This medicine is monitored intensively by the CHM and MHRA

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).

Concentrate for solution for infusion (sterile concentrate). Clear, colourless to pale yellow solution.

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 more than 2.

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 counts (ANC) as neutropenia is a frequent adverse reaction of vinflunine.
Posology The recommended posology is 320 mg/m² vinflunine as a 20minute intravenous infusion every 3 weeks. In case of WHO/ECOG performance status (PS) of 1 or 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 adjustment due to toxicity Table 1: Dose adjustments due to toxicity

*National Cancer Institute, Common Toxicity criteria (NCI-CTC)

In patients with ANC < 1,000/mm3 or platelets < 100,000/mm3 at the day of administration, the treatment should be delayed until recovery (ANC 1,000/mm3 and platelets  100,000/mm3). If recovery has not occurred within 2 weeks, the treatment will be definitively discontinued.

In case of Grade 4 neutropenia (ANC < 500/mm3) for more than 7 days or febrile neutropenia, dose adjustment is recommended (see table above).

The day of infusion, in case of Grade  2 organ toxicity, the treatment should be delayed until recovery to Grades 0, 1 or initial baseline status.

Special populations

Hepatic impairment

Vinflunine pharmacokinetics is not modified in patients with three levels of impaired liver function (see table below and section 5.2), however based on hepatic biologic parameter modifications following vinflunine administration (gamma glutamyl transferases (GGT), transaminases, bilirubin), the dose recommendations are as follows:

Table 2: Dose adjustments due to hepatic impairment

 NV: Normal Value ULN: Upper Limit of Normal

Vinflunine was evaluated neither in patients with Child-Pugh grade C, nor in patients with prothrombin time <50%NV or with bilirubin >5xULN or with transaminases >6xULN or with Gamma Glutamyl Transferases (GGT) >15xULN.

Renal impairment

In the 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.

Elderly ( > 65 years)

In the clinical studies, 103 patients  75 years old and 374 patients  65 and < 75 years old were treated at the recommended dose of vinflunine. No significant differences in safety were observed in these two age groups. No specific dose recommendation is necessary in the elderly.

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.

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. In case of small or sclerosed veins, lymphoedema, recent venipuncture at 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.

Recommended comedication

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.

Hypersensitivity to the active substance or other vinca alkaloids.

Recent (within 2 weeks) or current severe infection.

Baseline ANC < 1,500/mm³ or platelets < 100,000/mm³.

Lactation

Hematological toxicity

Neutropenia is a frequent adverse reaction of vinflunine. Adequate monitoring of complete blood counts should be conducted to verify the ANC value before each vinflunine infusion.

The recommended dose should be reduced in patients with Grade >3 haematological toxicity (see section 4.2).

Vinflunine should not be administered when the ANC < 1,000/mm³ and/or platelets < 100,000/mm³.

Gastrointestinal disorders

Severe constipation occurred in 15.3% of treated patients. Constipation is reversible and not cumulative. Special dietary measures such as oral hydration should be taken and laxatives should be administered 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 heavy abdominal surgery) should be medicated with polyethylene glycol from day 1 to day 7 administered once a day in the morning before breakfast.

In case of Grade 2 constipation for more than 5 days and Grade 3 of any duration, the dose of vinflunine should be adjusted.

In case of any Grade 3 gastrointestinal toxicity (except vomiting or nausea) and of mucositis (Grade 2 for more than 5 days and Grade 3 of any duration) dose adjustment is required.

Cardiac disorders:

Few QT interval prolongations have been observed after the administration of vinflunine. This effect may lead to an increased risk of ventricular arrhytmias although no ventricular arrhythmias were observed with vinflunine. Nevertheless, vinflunine should be used with caution in patients with increase of the proarrhytmic risk (e.g., congestive heart failure, known history of QT interval prolongation, hypokalemia). The concomittant use of two or more QT/QTc interval prolonging substances is not recommended.

Special attention is recommended when vinflunine is administered to patients with prior history of myocardial infarction/ischemia or angina pectoris. 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 impairement:

The recommended dose should be reduced in patients with moderate or severe hepatic impairment.

Renal impairement:

The recommended dose should be reduced in patients with moderate or severe renal impairment.

Others

The concomitant use of potent inhibitors or potent inducers of CYP3A4 with vinflunine should be avoided.

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.

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.

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 as the 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, doxorubicin or gemcitabine.

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 of 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 rifampicine and Hypericum perforatum (St John's wort)) should be avoided since they may increase or decrease vinflunine and DVFL concentrations.

The concomitant use of vinflunine with others QT/QTc interval prolonging drugs should be avoided.

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 doxorubicinol metabolite concentrations were not affected. According to an in vitro study, such changes could be related to an 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.

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, 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 ( 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.

Table 3 Adverse reactions observed in patients treated with transitional cell carcinoma of the urothelium treated with vinflunine

Adverse reactions in other indications

Adverse reactions occurring in patients with transitional cell carcinoma of the urothelium or in patients with other disease than the indication potentially severe and adverse reactions being a class effect of the vinca alkaloids are described below:

Blood and lymphatic system disorders

Grade 3/4 neutropenia was observed in 54.6% of patients. Severe anaemia and thrombocytopenia were less common (respectively 17.3 and 4.9%). 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 6.7% of patients. Infection with Grade 3/4 neutropenia is observed in 4.2% of patients.

Overall 6 patients (1.3% of the treated population) died from infection as a complication occurring during neutropenia

Gastrointestinal disorders

Constipation is a class effect of the vinca alkaloids: 15.3% of patients experienced severe constipation during treatment with vinflunine. Grade 3/4 ileus reported in 2.7% of patients was reversible when managed by medical care. Constipation is managed by medical care.

Nervous system disorders

Sensory peripheral neuropathy is a class effect of the vinca alkaloids. Grade 3 was experienced by 0.2% patients. All resolved during the study.

Cardiovascular disorders

Cardiac effects are a known class effect of the vinca alkaloids. Myocardial infarction or ischemia were experienced by 0.6% 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 3.6% of the patients but was rarely severe (Grade 3/4: 0.4%).

Bronchospam was reported in one patient treated with vinflunine for a different setting from the indication

Eye disorders:

One case of blurred vision and one case of reduced visual acuity have been reported.

Endocrine disorders

Three cases of suspected Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) have been reported in patients treated with vinflunine for a different setting from the indication.

Pierre Fabre Limited

POM – Prescription Only Medicine

05 March 2010