Special Warning : אזהרת שימוש

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/mm3 or platelets < 100,000/mm3. For subsequent administrations, vinflunine is contraindicated in subjects with baseline ANC < 1,000/mm3 or 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 5 days or more or Grade ≥ 3 of any duration, the dose of vinflunine should be adjusted (see section 4.2).

In case of any Grade ≥ 3 gastrointestinal toxicity (except vomiting or nausea) or of mucositis (Grade 2 for 5 days or more or Grade ≥ 3 of any duration) dose adjustment is required. Grade 2 is defined as “moderate”, Grade 3 as “severe” and Grade 4 as “life-threatening” (see Table 2 in section 4.2).

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.

Posterior Reversible Encephalopathy Syndrome (PRES)
Cases of PRES have been observed after administration of vinflunine.
The typical clinical symptoms are, with various degrees: neurological (headache, confusion, seizure, visual disorders), systemic (hypertension), and gastrointestinal (nausea, vomiting).
Radiological signs are white matter abnormalities in the posterior regions of the brain. Blood pressure should be controlled in patients developing symptoms of PRES. To confirm the diagnosis, brain imaging is recommended.
Clinical and radiological features usually resolved rapidly without sequelae after treatment discontinuation.
Discontinuation of vinflunine should be considered in patients who develop neurological signs of PRES (see section 4.8).

Hyponatraemia
Severe hyponatraemia, including cases due to syndrome of inappropriate antidiuretic hormone secretion (SIADH), has been observed with the use of vinflunine (see section 4.8). Therefore, regular monitoring of serum sodium levels is recommended during treatment with vinflunine.

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 patients (≥ 75 years)
The recommended dose should be reduced in patients 75 years old and beyond (see section 4.2).

Interactions
The concomitant use of potent inhibitors or potent inducers of CYP3A4 with vinflunine should be avoided (see section 4.5).

Administration
Intrathecal administration of Javlor may be fatal.
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.

Contraception
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).

Effects on Driving

4.7   Effects on ability to drive and use machines
Javlor may cause adverse reactions such as fatigue (very common) and dizziness (common) which may lead to a minor or moderate influence on the ability to drive and use machines . 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 (see section 4.8).