Javlor

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Javlor 25 mg/mL concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One mL of concentrate contains 25 mg of vinflunine (as ditartrate). 
 
One 2 mL vial contains 50 mg of vinflunine (as ditartrate). 
One 4 mL vial contains 100 mg of vinflunine (as ditartrate). 
One 10 mL vial contains 250 mg of vinflunine (as ditartrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
Clear, colourless to pale yellow solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Javlor is indicated in monotherapy for the treatment of adult patients with advanced or metastatic 
transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen 
 
Efficacy and safety of vinflunine have not been studied in patients with performance status ≥ 2. 
 
4.2 Posology and method of administration 
 
Vinflunine treatment should be initiated under the responsibility of a physician qualified in the use of 
anticancer chemotherapy and is confined to units specialised in the administration of cytotoxic 
chemotherapy. 
 
Before each cycle, adequate monitoring of complete blood counts should be conducted to verify the 
absolute neutrophil count (ANC), platelets and haemoglobin as neutropenia, thrombocytopenia and 
anaemia are frequent adverse reactions of vinflunine. 
 
Posology 
The recommended dose is 320 mg/m² vinflunine as a 20 minute intravenous infusion every 3 weeks. 
 
In case of  WHO/ECOG performance status (PS) of 1 or PS of 0 and 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 will be increased to 
320 mg/m² every 3 weeks for the subsequent cycles. 
 
Recommended co-medication  
In order to prevent constipation, laxatives and dietary measures including oral hydration are 
recommended from day 1 to day 5 or 7 after each vinflunine administration (see section 4.4). 
 



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Dose delay or discontinuation due to toxicity 

Table 1: Dose delay for subsequent cycles due to toxicity 

Toxicity Day 1 treatment administration 
Neutropenia (ANC < 1000/mm3 ) 
or 
Thrombocytopenia 
(platelets < 100,000/mm3) 

- Delay until recovery (ANC ≥ 1,000/mm3 and 
platelets ≥ 100,000/mm3) and adjust the dose if necessary (see 

table 2) 
- Discontinuation if recovery has not occurred within 2 weeks 

Organ toxicity: moderate, severe or life 
threatening 

- Delay until recovery to mild toxicity or none, or to initial 
baseline status and adjust the dose if necessary (see table 2) 

- Discontinuation if recovery has not occurred within 2 weeks 
Cardiac ischaemia in patients with prior 
history of myocardial infarction or angina 
pectoris 

- Discontinuation 

 
Dose adjustments due to toxicity  
 

Table 2: Dose adjustments due to toxicity 

Toxicity Dose adjustment 

(NCI CTC v 2.0)* Vinflunine initial dose of 320 mg/m² Vinflunine initial dose of 
280 mg/m² 

 First  
Event 

 

2nd 
consecutive 

event 

3rd consecutive 
event 

First  
Event 

 

2nd consecutive 
event 

Neutropenia Grade 4 
(ANC < 500/mm3) > 7 days 

 
280 mg/m² 

 
250 mg/m² 

Definitive 
Treatment 

discontinuation 

 
250 mg/m² 

 

Definitive 
Treatment 

discontinuation 

Febrile Neutropenia 
(ANC < 1,000/mm3 and  
fever ≥ 38,5 °C)  
Mucositis or Constipation 
Grade 2 ≥ 5 days or 
Grade ≥ 3 any duration1 
Any other toxicity Grade ≥ 3 
(severe or life-threatening) 
(except Grade 3 vomiting or 
nausea2) 
*National Cancer Institute, Common Toxicity Criteria Version 2.0 (NCI CTC v 2.0) 
1 NCI CTC Grade 2 constipation is defined as requiring laxatives, Grade 3 as an obstipation requiring manual 
evacuation or enema, Grade 4 as an obstruction or toxic megacolon. Mucositis Grade 2 is defined as “moderate”, 
Grade 3 as “severe” and Grade 4 as “life-threatening”. 
2  NCI CTC Grade 3 nausea is defined as no significant intake, requiring intravenous fluids. Grade 3 vomiting 
as ≥ 6 episodes in 24 hours over pretreatment; or need for intravenous fluids. 
 
Special populations 
 
Patients with hepatic impairment  
A pharmacokinetic and tolerability phase I study in patients with altered liver functions test has been 
completed (see section 5.2). Vinflunine pharmacokinetics was not modified in those patients, however 
based on hepatic biologic parameter modifications following vinflunine administration (gamma 
glutamyl transferases (GGT), transaminases, bilirubin), the dose recommendations are as follows: 



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- No dose adjustment is necessary in patients: 
- with a prothrombin time > 70% NV (Normal Value) and presenting at least one of the 

following criteria: [ ULN (Upper Limit of Normal) < bilirubin ≤ 1.5×ULN and/or 
1.5xULN < transaminases ≤ 2.5×ULN and/or ULN < GGT ≤ 5×ULN ]. 

- with transaminases ≤ 2.5xULN ( < 5xULN only in case of liver metastases). 
 
- The recommended dose of vinflunine is 250 mg/m² given once every 3 weeks in patients with mild 
liver impairment (Child-Pugh grade A) or in patients with a prothrombin time ≥  60% NV and 
1.5×ULN < bilirubin ≤ 3×ULN and presenting at least one of the following criteria:  
[ transaminases > ULN and/or GGT > 5×ULN ]. 
 
- The recommended dose of vinflunine is 200 mg/m² given once every 3 weeks in patients with 
moderate liver impairment (Child-Pugh grade B) or in patients with a prothrombin time ≥ 50% NV 
and bilirubin > 3×ULN and transaminases > ULN and GGT > ULN. 
 
Vinflunine has not been evaluated in patients with severe hepatic impairment (Child-Pugh grade C), or 
in patients with a prothrombin time < 50%NV or with bilirubin > 5xULN or with isolated 
transaminases > 2.5xULN ( ≥ 5xULN only in case of liver metastases) or with GGT > 15xULN. 
 
Patients with renal impairment 
In clinical studies, patients with CrCl (creatinine clearance) > 60 mL/min were included and treated at 
the recommended dose. 
In patients with moderate renal impairment (40 mL/min ≤ CrCl ≤ 60 mL/min), the recommended dose 
is 280 mg/m² given once every 3 weeks.  
In patients with severe renal impairment (20 mL/min ≤ CrCl < 40 mL/min) the recommended dose is 
250 mg/m² every 3 weeks (see section 5.2). 
 
For further cycles, the dose should be adjusted in the event of toxicities, as shown in table 3 below. 
 
Elderly patients (≥ 75 years) 
No age-related dose modification is required in patients less than 75 years old (see section 5.2).  
The doses recommended in patients of at least 75 years old are as follows: 
- in patients of at least 75 years old but less than 80 years, the dose of vinflunine to be given is 
280 mg/m² every 3 weeks. 
- in patients 80 years old and above, the dose of vinflunine to be given is 250 mg/m² every 3 weeks.  
 
For further cycles, the dose should be adjusted in the event of toxicities, as shown in table 3 below: 

Table 3: Dose adjustments due to toxicity in renal impaired or elderly patients 

Toxicity 

(NCI CTC v 2.0)* 

Dose adjustment 

Vinflunine initial dose of 
280 mg/m² 

Vinflunine initial dose of 
250 mg/m² 

 First Event 
2nd consecutive 

event 
First 
Event 

2nd consecutive 
event 

Neutropenia Grade 4  
(ANC < 500/mm3) > 7 days 

250 mg/m² 
 

Definitive 
Treatment 

discontinuation 

225 mg/m² 
 

Definitive 
Treatment 

discontinuation 

Febrile Neutropenia 
(ANC < 1,000/mm3 and 
fever ≥ 38,5 °C) 
Mucositis or Constipation 
Grade 2 ≥ 5  days or Grade ≥ 3 any 
duration1 
Any other toxicity Grade  ≥ 3 (severe 
or life-threatening) 
(except Grade 3 vomiting or nausea2) 
 



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*National Cancer Institute, Common Toxicity Criteria Version 2.0 (NCI CTC v 2.0)  
1 NCI CTC Grade 2 constipation is defined as requiring laxatives, Grade 3 as an obstipation requiring manual 
evacuation or enema, Grade 4 as an obstruction or toxic megacolon. Mucositis Grade 2 is defined as “moderate”, 
Grade 3 as “severe” and Grade 4 as “life-threatening”. 
2 NCI CTC Grade 3 nausea is defined as no significant intake, requiring intravenous fluids. Grade 3 vomiting 
as ≥ 6 episodes in 24 hours over pretreatment; or need for intravenous fluids. 
 
Paediatric population 
There is no relevant use of Javlor in the paediatric population. 
 
Method of administration 
Precautions to be taken before handling or administering the medicinal product 
Javlor must be diluted prior to administration. Javlor is for single use only. 
For instructions on dilution of the medicinal product before administration, see section 6.6. 
 
Javlor MUST ONLY be administered intravenously.  
Javlor should be administered by a 20-minute intravenous infusion and NOT be given by rapid 
intravenous bolus. 
 
Either peripheral lines or a central catheter can be used for vinflunine administration. When infused 
through a peripheral vein, vinflunine can induce venous irritation (see section 4.4). In case of small or 
sclerosed veins, lymphoedema or recent venipuncture of the same vein, the use of a central catheter 
may be preferred. To avoid extravasations it is important to be sure that the needle is correctly 
introduced before starting the infusion. 
 
In order to flush the vein, administration of diluted Javlor should always be followed by at least an 
equal volume of sodium chloride 9 mg/mL (0.9%) solution for infusion or of glucose 50 mg/mL (5%) 
solution for infusion.  
For detailed instructions on administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or other vinca alkaloids. 
Recent (within 2 weeks) or current severe infection. 
Baseline ANC < 1,500/mm3 for the first administration, baseline ANC < 1,000/mm3 for subsequent 
administrations (see section 4.4). 
Platelets < 100,000/mm3(see section 4.4). 
Breast-feeding (see section 4.6). 
 
4.4 Special warnings and precautions for use 
 
Hematological toxicity 
Neutropenia, leucopenia, anaemia and thrombocytopenia are frequent adverse reactions of vinflunine. 
Adequate monitoring of complete blood counts should be conducted to verify the ANC, platelet and 
haemoglobin values before each vinflunine infusion (see section 4.3). 
Initiation of vinflunine is contraindicated in subjects with baseline ANC < 1,500/mm3 or 
platelets < 100,000/mm3. For subsequent administrations, vinflunine is contraindicated in subjects 
with baseline ANC < 1,000/mm3 or platelets < 100,000/mm3. 
The recommended dose should be reduced in patients with haematological toxicity (see section 4.2). 
 
Gastrointestinal disorders 
Grade ≥ 3 constipation occurred in 15.3% of treated patients. NCI CTC Grade 3 constipation is 
defined as an obstipation requiring manual evacuation or enema, Grade 4 constipation as an 
obstruction or toxic megacolon. Constipation is reversible and can be prevented by special dietary 
measures such as oral hydration and fibre intake, and by administration of laxatives such as stimulant 
laxatives or faecal softners from day 1 to day 5 or 7 of the treatment cycle. Patients at high risk of 
constipation (concomitant treatment with opiates, peritoneal carcinomas, abdominal masses, prior 



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major abdominal surgery) should be medicated with an osmotic laxative from day 1 to day 7 
administered once a day in the morning before breakfast.  
In case of Grade 2 constipation, defined as requiring laxatives, for 5 days or more or Grade ≥ 3 of any 
duration, the dose of vinflunine should be adjusted (see section 4.2).  
 
In case of any Grade ≥ 3 gastrointestinal toxicity (except vomiting or nausea) or of mucositis (Grade 2 
for 5 days or more or Grade ≥ 3 of any duration) dose adjustment is required. Grade 2 is defined as 
“moderate”, Grade 3 as “severe” and Grade 4 as “life-threatening” (see Table 2 in section 4.2).  
 
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 
increase of the proarrhythmic risk (e.g. congestive heart failure, known history of QT interval 
prolongation, hypokalaemia) (see section 4.8). The concomittant use of two or more QT/QTc interval 
prolonging substances is not recommended (see section 4.5). 
Special attention is recommended when vinflunine is administered to patients with prior history of 
myocardial infarction/ischaemia or angina pectoris (see section 4.8). Ischaemic cardiac events may 
occur, especially in patients who have underlying cardiac disease. Thus, patients receiving Javlor 
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. 
 
Posterior Reversible Encephalopathy Syndrome (PRES) 
Cases of PRES have been observed after administration of vinflunine. 
The typical clinical symptoms are, with various 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 resolved rapidly without sequelae after treatment 
discontinuation. 
Discontinuation of vinflunine should be considered in patients who develop neurological signs of 
PRES (see section 4.8). 
 
Hyponatraemia 
Severe hyponatraemia, including cases due to syndrome of inappropriate antidiuretic hormone 
secretion (SIADH), has been observed with the use of vinflunine (see section 4.8). Therefore, regular 
monitoring of serum sodium levels is recommended during treatment with vinflunine.   
 
Hepatic impairment 
The recommended dose should be reduced in patients with hepatic impairment (see section 4.2). 
 
Renal impairment 
The recommended dose should be reduced in patients with moderate or severe renal impairment (see 
section 4.2). 
 
Elderly patients (≥ 75 years) 
The recommended dose should be reduced in patients 75 years old and beyond (see section 4.2). 
 
Interactions 
The concomitant use of potent inhibitors or potent inducers of CYP3A4 with vinflunine should be 
avoided (see section 4.5). 
 
 



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Administration 
Intrathecal administration of Javlor may be fatal. 
When infused through a peripheral vein, vinflunine can induce Grade 1 (22% of the patients, 14.1% of 
the cycles), Grade 2 (11.0% of the patients, 6.8% of the cycles) or Grade 3 (0.8% of the patients, 0.2% 
of the cycles) venous irritation. All cases resolved rapidly without treatment discontinuation.  
Instructions for administration should be followed as described in section 6.6. 
 
Contraception 
Men and women with reproductive potential must use an effective method of contraception during the 
treatment and up to 3 months after the last vinflunine administration (see section 4.6). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In vitro studies showed that vinflunine had neither inducing effects on CYP1A2, CYP2B6 or CYP3A4 
activity nor inhibition effects on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and 
CYP3A4. 
 
In vitro studies showed that vinflunine is a Pgp-substrate like other vinca alkaloids, but with a lower 
affinity. Therefore, risks of clinically significant interactions should be unlikely. 
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 potent CYP3A4 inhibitor) on 
vinflunine pharmacokinetics indicated that co-administration of ketoconazole (400 mg orally once 
daily for 8 days) resulted in a 30% and 50% increase in blood exposures to vinflunine and its 
metabolite 4Odeacetyl-vinflunine (DVFL), 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 since they may increase or decrease vinflunine and 
DVFL concentrations (see section 4.4 and 5.2).  
 
The concomitant use of vinflunine with others QT/QTc interval prolonging medicinal products should 
be avoided (see section 4.4). 
 
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 for doxorubicinol, the concentrations of the metabolite were not 
affected. According to an in vitro study, such changes could be related to adsorption of vinflunine on 
the liposomes and a modified blood distribution of both compounds. Therefore, caution should be 
excercised when this type of combination is used. 
 
A possible interaction with paclitaxel and docetaxel (CYP3 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 carried out yet. 
 
The concomitant use of opioids could enhance the risk of constipation. 
 



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4.6 Fertility, pregnancy and lactation 
 
Contraception in males and females 
Both male and female patients should take adequate contraceptive measures up to three months after 
the discontinuation of the therapy.  
 
Pregnancy 
There are no data available on the use of vinflunine in pregnant women. Studies in animals have 
shown embryotoxicity and teratogenicity (see section 5.3). On the basis of the results of animal studies 
and the pharmacological action of the medicinal product, 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. 
 
Breast-feeding 
It is unknown whether vinflunine or its metabolites are excreted in human milk. Due to the possible 
very harmful effects on the infants, breast-feeding during treatment with vinflunine is contraindicated 
(see section 4.3).  
 
Fertility  
Advice on conservation of sperm should be sought prior to treatment because of the possibility of 
irreversible infertility due to therapy with vinflunine. 
 
4.7 Effects on ability to drive and use machines 
 
Javlor may cause adverse reactions such as fatigue (very common) and dizziness (common) which 
may lead to a minor or moderate influence on the ability to drive and use machines..Patients should be 
advised not to drive or use machines if they experience any adverse reaction with a potential impact on 
the ability to perform these activities (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most frequent treatment-related adverse reactions reported in the two phase II and one phase III 
trials in patients with transitional cell carcinoma of the urothelium (450 patients treated with 
vinflunine) were haematological disorders, mainly neutropenia and anaemia; gastrointestinal 
disorders, especially constipation, anorexia, nausea, stomatitis/mucositis, vomiting, abdominal pain 
and diarrhoea, and general disorders such as asthenia/fatigue. 
 
Tabulated list of adverse reactions 
Adverse reactions are listed below by System Organ Class, frequency and grade of severity (NCI CTC 
version 2.0). Frequency of adverse reactions is defined using the following convention: very common 
(≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to 
< 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each 
frequency grouping, adverse reactions are presented in order of decreasing seriousness. 



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Table 4 Adverse reactions observed in patients with transitional cell carcinoma of the 

urothelium treated with vinflunine 
System Organ Class Frequency Adverse Reactions Worst NCI Grade per 

patient (%) 

   All grades Grade 3-4 
Infections and infestations Common Neutropenic infection 2.4 2.4 

Infections (viral, bacterial, 
fungal) 

7.6 3.6 

Uncommon Neutropenic sepsis 0.2 0.2 
Neoplasm benign, 
malignant and unspecified 

Uncommon Tumour pain 0.2 0.2 

Blood and lymphatic 
system disorders 

Very common Neutropenia 79.6 54.6 
Leucopenia 84.5 45.2 
Anaemia 92.8 17.3 
Thrombocytopenia 53.5 4.9 

Common Febrile neutropenia 6.7 6.7 
Immune system disorders Common Hypersensitivity 1.3 0.2 
Endocrine disorders Uncommon Syndrome of Inappropriate 

Antidiuretic Hormone 
Secretion (SIADH) a 

0.4 b 0.4 b 

Metabolism and nutrition 
disorders 

Very common Hyponatraemia 39.8 11.7 
Decreased appetite 34.2 2.7 

Common Dehydration 4.4 2.0 
Psychiatric disorders Common Insomnia 5.1 0.2 
Nervous system disorders Very common Peripheral sensory 

neuropathy 11.3 0.9 

Common Syncope  1.1 1.1 
Headache 6.2 0.7 
Dizziness 5.3 0.4 
Neuralgia 4.4 0.4 
Dysgeusia 3.3 0 
Neuropathy 1.3 0 

Uncommon Peripheral motor neuropathy 0.4 0 
Rare Posterior Reversible 

Encephalopathy Syndromea 0.03
b 0.03b 

Eye disorders Uncommon Visual disturbance 0.4 0 
Ear and Labyrinth 
disorders 

Common Ear pain 1.1 0 
Uncommon Vertigo  0.9 0.4 

Tinnitus 0.9 0 
Cardiac disorders Common Tachycardia 1.8 0.2 

Uncommon Myocardial ischaemia 0.7 0.7 
Myocardial infarction 0.2 0.2 

Vascular disorders Common Hypertension 3.1 1.6 
Vein thrombosis 3.6 0.4 
Phlebitis 2.4 0 
Hypotension 1.1 0.2 

Respiratory, thoracic and 
mediastinal disorders 

Common Dyspnoea 4.2 0.4 
Cough 2.2 0 

Uncommon Acute respiratory distress 
syndrome 0.2 0.2 

Pharyngolaryngeal pain 0.9 0 
Gastrointestinal disorders Very common Constipation 54.9 15.1 

Abdominal pain  21.6 4.7 



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Vomiting 27.3 2.9 
Nausea 40.9 2.9 
Stomatitis 27.1 2.7 
Diarrhoea 12.9 0.9 

Common Ileus 2.7 2.2 
Dysphagia 2.0 0.4 
Buccal disorders 4.0 0.2 
Dyspepsia 5.1 0.2 

Uncommon Odynophagia 0.4 0.2 
Gastric disorders 0.8 0 
Oesophagitis 0.4 0.2 
Gingival disorders 0.7 0 

Skin and subcutaneous 
tissue disorders 

Very common Alopecia 28.9 NA 
Common Rash 1.8 0 

Urticaria 1.1 0 
Pruritus 1.1 0 
Hyperhidrosis 1.1 0 

Uncommon Dry skin 0.9 0 
Erythema 0.4 0 

Musculoskeletal and 
connective tissue 
disorders 

Very common Myalgia 16.7 3.1 
Common Muscular weakness 1.8 0.7 

Arthralgia 7.1 0.4 
Back pain 4.9 0.4 
Pain in jaw 5.6 0 
Pain in extremity 2.4 0 
Bone pain  2.9 0 
Musculoskeletal pain 2.7 0.2 

Renal and urinary 
disorders 

Uncommon Renal failure 0.2 0.2 

General disorders and 
administration site 
conditions 

Very common Asthenia/Fatigue 55.3 15.8 
Injection site reaction 26.4 0.4 
Pyrexia 11.7 0.4 

Common Chest pain 4.7 0.9 
Chills 2.2 0.2 
Pain 3.1 0.2 
Oedema 1.1 0 

Uncommon Extravasation 0.7 0 
Investigations Very common Weight decreased 24.0 0.4 

Uncommon Transaminases increased 0.4 0 
Weight increased 0.2 0 

aadverse reactions reported from post-marketing experience 
bfrequency calculated on the basis of non-TCCU clinical trial 
 
Adverse reactions in all indications  
Adverse reactions occurring in patients with transitional cell carcinoma of the urothelium and in 
patients with other disease than this indication and potentially severe or adverse reactions that are a 
class effect of the vinca alkaloids are described below: 
 
Blood and lymphatic system disorders 
Grade 3/4 neutropenia was observed in 43.8% of patients. Severe anaemia and thrombocytopenia were 
less common (respectively 8.8 and 3.1 %). Febrile neutropenia defined as ANC < 1,000/mm3and fever 
≥ 38.5°C of unknown origin without clinically microbiologically documented infection (NCI CTC 
version 2.0) was observed in 5.2% of patients. Infection with Grade 3/4 neutropenia was observed in 
2.8 % of patients. 
Overall 8 patients (0.6% of the treated population) died from infection as a complication occurring 
during neutropenia. 



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Gastrointestinal disorders 
Constipation is a class effect of the vinca alkaloids: 11.8% of patients experienced severe constipation 
during treatment with vinflunine. Grade 3/4 ileus reported in 1.9% of patients was reversible when 
managed by medical care. Constipation is managed by medical care (see section 4.4). 
 
Nervous system disorders 
Sensory peripheral neuropathy is a class effect of the vinca alkaloids. Grade 3 was experienced by 
0.6% patients. All resolved during the study. 
Rare cases of Posterior Reversible Encephalopathy Syndrome have been reported (see section 4.4). 
 
Cardiovascular disorders 
Cardiac effects are a known class effect of the vinca alkaloids. Myocardial infarction or ischaemia 
were experienced by 0.5% of the patients and most of them had a pre-existing cardiovascular disease 
or risk factors. One patient died after myocardial infarction and another one due to a cardiopulmonary 
arrest. 
Few QT interval prolongations have been observed after the administration of vinflunine. 
 
Respiratory, thoracic and mediastinal disorders 
Dyspnoea occurred in 3.2% of the patients but was rarely severe (Grade 3/4: 1.2%). 
Bronchospam was reported in one patient treated with vinflunine for a different setting from the 
indication. 
 
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V 
 
4.9 Overdose 
 
The main toxic effect due to an overdose with vinflunine is bone marrow suppression with a risk of 
severe infection. 
There is no known antidote for vinflunine overdose. In case of overdose, the patient should be kept in 
a specialised unit and vital functions should be closely monitored. Other appropriate measures should 
be taken, such as blood transfusions, administration of antibiotics and growth factors. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplasic agents, vinca alkaloids and analogues, ATC code: 
L01CA05 
 
Mechanism of action 
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 dynamic, mitotic 
arrest and apoptosis. In vivo, vinflunine displays significant antitumor activity against a broad 
spectrum of human xenografts in mice both in terms of survival prolongation and tumour growth 
inhibition. 
 
Clinical efficacy and safety 
One phase III and two phase II trials support the use of Javlor for treatment of advanced or metastatic 
transitional cell carcinoma of the urothelium as second-line therapy after failure of a prior platinum-
containing regimen. 



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In the two multi-centre open-label, single-arm phase II clinical trials a total of 202 patients were 
treated with vinflunine. 
 
In the multi-centre, open-label controlled phase III clinical trial, 253 patients were randomised to 
treatment with vinflunine + BSC (best supportive care) and 117 patients to the BSC arm.  
The median overall survival was 6.9 months (vinflunine + BSC) vs. 4.6 months (BSC), but the 
difference did not reach statistical significance; hazard ratio 0.88 (95% CI 0.69, 1.12). However a 
statistically significant effect was seen on progression-free survival. Median PFS was 3.0 months 
(vinflunine + BSC) vs 1.5 months (BSC) (p=0.0012). 
 
In addition a pre-specified 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 (PS, visceral involvement, alkaline phosphatases, haemoglobin, pelvic irradiation) were taken 
into consideration; hazard ratio 0.77 (95% CI 0.61, 0.98). A statistically significant difference on 
overall survival (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); hazard 
ratio 0.78 (95% CI 0.61, 0.99). This is considered the most relevant population for the efficacy 
analysis, as it most closely reflects the population intended for treatment.  
 
Efficacy was demonstrated in both patients with or without prior cisplatin use.  
In the eligible population, the subgroup analyses according to the prior cisplatin use versus BSC on 
overall survival (OS) showed a HR (95% CI) = [0.64 (0.40 – 1.03); p=0.0821] in the absence of prior 
cisplatin, and a HR (95% CI) = [0.80 (0.60 – 1.06); p=0.1263] in the presence of prior cisplatin. When 
adjusted on prognostic factors, the analyses of OS in the subgroups of patients without or with prior 
cisplatin showed a HR (95% CI) = [0.53 (0.32 – 0.88); p=0.0143] and a HR (95% CI) = [0.70 (0.53 – 
0.94); p=0.0174], respectively. 
In the subgroup analyses of prior cisplatin use versus BSC for progression free survival (PFS), the 
results were: HR (95% CI) = [0.55 (0.34 – 0.89); p=0.0129] in the absence of prior cisplatin, and a HR 
(95% CI) = [0.64 (0.48 – 0.85); p=0.0040] in the presence of prior cisplatin. When adjusted on 
prognostic factors, the analyses of PFS in the subgroups of patients without or with prior cisplatin 
showed a HR (95% CI) = [0.51(0.31 – 0.86); p=0.0111] and a HR (95% CI) = [0.63(0.48 – 0.84); 
p=0.0016], respectively. 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with Javlor 
in all subsets of the paediatric population in the treatment of ureter and bladder carcinoma and the 
treatment of breast carcinoma (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Vinflunine pharmacokinetics is linear in the range of administered doses (from 30 mg/m² 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 proteins (67.2±1.1%) with a ratio between plasma 
and whole blood concentrations of 0.80±0.12. Protein binding mainly involves high density 
lipoproteins and serum albumin and is non-saturable on 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, 2422±676 litres (about 35 l/kg) suggesting extensive 
distribution  into tissues.  
 



13 

Biotransformation 
All metabolites identified are formed by the cytochrome CYP3A4 isoenzyme, except for 
4-O-deacetylvinflunine (DVFL), the only active metabolite and main metabolite in blood which is 
formed by multiple esterases.  
 
Elimination  
Vinflunine is eliminated following a multi-exponential concentration decay, with a terminal half-life 
(t1/2) close to 40 h. DVFL is slowly formed and more slowly eliminated than vinflunine (t1/2 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 inter and intra-individual variability (25% and 8%, respectively, 
expressed as coefficient of variation). 
 
Pharmacokinetics in special populations 
 
Hepatic impairment 
No modification of vinflunine and DVFL pharmacokinetics was observed in 25 patients presenting 
varying degrees of hepatic impairment, compared to patients with normal hepatic function. This was 
further confirmed by the population pharmacokinetic analysis (absence of relationship between 
vinflunine clearance and biology markers of hepatic impairment). However, dose adjustments are 
recommended in patients with liver impairment (see section 4.2).  
 
Renal impairment 
A pharmacokinetic phase I study was performed in 2 groups of patients with renal impairment 
classified according to the calculated creatinine clearance (CrCl) values: group 1 (n=13 patients) with 
moderate impairment (40 mL/min ≤ CrCl ≤ 60 mL/min) and group 2 (n=20 patients) with severe 
impairment (20 mL/min ≤ CrCl < 40 mL/min). The pharmacokinetic results of this study indicated a 
reduction of vinflunine clearance when CrCl is decreased. This is further confirmed by the population 
pharmacokinetic analysis (56 patients with CrCl between 20 mL/min and 60 mL/min), showing that 
vinflunine clearance is influenced by the creatinine clearance value (Cockcroft and Gault formula). 
Dose adjustments are recommended in patients with moderate and severe renal impairment (see 
section 4.2).  
 
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 below:  
 

Age (y) Number of patients Vinflunine (mg/m²) 

[ 70 – 75 [   17 320 

[ 75 – 80 [ 15 280 

≥ 80 14 250 
 
Vinflunine clearance was significantly decreased in patients ≥ 80 years old as compared to a control 
group of younger patients < 70 years.  
Pharmacokinetics of vinflunine was not modified for patients 70 ≤ age < 75 years and 
75 ≤ age < 80 years.  
Based on both PK and safety data, dose reductions are recommended in the elder groups: 
75 ≤ age < 80 years; and age ≥ 80 years.  
For further cycles the dose should be adjusted in the event of toxicities (see section 4.2).  
 
Others 
According to the population pharmacokinetic analysis, neither gender nor performance status (ECOG 
score) had an impact on vinflunine clearance which is directly proportional to body surface area. 



14 

 
5.3 Preclinical safety data 
 
Imaging distribution studies following radioactive vinflunine in rats, illustrated that the compound 
levels in lungs, kidneys, liver, salivary and endocrine glands, and gastrointestinal tract were rapidly 
higher than those in blood.  
 
Preclinical data revealed moderate to severe neutropenia and mild anaemia, in all species tested, with  
liver toxicity in dogs and rats (characterized by dose-dependent increases in liver transaminases and 
hepatic necrosis/hepatocellular alterations at high doses). These toxic effects were dose-related and 
fully or-partially reversible following a 1-month recovery period. Vinflunine did not induce peripheral 
neuropathy in animals. 
Vinflunine has shown to be clastogenic (induces chromosome breakage) in the in vivo micronucleus 
test in rat as well as mutagenic and clastogenic in a mouse lymphoma assay (without metabolic 
activation). 
 
The carcinogenic potential of vinflunine has not been studied.  
In the reproduction studies, vinflunine appeared to be embryolethal and teratogenic in rabbits and 
teratogenic in rats. During the pre- and post-natal development study in rat, vinflunine induced 
malformations of the uterus and vagina in 2 females, and adversely affected mating and/or ovule 
implantation and markedly lowered the number of concepti. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Water for injections 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vial  
3 years. 
 
Diluted solution  
Chemical and physical in-use stability has been demonstrated for the diluted medicinal product as 
follows:  
 - protected from light in polyethylene or polyvinylchloride infusion bag: for up to 6 days in a 
refrigerator (2°C-8°C) or for up to 24 hours at 25°C;  
 - exposed to light in polyethylene or polyvinylchloride infusion set for up to 1 hour at 25°C. 
 
From a microbiological point of view, the product should be used immediately after dilution. If not 
used immediately, in-use storage times and conditions prior to use are the responsibility of the user 
and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in 
controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C-8°C). 
Store in the original package in order to protect from light. 
 



15 

For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Clear type I glass vials closed by a grey butyl or black chlorobutyl rubber stopper covered with a 
crimped-on aluminium ring and a cap. Each vial contains either 2 mL (50 mg vinflunine), 4 mL 
(100 mg vinflunine) or 10 mL (250 mg vinflunine) of concentrate for solution for infusion. 
 
Pack size of 1 and 10 vials. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
General precautions for preparation and administration. 
Vinflunine is a cytotoxic anticancer medicinal product and, as with other potentially toxic compounds, 
caution should be exercised in handling Javlor. Procedure for proper handling and disposal of 
anticancer medicinal products should be considered. All transfer procedures require strict adherence to 
aseptic techniques, preferably employing a vertical laminar flow safety hood. Javlor solution for 
infusion should only be prepared and administered by personnel appropriately trained in the handling 
of cytotoxic agents. Pregnant staff should not handle Javlor. The use of gloves, goggles and protective 
clothing is recommended. 
If the solution comes into contact with the skin, this should be washed immediately and thoroughly 
with soap and water. If it comes into contact with mucous membranes, the membranes should be 
flushed  thoroughly with water.  
 
Dilution of the concentrate  
The volume of Javlor (concentrate) corresponding to the calculated dose of vinflunine should be 
mixed in a 100 mL bag of sodium chloride 9 mg/mL (0.9%) solution for infusion. Glucose 50 mg/mL 
(5%) solution for infusion may also be used. The diluted solution should be protected from light until 
administration (see section 6.3). 
 
Method of administration 
Javlor is for intravenous use ONLY. 
Javlor is for single use only. 
After dilution of the Javlor concentrate, the solution for infusion will be administered as follows: 

• A venous access should be established for a 500 mL bag of sodium chloride 9 mg/mL (0.9%) 
solution for injection or glucose 50 mg/mL (5%) solution for infusion, on a large vein 
preferably in the upper part of the forearm or using a central venous line. The veins of the 
hand dorsum and those close to joints should be avoided. 

• The intravenous infusion should be started with half of the 500 mL bag of sodium chloride 
9 mg/mL (0.9%) solution for infusion or of glucose 50 mg/mL (5%) solution for infusion, i.e. 
250 mL, at a free flowing rate to flush the vein. 

• The Javlor solution for infusion should be piggy-backed to the side injection port closest to the 
500 mL bag to further dilute Javlor during administration.  

• The Javlor solution for infusion should be infused over 20 minutes. 
• The patency should be assessed frequently and extravasation precautions should be 

maintained throughout the infusion. 
• After the infusion is completed, the remaining 250 mL from the sodium chloride 9 mg/mL 

(0.9%) solution for infusion or of glucose 50 mg/mL (5%) solution for infusion bag should be 
run at a flowing rate of 300 mL/h. In order to flush the vein, administration of Javlor solution 
for infusion should always be followed by at least an equal volume of sodium chloride 
9 mg/mL (0.9%) solution for infusion or of glucose 50 mg/mL (5%) solution for infusion. 

 



16 

Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements for cytotoxic medicinal products. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pierre Fabre Médicament 
45, place Abel Gance 
F-92100 Boulogne 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/550/001-012 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21 September 2009 
Date of the latest renewal: 16 May 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
XX month YYYY 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR  
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS 

REGARDING SUPPLY AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D.      CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



18 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Pierre Fabre Médicament Production 
Etablissement Aquitaine Pharm International 
Avenue du Béarn 
F-64320 Idron 
France 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING THE SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

• Periodic Safety Update Reports  
 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) ) provided 
for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-
portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

• Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
An updated RMP should be submitted:  
• At the request of the European Medicines Agency;  
• Whenever the risk management system is modified, especially as the result of new information being 
received that may lead to a significant change to the benefit/risk profile or as the result of an important 
(pharmacovigilance or risk minimisation) milestone being reached.  
 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 
 
 
 
 
 
 
 
 
 

 
 
 
 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



21 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Javlor 25 mg/mL concentrate for solution for infusion 
vinflunine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One mL of concentrate contains 25 mg of vinflunine (as ditartrate). 
 
One 2 mL vial contains 50 mg of vinflunine (as ditartrate) 
One 4 mL vial contains 100 mg of vinflunine (as ditartrate) 
One 10 mL vial contains 250 mg of vinflunine (as ditartrate) 
 
 
3. LIST OF EXCIPIENTS 
 
Water for injections as excipient. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
 
1 vial of 2 mL  
10 vials of 2 mL  
1 vial of 4 mL  
10 vials of 4 mL  
1 vial of 10 mL  
10 vials of 10 mL  
 
50 mg /2 mL  
100 mg /4 mL  
250 mg /10 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use ONLY, after dilution. 
Fatal if given by other routes. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 



22 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic: Handle with caution 
 
 
8. EXPIRY DATE 
 
EXP:  
Read the leaflet for the shelf life of diluted medicine. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
 
 
 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pierre Fabre Médicament 
45, Place Abel Gance 
F-92100 Boulogne 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/550/001 (box of 1 vial of 2 mL with grey stopper)  
EU/1/09/550/002 (box of 10 vials of 2 mL with grey stopper)  
EU/1/09/550/003 (box of 1 vial of 4 mL with grey stopper)  
EU/1/09/550/004 (box of 10 vials of 4 mL with grey stopper)  
EU/1/09/550/005 (box of 1 vial of 10 mL with grey stopper)  
EU/1/09/550/006 (box of 10 vials of 10 mL with grey stopper) 
EU/1/09/550/007 (box of 1 vial of 2 mL with black stopper)  
EU/1/09/550/008 (box of 10 vials of 2 mL with black stopper)  
EU/1/09/550/009 (box of 1 vial of 4 mL with black stopper)  
EU/1/09/550/010 (box of 10 vials of 4 mL with black stopper) 
EU/1/09/550/011 (box of 1 vial of 10 mL with black stopper)  
EU/1/09/550/012 (box of 10 vials of 10 mL with black stopper)  
 
 
13. BATCH NUMBER 
 
Lot 



23 

 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}   
SN: {number}   
NN: {number}   
 



24 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Javlor 25 mg/mL sterile concentrate  
vinflunine 
IV use ONLY, after dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
See leaflet 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
50 mg/2 mL 
100 mg/4 mL 
250 mg/10 mL 
 
 
6. OTHER 
 



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 



26 

Package Leaflet: Information for the user 
 

Javlor 25 mg/mL concentrate for solution for infusion 
vinflunine 

 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
-     If you have any further questions, ask your doctor. 
- If you get any side effects talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See Section 4. 
 
 
What is in this leaflet  
1. What Javlor is and what it is used for 
2. What you need to know before you use Javlor 
3. How to use Javlor 
4. Possible side effects 
5. How to store Javlor 
6. Content of the pack and other information 
 
 
1. What Javlor is and what it is used for 
 
Javlor contains the active substance vinflunine, which belongs to a group of anticancer medicines 
called  vinca alkaloids. These medicines affect cancer cell growth by stopping cell division, leading to 
cell death (cytotoxicity). 
 
Javlor is used to treat advanced or metastatic cancer of the bladder and urinary tract when a previous 
therapy with platinum-containing medicines has failed. 
 
 
2. What you need to know before you use Javlor 
 
Do not use Javlor 
- if you are allergic to the active substance (vinflunine) or to other vinca alkaloids (vinblastine, 

vincristine, vindesine, vinorelbine), 
-  if you have had (in the last 2 weeks) or currently have a severe infection, 
- if you are breast-feeding, 
- if your levels of white blood cells and/or platelets are too low 
 
Warnings and precautions 
Tell your doctor: 
- if you have liver, kidney or heart problems, 
- if you experience any neurological symptoms such as headaches, changed mental state which may 

lead to confusion and coma, convulsions, blurred vision and high blood pressure as you may need 
to stop taking this medicine, 

- if you are taking other medicines mentioned in “Using other medicines” below, 
- if you have constipation, or if you are treated with medicines against pain (opioids), or if you have 

an abdominal cancer, or if you had abdominal surgery, 
- if you would like to father a child (see “Pregnancy, breast-feeding and fertility” below). 
 
Your blood cell counts will be checked regularly before and during your treatment, since low counts 
of blood cells is a very common side effect with Javlor. 
Constipation is a very common side effect of Javlor. To prevent constipation you may be given 
laxatives. 



27 

 
Used in children and adolescents 
Javlor is not intended for use in children and adolescents. 
 
Other medicines and Javlor 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
In particular, you should tell your doctor if you are taking medicines containing any of the following 
active substances: 
- ketoconazole and itraconazole, used to treat fungal infection, 
- opioids, used to treat pain, 
- ritonavir, used to treat HIV infection,  
- doxorubicin and pegylated liposomal doxorubicin, used to treat some kinds of cancer,  
- rifampicin, used to treat tuberculosis or meningitis, 
- herbal preparation containing hypericum perforatum (St John’s wort) used to treat minor to 

moderate depression. 
 
Javlor with food and drink 
You should tell your doctor if you are drinking grapefruit juice since it may increase the effect of 
Javlor. 
You should also drink water and eat high fibre foods. 
 
Pregnancy, breast-feeding and fertility 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before starting your therapy.  
 
If you are a woman or a man of reproductive  potential, you should use an adequate method of 
contraception during treatment and for 3 months after your last dose of Javlor.  
 
You should not be given Javlor if you are pregnant, unless it is absolutely necessary. 
 
You must not breastfeed during treatment with Javlor 
 
If you would like to father a child, seek advice from your doctor. You may want to seek counseling on 
sperm storage before starting your therapy. 
 
Driving and using machines 
Javlor may cause side effects such as tiredness and dizziness. Do not drive or use machines if you 
experience side effects that affect your ability to concentrate and react. 
 
 
3. How to use Javlor 
 
Dose 
The recommended dose in adult patients is 320 mg/m² body surface (this is calculated by the doctor 
based on your weight and your height). The treatment will be repeated every 3 weeks.  
 
Your doctor will adjust the starting dose of Javlor based on your age and physical conditions and in 
specific situations:  
- if you had a previous irradiation of the pelvis  
- if you have moderate or severe kidney problems 
- if you have liver problems. 
 
During treatment, your doctor may reduce the dose of Javlor, delay or interrupt the treatment if you 
experience certain side effects. 
 



28 

How Javlor is given 
Javlor will be given to you by a qualified healthcare professional as an intravenous infusion (drip into 
your vein) lasting 20 minutes. Javlor must not be given intrathecally (into the spine). 
Javlor is a concentrate that has to be diluted before administration.  
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately if you develop any of the following serious side effects while being 
treated with Javlor: 
- fever and / or chills which could be signs of infection, 
- chest pain which could be sign of heart attack, 
- constipation that resists to laxative treatment, 
- headaches, changed mental state which may lead to confusion and coma, convulsions, blurred 

vision and high blood pressure, which could be sign of a neurological disorder such as “posterior 
reversible encephalopathy syndrome” (see section 2 “warnings and precautions”). 

 
Other side effects may include:  
Very common (may affect more than 1 in 10 people) 
- abdominal pain, nausea, vomiting 
- constipation, diarrhoea 
- inflammation of the mucosa of the mouth 
- tiredness, muscle pain 
- lack of sense of touch 
- weight decrease, decrease of appetite 
- loss of hair 
- reactions at injection site (pain, redness, swelling) 
- fever 
- low levels of white blood cells, red blood cells and/or platelets (seen in blood test) 
- low levels of blood sodium (hyponatraemia). 
 
Common (may affect up to 1 in 10 people) 
- chills, excessive sweating 
- allergy, dehydration, headache, skin rash, itching 
- digestive problems, pain in the mouth, on the tongue and toothache, taste alteration 
- muscular weakness, pain in jaw, pain in extremity, back pain, pain in joints, muscular pain, bone 

pain, ear pain 
- dizziness, insomnia, transiant loss of consciousness  
- difficulties with body movements  
- fast heartbeat, raised blood pressure, reduced blood pressure 
- breathing difficulties, cough, chest pain 
- swelling of your arms, hands, feet, ankles, legs or other parts of your body 
- inflammation of the veins (phlebitis). 
 
Uncommon (may affect up to 1 in 100 people) 
-     visual disturbances 
- dry skin, redness of the skin 
- muscle contraction disorders 
- pain in the throat, gum disorders 
- weight increase 
- urinary problems 
- ringing or buzzing in the ears (tinnitus) 
- increase in liver enzymes (seen in blood test) 



29 

- “Syndrome of inappropriate antidiuretic hormone secretion”, which is a condition that causes low 
levels of blood sodium 

- tumour pain. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store Javlor 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the vial label and the carton after 
EXP. 
 
It is most unlikely that you will be asked to store this medicine yourself. 
Storage conditions are detailed in the section intended for medicinal or heathcare professionals. 
 
Unopened vials 
Store in a refrigerator (2°C-8°C). 
Store in the original package in order to protect from light. 
 
Diluted solution 
The diluted solution should be use immediately 
 
Do not throw away any medicine via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Content of the pack and other information 
 
What Javlor contains 
- The active substance is vinflunine. Each mL of  concentrate contains 25 mg of vinflunine (as 

ditartrate). 
One 2 mL vial contains 50 mg of vinflunine (as ditartrate). 
One 4 mL vial contains 100 mg of vinflunine (as ditartrate). 
One 10 mL vial contains 250 mg of vinflunine (as ditartrate). 

- The other ingredient is water for injections. 
 
What Javlor looks like and contents of the pack 
 
Javlor  is a clear, colourless to pale yellow solution. It comes in clear glass vials closed by a rubber 
stopper containing 2 mL, 4 mL or 10 mL of concentrate. Each pack contains 1 or 10 vials. 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder  
 
Pierre Fabre Médicament 
45 place Abel Gance 
F-92100 Boulogne  
France 
 



30 

Manufacturer 
 
Pierre Fabre Médicament Production 
Etablissement Aquitaine Pharm International 
Avenue du Béarn 
F-64320 Idron 
France 
 
For any information about this medicine, please contact the Marketing Authorisation Holder. 
 
This leaflet was last revised in MM/YYYY 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 
<------------------------------------------------------------------------------------------------------------------------> 
The following information is intended for medical or healthcare professionals only: 
 
INSTRUCTION FOR USE 
 
General precautions for preparation and administration. 
Vinflunine is a cytotoxic anticancer medicinal product and, as with other potentially toxic compounds, 
caution should be exercised in handling Javlor. Procedure for proper handling and disposal of 
anticancer medicinal products should be considered. All transfer procedures require strict adherence to 
aseptic techniques, preferably employing a vertical laminar flow safety hood. Javlor solution for 
infusion should only be prepared and administered by personnel appropriately trained in the handling 
of cytotoxic agents. Pregnant staff should not handle Javlor. The use of gloves, goggles and protective 
clothing is recommended. 
If the solution comes into contact with the skin, this should be washed immediately and thoroughly 
with soap and water. If it comes into contact with mucous membranes, the membranes should be 
flushed  thoroughly with water.  
 
Dilution of the concentrate  
The volume of Javlor (concentrate) corresponding to the calculated dose of vinflunine should be 
mixed in a 100 mL bag of sodium chloride 9 mg/mL (0.9%) solution for infusion. Glucose 50 mg/mL 
(5%) solution for infusion may also be used. The diluted solution should be protected from light until 
administration (see section 6.3). 
 
Method of administration 
Javlor is for intravenous use ONLY. 
Javlor is for single use only.  
After dilution of the Javlor concentrate, the solution for infusion will be administered as follows: 

• A venous access should be established for a 500 mL bag of sodium chloride 9 mg/mL (0.9%) 
solution for injection or glucose 50 mg/mL (5%) solution for infusion, on a large vein 
preferably in the upper part of the forearm or using a central venous line. The veins of the 
hand dorsum and those close to joints should be avoided. 

• The intravenous infusion should be started with half of the 500 mL bag of sodium chloride 
9 mg/mL (0.9%) solution for infusion or of glucose 50 mg/mL (5%) solution for infusion, i.e. 
250 mL, at a free flowing rate to flush the vein. 

• The Javlor solution for infusion should be piggy-backed to the side injection port closest to the 
500 mL bag to further dilute Javlor during administration.  

• The Javlor solution for infusion should be infused over 20 minutes. 
• The patency should be assessed frequently and extravasation precautions should be 

maintained throughout the infusion. 



31 

• After the infusion is completed, the remaining 250 mL from the sodium chloride 9 mg/mL 
(0.9%) solution for infusion or of glucose 50 mg/mL (5%) solution for infusion bag should be 
run at a flowing rate of 300 mL/h. In order to flush the vein, administration of Javlor solution 
for infusion should always be followed by at least an equal volume of sodium chloride 
9 mg/mL (0.9%) solution for infusion or of glucose 50 mg/mL (5%) solution for infusion. 

 
Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements for cytotoxic medicinal products. 
 
Storage conditions 
Unopened vials 
Store in a refrigerator (2°C-8°C). 
Store in the original packaging in order to protect from light. 
 
Diluted solution 
Chemical and physical in-use stability has been demonstrated for the diluted medicinal product as 
follows:  
 - protected from light in polyethylene or polyvinylchloride infusion bag: for up to 6 days in a 
refrigerator (2°C-8°C) or for up to 24 hours at 25°C;  
 - exposed to light in polyethylene or polyvinylchloride infusion set: for up to 1 hour at 25°C.  
From a microbiological point of view, the product should be used immediately after dilution. If not 
used immediately, in-use storage times and conditions prior to use are the responsibility of the user 
and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in 
controlled and validated aseptic conditions. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING THE SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET