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.
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).
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:
- No dose adjustment is necessary in patients:
- with transaminases ≤ 2.5xULN ( < 5xULN only in cas
