1. Name Of The Medicinal Product
Javlor 25 mg/ml concentrate for solution for infusion
2. Qualitative And Quantitative Composition
1 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 a 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
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.
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 posology 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.
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 3 and platelets 3) 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
|
|
|
|
|
|
Mucositis or Constipation
Grade 2 1
|
|
|
|
|
|
Any other toxicity Grade
(except Grade 3 vomiting or nausea2)
|
|
|
|
|
|
*National Cancer Institute, Common Toxicity Criteria Version 2.0 (NCI CTC v 2.0)
1 NCI CTC Grade 4 constipation is defined as an obstruction or toxic megacolon, Grade 3 as an obstipation requiring manual evacuation or enema, Grade 2 as requiring laxatives. 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 IV fluids. Grade 3 vomiting as
Special populations
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:
- 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 ].
- with Transaminases
|
- 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 [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
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 (
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
In patients with severe renal impairment (20 ml/min
For further cycles, the dose should be adjusted in the event of toxicities, as shown in table 3 below.
Elderly (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 beyond, 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
|
|
|
|
|
Mucositis or Constipation Grade 2 1
|
|
|
|
|
Any other toxicity Grade
(except Grade 3 vomiting or nausea2)
|
|
|
|
|
*National Cancer Institute, Common Toxicity Criteria Version 2.0 (NCI CTC v 2.0)
1 NCI CTC Grade 4 constipation is defined as an obstruction or toxic megacolon, Grade 3 as an obstipation requiring manual evacuation or enema, Grade 2 as requiring laxatives. 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 IV fluids. Grade 3 vomiting as
Paediatrics
Use in children – there is no relevant indication for use of Javlor in children.
Method of administration
Javlor must be diluted prior to administration. Javlor is for single use only.
For instructions on dilution before administration, see section 6.6.
Javlor MUST ONLY be administered intravenously. Intrathecal administration of Javlor may be fatal.
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.
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).
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.
Platelets < 100,000/mm3.
Lactation (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/mm3or platelets <100,000/mm3. For subsequent administrations, vinflunine is contraindicated in subjects with baseline ANC < 1,000/mm3or 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 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 more than 5 days or Grade
In case of any Grade
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.
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 (
The recommended dose should be reduced in patients 75 years old and beyond (see section 4.2).
Others
The concomitant use of potent inhibitors or potent inducers of CYP3A4 with vinflunine should be avoided (see section 4.5).
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.
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 drugs 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.
4.6 Pregnancy And Lactation
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.
Fertility
Both male and female patients should take adequate contraceptive measures up to three months after the discontinuation of the therapy. Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with vinflunine.
Lactation
It is unknown if vinflunine or its metabolites are excreted in breast milk. Due to the possible very harmful effects on the infants, breast-feeding during treatment with vinflunine is contraindicated (see section 4.3).
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. However, 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 (e.g. dizziness and syncope are common).
4.8 Undesirable Effects
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.
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 (. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
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
|
3.8
|
3.8
|
Infections (viral, bacterial, fungal)
|
6.9
|
2.7
|
|
|
Uncommon
|
Neutropenic sepsis
|
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
|
1.8
|
0.2
|
Metabolism and nutrition disorders
|
Very common
|
Anorexia
|
34.4
|
2.7
|
Common
|
Dehydration
|
4.4
|
2.0
|
|
Psychiatric disorders
|
Common
|
Insomnia
|
5.1
|
0.2
|
Nervous system disorders
|
Very common
|
Peripheral sensory neuropathy
|
9.8
|
0.9
|
Common
|
Syncope
|
1.1
|
1.1
|
|
Headache
|
6.2
|
0.7
|
|
|
Dizziness
|
5.3
|
0.4
|
|
|
Neuralgia
|
6.0
|
0.4
|
|
|
Dysgeusia
|
3.1
|
0
|
|
|
Neuropathy
|
1.8
|
0
|
|
|
Uncommon
|
Peripheral motor neuropathy
|
0.7
|
0
|
|
Eye disorders
|
Uncommon
|
Visual disturbance
|
0.4
|
0
|
Ear and Labyrinth disorders
|
Common
|
Ear pain
|
1.3
|
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
|
3.3
|
1.8
|
Vein thrombosis
|
3.3
|
0.4
|
|
|
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
|
15.3
|
Abdominal pain
|
21.6
|
4.7
|
|
|
Vomiting
|
27.3
|
2.9
|
|
|
Nausea
|
40.9
|
2.9
|
|
|
Stomatitis
|
26.9
|
2.7
|
|
|
Diarrhoea
|
12.9
|
0.9
|
|
|
Common
|
Ileus
|
2.7
|
2.2
|
|
Dysphagia
|
2.0
|
0.4
|
|
|
Buccal disorders
|
4.7
|
0.2
|
|
|
Dyspepsia
|
5.6
|
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
|
28.7
|
NA
|
Common
|
Rash
|
1.6
|
0
|
|
Urticaria
|
1.3
|
0
|
|
|
Pruritus
|
1.3
|
0
|
|
|
Hyperhidrosis
|
1.1
|
0
|
|
|
Uncommon
|
Dry skin
|
0.9
|
0
|
|
Erythema
|
0.4
|
0
|
|
|
Musculoskeletal and connective tissue disorders
|
Very common
|
Myalgia
|
16.4
|
3.1
|
Common
|
Muscular weakness
|
2.2
|
0.9
|
|
Arthralgia
|
|
