle pain;
unusual tiredness, weakness, sleepiness, drowsiness or lack of energy;
unusual hair loss or thinning;
pain at the site of injection;
headache;
aching muscles, muscle tenderness or weakness, not caused by exercise;
jaw pain;
joint pain; painful swollen joints;
dizziness;
back pain;
trouble sleeping;
bone pain
fainting;
change in or loss of taste;
ear pain;
ringing or buzzing in your ears;
spinning sensation;
coughing;
sore throat;
indigestion
problems with your gums or the insides of your cheeks;
excessive sweating;
skin reactions: redness, rash, itching;
dehydration

Tell your doctor or nurse as soon as possible if you notice any of the following:

frequent infections such as fever, severe chills, sore throat or mouth ulcers (symptoms of a lack of white blood cells);
tiredness, headaches, being short of breath when exercising, dizziness and looking pale (symptoms of a decreased number of red blood cells);
bleeding or bruising more easily than normal (symptoms of a low blood platelet count);
sore mouth, tongue, gums or toothache;
mouth ulcers and cold sores;
stomach pain;
viral, bacterial or fungal infections;
numbness or weakness of the arms and legs;
severe stabbing or throbbing pain along the nerves;
high blood pressure;
low blood pressure;
persistent constipation with a swollen stomach and vomiting;
difficulty swallowing;
painful swallowing;
an allergic reaction;
difficulties with body movement;
loss of sense of touch;
changes in your vision;
dry eye.

These may be serious side effects. You may need medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

difficulty breathing, short of breath;
chest pain;
palpitations, fast or irregular heart beat
rash, itching or hives on the skin
swelling of the feet and ankles, face, lips, tongue or other parts of the body.

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Other side effects not listed above may occur in some patients. Tell your doctor, nurse or pharmacist if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After treatment with Javlor

Storage

Javlor Concentrated Injection vials are usually stored in the doctor’s surgery or clinic, or at the pharmacy. However, if you need to store Javlor:

Store the Javlor vials in the refrigerator (2 to 8°C). Do not freeze it. Protect Javlor from light.

Transport the Javlor vials refrigerated (2 to 8°C) protected from light in its original packaging.

Keep it where children cannot reach it.

Keep the Javlor vials in the original pack/container until it is time for it to be given.

Do not store Javlor or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car Heat and dampness will destroy the medicine.

Disposal

If your doctor stops your treatment with Javlor, or it has passed its expiry date, return any left-over vials to your pharmacist. Do not dispose of Javlor via wastewater or household waste. This will help to protect the environment.

Product description

What it looks like

Javlor is a concentrated clear, colourless to pale yellow solution containing 25 mg vinflunine per mL. It comes in a clear glass vial closed with a rubber stopper and sealed with an aluminium seal.

Javlor is available in 50 mg/2 mL, 100 mg/4 mL* and 250 mg/10 mL single use vials. It is supplied in packs of 1 and 10 vials.

Ingredients

Active ingredient:

vinflunine ditartrate

Other ingredient:

water for injections

Javlor is supplied by:

Pierre Fabre Australia Pty Ltd
Suite 901,
1 Elizabeth Plaza
North Sydney NSW 2060

Australian Registration Number:

50 mg/2 mL: AUST R 166767

100 mg/4 mL*: AUST R 166772

250 mg/10 mL: AUST R 166773

* Not marketed

This leaflet was prepared in February 2011 and updated in August 2018.

Published by MIMS November 2018

BRAND INFORMATION

Brand name

Javlor

Active ingredient

Vinflunine

Schedule

Name of the medicine

Vinflunine (as ditartrate).

Excipients.

Water for injections.

Description

Molecular formula: C₅₃H₆₆F₂N₄O₂₀. MW: 1117.09. CAS: 194468-36-5. Vinflunine ditartrate is a white to off white powder. Vinflunine ditartrate is freely soluble in water, soluble in ethanol and practically insoluble in dichloromethane. It is very hygroscopic with a pKa value of 5.67 and 8.17 in water at 26°C-27°C.
Javlor Concentrated Injection is presented as a clear, colourless to pale yellow solution. It is supplied as a sterile, endotoxin free aqueous solution intended for dilution with a suitable parenteral fluid (sodium chloride 0.9% solution or glucose 5% solution). One mL of Javlor contains 25 mg of vinflunine (as vinflunine ditartrate).

Pharmacology

Pharmacodynamics.

Vinflunine is an antineoplastic drug. Vinflunine binds to tubulin at or near to the vinca binding sites inhibiting its polymerisation into microtubules, which results in treadmilling suppression, disruption of microtubule dynamics, mitotic arrest and apoptotic cell death.
In vivo, vinflunine displays significant antitumour activity against a broad spectrum of human xenografts in mice both in terms of survival prolongation and tumour growth inhibition.

Pharmacokinetics.

Vinflunine pharmacokinetics is linear up to 400 mg/m² in cancer patients. Blood exposure to vinflunine (AUC) significantly correlated with severity of leucopenia, neutropenia and fatigue.

Distribution.

Vinflunine is moderately bound to human plasma protein (67.2 ± 1.1%) with a plasma/ blood concentration ratio of 0.80 ± 0.12. Protein binding mainly involves high density lipoproteins and serum albumin and is nonsaturable in the range of vinflunine concentrations observed in patients. Binding to alpha-1 acid glycoprotein and to platelets is negligible (< 5%).
The terminal volume of distribution is large: 35 ± 9 L/kg suggesting extensive distribution into tissues.

Metabolism.

All metabolites identified are formed by the cytochrome CYP3A4 isoenzyme except for 4-O-deacetylvinflunine (DVFL) which is formed through multiple esterases.
DVFL is the only major active metabolite in blood.

Elimination.

Vinflunine is eliminated following a multiexponential concentration decay with a terminal half-life (t_1/2) close to 40 h. DVFL is slowly formed and more slowly eliminated than vinflunine (t_1/2 of approximately 120 h).
The excretion of vinflunine and its metabolites occurs through faeces (2/3) and urine (1/3).
In a population pharmacokinetic analysis in 372 patients (656 pharmacokinetic profiles), the total blood clearance was 40 L/h with low interindividual and intraindividual variability (coefficients of variation of 25% and 8% respectively).

Clinical Trials

The efficacy of vinflunine as second line therapy for the treatment of patients with advanced or metastatic transitional cell carcinoma of the urothelial tract (TCCU) after failure of a prior platinum containing regimen and with a performance status of ≤ 1 was demonstrated in one phase III (VFL 302) and two phase II (VFL 202 and CA 001) clinical trials.
The phase III clinical trial was an open label, randomised, multicentre study comparing vinflunine plus best supportive care to best supportive care (BSC) alone in patients with advanced TCCU previously treated with a first line platinum containing chemotherapy. Two hundred and fifty-three patients were randomised to the vinflunine + BSC arm and 117 patients to the BSC arm. The vinflunine dose was 320 mg/m² for patients with performance status of 0 and without previous pelvic irradiation and 280 mg/m² escalated to 320 mg/m² for patients with performance status of 1 or previous pelvic irradiation. The dose was given by intravenous infusion over 20 minutes every 3 weeks.
Vinflunine did not significantly increase overall survival, the primary endpoint, in the intent to treat analysis. There was a small significant increase in progression free survival of median 1.5 months (see Table 1).
In addition, a prespecified multivariate analysis performed on the ITT population demonstrated that vinflunine had a statistically significant treatment effect (p = 0.036) on overall survival when prognostic factors (performance status (PS), visceral involvement, alkaline phosphatases, haemoglobin, pelvic irradiation) were taken into consideration (see Table 1). A statistically significant difference in overall survival with vinflunine treatment (p = 0.040) was also seen in the eligible population (which excluded 13 patients with clinically significant protocol violations at baseline who were not eligible for treatment) (see Table 1).
In the two multicentre, open label, single arm phase II clinical trials, a total of 202 patients were treated with vinflunine (VFL 202: n = 51, CA 001: n = 151). The median progression free survival was 3.0 months and 2.7 months respectively. The median survival was 6.6 months and 7.9 months respectively.

Indications

Treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum containing regimen.

Contraindications

Hypersensitivity to vinflunine or other vinca alkaloids.
Recent (within 2 weeks) or current severe infection.
Baseline absolute neutrophil count (ANC) < 1.5 x 10⁹/L for the first administration, baseline ANC < 1.0 x 10⁹/L for subsequent administrations.
Platelets < 100 x 10⁹/L.
Lactation (see Precautions, Use in lactation).

Precautions

Performance status.

Vinflunine has a narrow safety threshold. If vinflunine is used in patients with poor performance status or patients likely to progress quickly to poor performance status, close observation is required since toxicity may be excessive.
For patients with WHO/ ECOG performance status 1, vinflunine dose reduction is recommended (see Dosage and Administration).
For patients with WHO/ ECOG performance status 2 or greater, physicians should carefully consider the benefits and risks of vinflunine since there is no experience of the use of vinflunine in such patients.

Haematological toxicity.

Neutropenia, leukopenia, anaemia and thrombocytopenia are frequent adverse reactions of vinflunine. Complete blood counts should be checked before each vinflunine infusion.
The recommended dose should be reduced in patients with grade > 3 haematological toxicity (see Dosage and Administration).
Javlor should not be administered when the ANC is < 1.5 x 10⁹/L and/or platelets < 100 x 10⁹/L for the first administration and ANC < 1.0 x 10⁹/L and/or platelets < 100 x 10⁹/L for subsequent administrations.

Gastrointestinal disorders.

Severe constipation (grade ≥ 3) occurred in 15.3% of treated patients. NCI CTC grade 3 constipation is defined as obstipation requiring manual evacuation or enema. Grade 4 constipation is defined as obstruction or toxic megacolon. Constipation is reversible and can be prevented by special dietary measures such as oral hydration, fibre intake and the administration of laxatives such as stimulant laxatives or faecal softeners from day 1 to day 5 or 7 of the treatment cycle.
For patients at high risk of constipation (concomitant treatment with opiates, peritoneal carcinomas, abdominal masses, prior abdominal surgery), an osmotic laxative should be administered once a day from day 1 to day 7 in the morning before breakfast.
In the case of grade 2 mucositis or constipation (defined as requiring laxatives) for 5 days or more or any grade ≥ 3 gastrointestinal toxicity (except nausea or vomiting), the dose of vinflunine should be reduced (see Dosage and Administration). Grade 2 is defined as moderate, grade 3 as severe and grade 4 as life threatening.
During the phase I study involving cancer patients with renal impairment (RI), a case of fatal colonic perforation was seen in a patient with colorectal adenocarcinoma in the moderate RI group (n = 13), 21 days after administration of vinflunine 280 mg/m². A sigmoid biopsy revealed massive necrosis of the colonic wall. Although this may have been the result of progressive disease, the role of vinflunine in this event cannot be excluded.

Neuropathy.

Neuropathy is a frequent adverse effect of vinflunine. Patients should be monitored for symptoms and signs of neuropathy before each vinflunine infusion. In the case of grade 2 neuropathy (weakness or sensory disturbance not interfering with activities of daily living), the vinflunine dose should be reduced (see Dosage and Administration). In the case of grade ≥ 3 neuropathy (weakness or sensory disturbance interfering with activities of daily living), vinflunine treatment should be discontinued.

Cardiac disorders.

Few QT interval prolongations have been observed after the administration of vinflunine. This effect may lead to an increased risk of ventricular arrhythmias although no ventricular arrhythmias were observed with vinflunine. Nevertheless, vinflunine should be used with caution in patients with increased proarrhythmic risk (e.g. congestive failure, known history of QT interval prolongation, hypokalemia) (see Adverse Effects). The concomitant use of two or more QT/ QTc interval prolonging substances is not recommended (see Interactions with Other Medicines).
Special attention is recommended when vinflunine is administered to patients with a prior history of myocardial infarction/ ischemia or angina pectoris (see Adverse Effects). Ischaemic cardiac events may occur, especially in patients who have underlying cardiac disease. Thus patients receiving vinflunine should be vigilantly monitored by physicians for the occurrence of cardiac events. Caution should be exercised in patients with a history of cardiac disease and the benefit/risk assessment should be carefully evaluated regularly. Discontinuation of vinflunine should be considered in patients who develop cardiac ischaemia.

Venous irritation.

When infused through a peripheral vein, vinflunine can induce grade 1 (22.0% of patients, 14.1% of cycles), grade 2 (11.0% of patients, 6.8% of cycles) or grade 3 (0.8% of patients, 0.2% of cycles) venous irritation. All cases resolved rapidly without treatment discontinuation. Instructions for administration should be followed as described in Dosage and Administration, Administration of Javlor.

Posterior reversible encephalopathy syndrome (PRES).

Cases of PRES have been observed after administration of vinflunine. The typical clinical symptoms are, with varying degrees: neurological (headache, confusion, seizure, visual disorders), systemic (hypertension) and gastrointestinal (nausea, vomiting). Radiological signs are white matter abnormalities in the posterior regions of the brain. Blood pressure should be controlled in patients developing symptoms of PRES. To confirm the diagnosis, brain imaging is recommended. Clinical and radiological features usually resolve rapidly without sequelae after treatment discontinuation. Discontinuation of vinflunine should be considered in patients who develop neurological signs of PRES.

Hyponatraemia/ syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Cases of severe hyponatraemia/ SIADH have been observed during treatment with vinflunine. Blood natraemia should be verified to identify severe hyponatraemia in patients developing central nervous system disorders such as confusion, lethargy, altered consciousness associated or not with important fluid losses.

Special populations.

Hepatic impairment.

No modification of vinflunine and DVFL pharmacokinetics was observed in 25 patients with mild to moderate hepatic impairment compared to patients with normal hepatic function. This was further confirmed by a population pharmacokinetic analysis which demonstrated an absence of relationship between vinflunine clearance and biology markers of hepatic impairment. However, lower vinflunine doses are recommended in patients with mild to moderate hepatic impairment because the standard vinflunine dose was not tolerated (see Dosage and Administration). Vinflunine is not recommended in severe hepatic impairment.

Renal impairment.

A pharmacokinetic phase I study was performed in 2 groups of cancer patients with renal impairment (RI) classified according to the calculated creatinine clearance values: group 1 (n = 13 patients) with moderate impairment (40 mL/min ≤ creatinine clearance ≤ 60 mL/min) and group 2 (n = 20 patients) with severe impairment (20 mL/min ≤ creatinine clearance < 40 mL/min). The pharmacokinetic results of this study indicated a reduction of vinflunine clearance when creatinine clearance is decreased. This was further confirmed by a population pharmacokinetic analysis which included 56 patients with a creatinine clearance between 20 mL/min and 60 mL/min which showed that vinflunine clearance is influenced by the creatinine clearance value (Cockcroft and Gault formula). Therefore the recommended dose should be reduced in patients with moderate and severe renal impairment (see Dosage and Administration).
In the phase I study, increased rates of some adverse events were seen (compared to those listed in Table 2), in either one or both groups in terms of asthenia, constipation, anorexia, nausea and vomiting, abdominal pain, myalgia, arthralgia, diarrhoea and dehydration, leukopenia, neutropenia, thrombocytopenia and anaemia. One grade 4 myocardial infarction was observed in the severe RI group (n = 20). A fatal colonic perforation in the moderate RI group (n = 13) , 21 days after the administration of vinflunine 280 mg/m² was attributed to disease progression (colorectal adenocarcinoma); however the role of vinflunine in this case cannot be excluded. Due to small patient numbers in the study, the significance of these numbers is uncertain.

Elderly (≥ 75 years).

A pharmacokinetic phase I study of vinflunine was performed in elderly patients (n = 46). Vinflunine doses were adjusted according to 3 age groups as shown in Table 2.

Vinflunine clearance was significantly decreased in patients ≥ 80 years old as compared to a control group of younger patients < 70 years. Pharmacokinetics of VFL were not modified for patients ≥ 70 and < 75 years old and patients ≥ 75 and < 80 years old.
Based on both PK and safety data, dose reductions are recommended in the elder groups: ≥ 75 and < 80 years old; and ≥ 80 years old. For further cycles, the dose should be adjusted in the event of toxicity (see Dosage and Administration).

Paediatric use.

The safety and effectiveness of vinflunine has not been established in patients below the age of 18 years. The subject indication does not apply to children.

Other.

According to the population pharmacokinetic analysis, neither gender nor patient performance status (ECOG score) had an impact on vinflunine clearance which is directly proportional to body surface area.

Effects on fertility.

There are no human data on the effects of vinflunine on male or female fertility. In animal studies, adverse effects on the male reproductive system of rats were observed at clinically relevant systemic exposures. Both male and female patients with reproductive potential should take adequate contraceptive measures during treatment and for three months after the discontinuation of therapy. Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with vinflunine.

Use in pregnancy.

(Category D)
There are no data available on the use of vinflunine in pregnant women. Studies in rats and rabbits have shown embryotoxicity and teratogenicity at subclinical exposures. On the basis of the results of animal studies and the pharmacological action of vinflunine, there is a potential risk of embryonic and foetal abnormalities.
Vinflunine should therefore not be used during pregnancy, unless it is strictly necessary. If pregnancy occurs during treatment, the patient should be informed about the risk for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered. Genetic counselling is also recommended for patients wishing to have children after therapy.

Use in lactation.

It is not known whether vinflunine or its metabolites are excreted in breast milk. In animal studies, adverse effects on postnatal development were seen in rat pups. Therefore, because of the potential harm to infants, breastfeeding during treatment with vinflunine is contraindicated.

Carcinogenicity.

The carcinogenic potential of vinflunine has not been studied. However, positive findings in genotoxicity assays suggest that vinflunine may have a carcinogenic potential.

Genotoxicity.

Vinflunine was shown to be clastogenic (induces chromosome breakage) in a rat micronucleus test as well as mutagenic and clastogenic in mouse lymphoma assay. Negative results were obtained in bacterial mutagenicity assays (Ames test).

Effects on ability to drive and operate machinery.

The effect of vinflunine on the ability to drive and use machines has not been studied. However, patients should be advised not to drive or operate machinery if they experience any adverse reactions with a potential impact on their ability to perform these activities (e.g. dizziness and syncope are common).

Interactions

In vitro studies showed that vinflunine neither induced CYP1A2, CYP2B6 or CYP3A4 activity nor inhibited CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activity.
In vitro studies showed that vinflunine is a Pgp substrate like the other vinca alkaloids. The clinical relevance of this is unknown.
No pharmacokinetic interaction was observed in patients when vinflunine was combined with either cisplatin, carboplatin, capecitabine, or gemcitabine. No pharmacokinetic interaction was observed in patients when vinflunine was combined with doxorubicin however, this combination was associated with a particularly high risk of haematological toxicity.
A phase I study evaluating the effect of ketoconazole treatment (a strong CYP3A4 inhibitor) on vinflunine pharmacokinetics indicated that coadministration of ketoconazole (400 mg p.o. once daily for 8 days) induced a 30% and 50% increase of both vinflunine and DVFL blood exposures respectively.
Therefore the concomitant use of vinflunine and potent CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole and grapefruit juice) or inducers (such as rifampicin and Hypericum perforatum (St John's wort)) should be avoided as they may increase or decrease vinflunine and DVFL concentrations.
The concomitant use of vinflunine with other QT/ QTc interval prolonging drugs or proarrhythmic drugs should be avoided (see Precautions, Cardiac disorders).
A pharmacokinetic interaction between vinflunine and pegylated/ liposomal doxorubicin was observed resulting in a 15% to 30% apparent increase in vinflunine exposure and a 2 to 3-fold apparent decrease of doxorubicin AUC whereas doxorubicinol metabolite concentrations were not affected. According to an in vitro study, such changes could be related to an adsorption of vinflunine to the liposomes and a modified blood distribution of both compounds. Therefore, caution should be exercised when this type of combination is used.
A possible interaction with paclitaxel and docetaxel (CYP3A substrates) has been suggested from an in vitro study (slight inhibition of vinflunine metabolism). No specific clinical studies of vinflunine in combination with these compounds have been conducted.
The concomitant use of opioids could enhance the risk of constipation.

Adverse Effects

The most frequent treatment related adverse reactions reported in the one phase III and two phase II trials in patients with transitional cell carcinoma of the urothelium (450 patients treated with vinflunine) were haematological disorders, mainly neutropenia, anaemia; gastrointestinal disorders, especially constipation, anorexia, nausea, stomatitis/ mucositis, vomiting, abdominal pain and diarrhoea; and general disorders such as asthenia/ fatigue.
Adverse reactions are listed in Table 3 by System Organ Class, frequency and grade of severity (NCI CTC (National Cancer Institute Common Terminology Criteria) version 2.0).
Frequency of adverse reactions is defined as: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100); rare (≥ 1/10,000 and < 1/1000); very rare (< 1/10,000); and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions with a frequency below 1% reported in clinical trials in other indications.

In other indications, the adverse reaction profile of vinflunine was similar to that in transitional cell carcinoma of the urothelium except for the following additional reactions.

Endocrine disorders.

Uncommon: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Nervous system disorders.

Rare: posterior reversible encephalopathy syndrome.

Postmarketing experience.

In addition to the adverse reactions reported during preregistration clinical studies listed above, the following adverse drug reactions have been reported with postmarketing experience (frequency not known, cannot be estimated from the available data).

Nervous system disorders.

Posterior reversible encephalopathy syndrome.

Endocrine disorders.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Dosage and Administration

Javlor Concentrated Injection should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.
Before each cycle, adequate monitoring of complete blood counts should be conducted to verify the absolute neutrophil count (ANC) value, platelets and haemoglobin as neutropenia, thrombocytopenia and anaemia are frequent adverse reactions of vinflunine.

Recommended dose.

The recommended dose is 320 mg/m² as a 20 minute intravenous infusion every 3 weeks.
For patients with WHO/ ECOG performance status (PS) of 1 or prior pelvic irradiation, the treatment should be started at the dose of 280 mg/m². In the absence of any haematological toxicity during the first cycle causing treatment delay or dose reduction, the dose can be increased to 320 mg/m² every 3 weeks for subsequent cycles.

Dose adjustment due to toxicity.

See Table 4.

Dose delay or discontinuation due to toxicity.

See Table 5.