This information is intended for use by health professionals
PosologyThe 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-medicationIn 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 toxicityTable 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 toxicityTable 2: Dose adjustments due to toxicity
|(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)|
Patients with hepatic impairmentA 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).|
Patients with renal impairmentIn 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 (NCI CTC v 2.0)*||Dose adjustment|
|Vinflunine initial dose of 280 mg/m2||Vinflunine initial dose of 250 mg/m2|
|First Event||2nd consecutive event||First Event||2nd consecutive event|
|Neutropenia Grade 4 (ANC < 500/mm3) > 7 days||250 mg/m2||Definitive Treatment discontinuation||225 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)|
Paediatric populationThere is no relevant use of Javlor in the paediatric population.
Method of administration
Precautions to be taken before handling or administering the medicinal productJavlor 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.
Gastrointestinal disordersGrade ≥ 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 disordersFew 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).
HyponatraemiaSevere 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 impairmentThe recommended dose should be reduced in patients with hepatic impairment (see section 4.2).
Renal impairmentThe 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).
InteractionsThe concomitant use of potent inhibitors or potent inducers of CYP3A4 with vinflunine should be avoided (see section 4.5).
AdministrationIntrathecal 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.
ContraceptionMen 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).
Contraception in males and femalesBoth male and female patients should take adequate contraceptive measures up to three months after the discontinuation of the therapy.
PregnancyThere are no data available on the use of vinflunine in pregnant women. Studies in animals have shown embryotoxicity and teratogenicity (see section 5.3). On the basis of the results of animal studies and the pharmacological action of the medicinal product, there is a potential risk of embryonic and foetal abnormalities.Vinflunine should therefore not be used during pregnancy, unless it is strictly necessary. If pregnancy occurs during treatment, the patient should be informed about the risk for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered. Genetic counselling is also recommended for patients wishing to have children after therapy.
Breast-feedingIt is unknown whether vinflunine or its metabolites are excreted in human milk. Due to the possible very harmful effects on the infants, breast-feeding during treatment with vinflunine is contraindicated (see section 4.3).
FertilityAdvice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with vinflunine.
Tabulated list of adverse reactionsAdverse 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 4 Adverse reactions observed in patients with transitional cell carcinoma of the urothelium treated with vinflunine
|System Organ Class||Frequency||Adverse Reactions||Worst NCI Grade per patient (%)|
|All grades||Grade 3-4|
|Infections and infestations||Common||Neutropenic infection||2.4||2.4|
|Infections (viral, bacterial, fungal)||7.6||3.6|
|Neoplasm benign, malignant and unspecified||Uncommon||Tumour pain||0.2||0.2|
|Blood and lymphatic system disorders||Very common||Neutropenia||79.6||54.6|
|Immune system disorders||Common||Hypersensitivity||1.3||0.2|
|Endocrine disorders||Uncommon||Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) a||0.4 b||0.4 b|
|Metabolism and nutrition disorders||Very common||Hyponatraemia||39.8||11.7|
|Nervous system disorders||Very common||Peripheral sensory neuropathy||11.3||0.9|
|Uncommon||Peripheral motor neuropathy||0.4||0|
|Rare||Posterior Reversible Encephalopathy Syndromea||0.03b||0.03b|
|Eye disorders||Uncommon||Visual disturbance||0.4||0|
|Ear and Labyrinth disorders||Common||Ear pain||1.1||0|
|Respiratory, thoracic and mediastinal disorders||Common||Dyspnoea||4.2||0.4|
|Uncommon||Acute respiratory distress syndrome||0.2||0.2|
|Gastrointestinal disorders||Very common||Constipation||54.9||15.1|
|Skin and subcutaneous tissue disorders||Very common||Alopecia||28.9||NA|
|Musculoskeletal and connective tissue disorders||Very common||Myalgia||16.7||3.1|
|Pain in jaw||5.6||0|
|Pain in extremity||2.4||0|
|Renal and urinary disorders||Uncommon||Renal failure||0.2||0.2|
|General disorders and administration site conditions||Very common||Asthenia/Fatigue||55.3||15.8|
|Injection site reaction||26.4||0.4|
|Investigations||Very common||Weight decreased||24.0||0.4|
Adverse reactions in all indicationsAdverse reactions occurring in patients with transitional cell carcinoma of the urothelium and in patients with other disease than this indication and potentially severe or adverse reactions that are a class effect of the vinca alkaloids are described below:
Blood and lymphatic system disordersGrade 3/4 neutropenia was observed in 43.8% of patients. Severe anaemia and thrombocytopenia were less common (respectively 8.8 and 3.1 %). 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 5.2% of patients. Infection with Grade 3/4 neutropenia was observed in 2.8 % of patients.Overall 8 patients (0.6% of the treated population) died from infection as a complication occurring during neutropenia.
Gastrointestinal disordersConstipation is a class effect of the vinca alkaloids: 11.8% of patients experienced severe constipation during treatment with vinflunine. Grade 3/4 ileus reported in 1.9% of patients was reversible when managed by medical care. Constipation is managed by medical care (see section 4.4).
Nervous system disordersSensory peripheral neuropathy is a class effect of the vinca alkaloids. Grade 3 was experienced by 0.6% patients. All resolved during the study.Rare cases of Posterior Reversible Encephalopathy Syndrome have been reported (see section 4.4).
Cardiovascular disordersCardiac effects are a known class effect of the vinca alkaloids. Myocardial infarction or ischaemia were experienced by 0.5% 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 disordersDyspnoea occurred in 3.2% of the patients but was rarely severe (Grade 3/4: 1.2%).Bronchospam was reported in one patient treated with vinflunine for a different setting from the indication.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via
United KingdomYellow Card Scheme Website: www.mhra.gov.uk/yellowcard
IrelandHPRA PharmacovigilanceEarlsfort Terrace IRL - Dublin 2Tel: +353 1 6764971Fax: +353 1 6762517Website: www.hpra.ie e-mail: [email protected]
Mechanism of actionVinflunine binds to tubulin at or near to the vinca binding sites inhibiting its polymerisation into microtubules, which results in treadmilling suppression, disruption of microtubule dynamic, mitotic arrest and apoptosis. In vivo, vinflunine displays significant antitumor activity against a broad spectrum of human xenografts in mice both in terms of survival prolongation and tumour growth inhibition.
Clinical efficacy and safetyOne phase III and two phase II trials support the use of Javlor for treatment of advanced or metastatic transitional cell carcinoma of the urothelium as second-line therapy after failure of a prior platinum-containing regimen. In the two multi-centre open-label, single-arm phase II clinical trials a total of 202 patients were treated with vinflunine. In the multi-centre, open-label controlled phase III clinical trial, 253 patients were randomised to treatment with vinflunine + BSC (best supportive care) and 117 patients to the BSC arm. The median overall survival was 6.9 months (vinflunine + BSC) vs. 4.6 months (BSC), but the difference did not reach statistical significance; hazard ratio 0.88 (95% CI 0.69, 1.12). However a statistically significant effect was seen on progression-free survival. Median PFS was 3.0 months (vinflunine + BSC) vs 1.5 months (BSC) (p=0.0012). In addition a pre-specified multivariate analysis performed on the ITT population demonstrated that vinflunine had a statistically significant treatment effect (p=0.036) on overall survival when prognostic factors (PS, visceral involvement, alkaline phosphatases, haemoglobin, pelvic irradiation) were taken into consideration; hazard ratio 0.77 (95% CI 0.61, 0.98). A statistically significant difference on overall survival (p=0.040) was also seen in the eligible population (which excluded 13 patients with clinically significant protocol violations at baseline who were not eligible for treatment); hazard ratio 0.78 (95% CI 0.61, 0.99). This is considered the most relevant population for the efficacy analysis, as it most closely reflects the population intended for treatment. Efficacy was demonstrated in both patients with or without prior cisplatin use. In the eligible population, the subgroup analyses according to the prior cisplatin use versus BSC on overall survival (OS) showed a HR (95% CI) = [0.64 (0.40 - 1.03); p=0.0821] in the absence of prior cisplatin, and a HR (95% CI) = [0.80 (0.60 - 1.06); p=0.1263] in the presence of prior cisplatin. When adjusted on prognostic factors, the analyses of OS in the subgroups of patients without or with prior cisplatin showed a HR (95% CI) = [0.53 (0.32 - 0.88); p=0.0143] and a HR (95% CI) = [0.70 (0.53 - 0.94); p=0.0174], respectively. In the subgroup analyses of prior cisplatin use versus BSC for progression free survival (PFS), the results were: HR (95% CI) = [0.55 (0.34 - 0.89); p=0.0129] in the absence of prior cisplatin, and a HR (95% CI) = [0.64 (0.48 - 0.85); p=0.0040] in the presence of prior cisplatin. When adjusted on prognostic factors, the analyses of PFS in the subgroups of patients without or with prior cisplatin showed a HR (95% CI) = [0.51(0.31 - 0.86); p=0.0111] and a HR (95% CI) = [0.63(0.48 - 0.84); p=0.0016], respectively.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with Javlor in all subsets of the paediatric population in the treatment of ureter and bladder carcinoma and the treatment of breast carcinoma (see section 4.2 for information on paediatric use).
DistributionVinflunine is moderately bound to human plasma proteins (67.2±1.1%) with a ratio between plasma and whole blood concentrations of 0.80±0.12. Protein binding mainly involves high density lipoproteins and serum albumin and is non-saturable on the range of vinflunine concentrations observed in patients. Binding to alpha-1 acid glycoprotein and to platelets is negligible (< 5%).The terminal volume of distribution is large, 2422±676 litres (about 35 l/kg) suggesting extensive distribution into tissues.
BiotransformationAll metabolites identified are formed by the cytochrome CYP3A4 isoenzyme, except for 4-O-deacetylvinflunine (DVFL), the only active metabolite and main metabolite in blood which is formed by multiple esterases.
EliminationVinflunine is eliminated following a multi-exponential concentration decay, with a terminal half-life (t1/2) close to 40 h. DVFL is slowly formed and more slowly eliminated than vinflunine (t1/2 of approximately 120 h).The excretion of vinflunine and its metabolites occurs through faeces (2/3) and urine (1/3). In a population pharmacokinetic analysis in 372 patients (656 pharmacokinetic profiles), the total blood clearance was 40 l/h with low inter and intra-individual variability (25% and 8%, respectively, expressed as coefficient of variation).
Pharmacokinetics in special populations
Hepatic impairmentNo modification of vinflunine and DVFL pharmacokinetics was observed in 25 patients presenting varying degrees of hepatic impairment, compared to patients with normal hepatic function. This was further confirmed by the population pharmacokinetic analysis (absence of relationship between vinflunine clearance and biology markers of hepatic impairment). However, dose adjustments are recommended in patients with liver impairment (see section 4.2).
Renal impairmentA pharmacokinetic phase I study was performed in 2 groups of patients with renal impairment classified according to the calculated creatinine clearance (CrCl) values: group 1 (n=13 patients) with moderate impairment (40 mL/min ≤ CrCl ≤ 60 mL/min) and group 2 (n=20 patients) with severe impairment (20 mL/min ≤ CrCl < 40 mL/min). The pharmacokinetic results of this study indicated a reduction of vinflunine clearance when CrCl is decreased. This is further confirmed by the population pharmacokinetic analysis (56 patients with CrCl between 20 mL/min and 60 mL/min), showing that vinflunine clearance is influenced by the creatinine clearance value (Cockcroft and Gault formula). Dose adjustments are recommended in patients with moderate and severe renal impairment (see section 4.2). Elderly (≥ 75 years) A pharmacokinetic phase I study of vinflunine was performed in elderly patients (n=46). Vinflunine doses were adjusted according to 3 age groups as shown below:
|Age (y)||Number of patients||Vinflunine (mg/m2)|
|[ 70 - 75 ]||17||320|
|[ 75 - 80 ]||15||280|
OthersAccording to the population pharmacokinetic analysis, neither gender nor performance status (ECOG score) had an impact on vinflunine clearance which is directly proportional to body surface area.
Unopened vial3 years.
Diluted solutionChemical 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.
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 concentrateThe 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 administrationJavlor 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.
DisposalAny unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic medicinal products.
|Date of first authorisation:||21 September 2009|
|Date of the latest renewal:||16 May 2014|