Posology : מינונים

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
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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).

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 )
- Delay until recovery (ANC ≥ 1,000/mm3 and platelets or Thrombocytopenia
≥ 100,000/mm3) and adjust the dose if necessary (see table 2)
(platelets < 100,000/mm3)
- Discontinuation if recovery has not occurred within 2 weeks

- Delay until recovery to mild toxicity or none, or to initial
Organ toxicity: moderate, severe or life baseline status and adjust the dose if necessary (see table 2) threatening
- Discontinuation if recovery has not occurred within 2 weeks
Cardiac ischaemia in patients with prior history of myocardial infarction or angina                                - Discontinuation pectoris

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            2nd          3rd consecutive         First     2nd consecutive Event        consecutive           event             Event           event event
Neutropenia Grade 4
(ANC< 500/mm3)> 7 days
Febrile Neutropenia
(ANC< 1,000/mm3 and fever ≥ 38,5 °C)
Mucositis or Constipation                                         Definitive                          Definitive Grade 2 ≥ 5 days or       280 mg/m²           250 mg/m²           Treatment         250 mg/m²         Treatment Grade ≥ 3 any duration 1                                       discontinuation                     discontinuation 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: - 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                                                            Dose adjustment 
(NCI CTC v 2.0)*                                Vinflunine initial dose of      Vinflunine initial dose of 280 mg/m²                        250 mg/m²
First     2nd consecutive        First    2nd consecutive
Event           event           Event          event
Neutropenia Grade 4                              250         Definitive          225         Definitive (ANC< 500/mm3) > 7 days                         mg/m²        Treatment          mg/m²        Treatment Febrile Neutropenia (ANC < 1,000/mm3                      discontinuation                 discontinuation 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”.
NCI CTC Grade 3 nausea is defined as no significant intake, requiring intavenous fluids. Grade 3 vomiting as ≥ 2

6 episodes in 24 hours over pretreatment; or need for intavenous 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.