JAVLOR Concentrate for solution for infusion Ref.[9073] Active ingredients: Vinflunine

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:

Dose adjustments due to toxicity

Table 2. Dose adjustments due to toxicity:

* 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:

* 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.

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.

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.

Store in a refrigerator (2°C-8°C).

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

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.

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.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic medicinal products.