ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Javlor 25 mg/ml concentrate for solution for infusion
2.
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).
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion (sterile concentrate).
Clear, colourless to pale yellow solution.
4.
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 ≥ 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 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.
2
Dose adjustment due to toxicity
Table 1: 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
2
nd
consecutive
event
3
rd
consecutive
event
First Event
2
nd
consecutive
event
Neutropenia Grade 4
(ANC< 500/mm
3
)> 7
days
Febrile Neutropenia
(ANC< 1,000/mm
3
and
fever ≥
38,5 °C)
Mucositis or
Constipation Grade
2 ≥ 5 days
or ≥ 3 any duration
Any other toxicity
Grade ≥ 3
(except Grade 3
vomiting or nausea)
280 mg/m²
250 mg/m²
Definitive
Treatment
discontinuation
250 mg/m²
Definitive
Treatment
discontinuation
*National Cancer Institute, Common Toxicity criteria (NCI-CTC)
In patients with ANC < 1,000/mm
3
or platelets < 100,000/mm
3
on the day of administration, the
treatment should be delayed until recovery (ANC≥ 1,000/mm
3
and platelets ≥ 100,000/mm
3
). If
recovery has not occurred within 2 weeks, the treatment will be definitively discontinued.
In case of Grade 4 neutropenia (ANC < 500/mm
3
) for more than 7 days or febrile neutropenia, dose
adjustment is recommended (see table above).
If on the day of infusion, there is organ toxicity of Grade ≥ 2, the treatment should be delayed until
recovery to Grades 0, 1 or initial baseline status.
Special populations
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:
- 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
],
no dose adjustment is necessary.
- 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 250 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, the
recommended dose of vinflunine is 200 mg/m² given once every 3 weeks.
Vinflunine was evaluated neither in patients with severe hepatic impairment (Child-Pugh grade C), nor
in patients with a prothrombin time <50%NV or with bilirubin >5xULN or with transaminases
>6xULN or with GGT>15xULN.
Renal impairment
3
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).
Elderly (
≥
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 at least 75 years old are as follows:
- in patients 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 beyond, 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 2 below:
Table 2: Dose adjustment due to toxicity in elderly patients
Dose adjustment
Vinflunine initial dose of
280 mg/m²
Vinflunine initial dose of
250 mg/m²
First
Event
2
nd
consecutive event
First
Event
2
nd
consecutive event
Neutropenia
Grade 4
(ANC< 500/mm
3
) > 7 days
Febrile Neutropenia (ANC < 1,000/mm
3
and fever ≥ 38,5 °C)
Mucositis or Constipation Grade
2 ≥ 5 days
or ≥ 3 any duration
Any other toxicity Grade ≥ 3
(except Grade 3 vomiting or nausea)
250
mg/m²
Definitive
Treatment
discontinuation
225
mg/m²
Definitive
Treatment
discontinuation
*National Cancer Institute, Common Toxicity criteria (NCI-CTC)
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.
For instructions on dilution before administration, see section 6.6.
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 (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.
4
Toxicity
(NCI CTC v 2.0)*
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 (see section 4.4).
Hypersensitivity to the active substance or other vinca alkaloids.
Recent (within 2 weeks) or current severe infection.
Baseline ANC < 1,500/mm
3
or platelets < 100,000/mm
3
.
Lactation (see section 4.6).
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/mm
3
and/or platelets < 100,000/mm
3
.
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 (see section 4.2).
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 (see 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, hypokalemia) (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.
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
(
≥
75 years)
5
The recommended dose should be reduced in patients 75 years old and beyond (see section 4.2).
Others
The concomitant use of potent inhibitors or potent inducers of CYP3A4 with vinflunine should be
avoided (see section 4.5).
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.
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).
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 like 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 in 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 (see section 4.4 and 5.2).
The concomitant use of vinflunine with others QT/QTc interval prolonging drugs should be avoided
(see section 4.4).
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 for doxorubicinol, the concentrations of the metabolite were not
affected. According to an
in vitro
study, such changes could be related to 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.
Pregnancy
There 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
6
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.
Fertility
Both male and female patients should take adequate contraceptive measures up to three months after
the discontinuation of the therapy. Advice on conservation of sperm should be sought prior to
treatment because of the possibility of irreversible infertility due to therapy with vinflunine.
Lactation
It is unknown if vinflunine or its metabolites are excreted in breast milk. Due to the possible very
harmful effects on the infants, breast-feeding during the treatment with vinflunine is contraindicated
(see section 4.3).
No studies on the effects on the ability to drive and use machines have been performed. However,
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 (e.g. dizziness, syncope are common).
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 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
3.8
3.8
Infections (viral,
bacterial, fungal)
6.9
2.7
Uncommon
Neutropenic sepsis
0.2
0.2
Blood and lymphatic
system disorders
Very common
Neutropenia
79.6
54.6
Leucopenia
84.5
45.2
Anaemia
92.8
17.3
Thrombocytopenia
53.5
4.9
Common
Febrile neutropenia
6.7
6.7
Immune system
disorders
Common
Hypersensitivity
1.8
0.2
Metabolism and
nutrition disorders
Very common Anorexia
34.4
2.7
Common
Dehydration
4.4
2.0
Psychiatric disorders
Common
Insomnia
5.1
0.2
7
Nervous system
disorders
Very common Peripheral sensory
neuropathy
9.8
0.9
Common
Syncope
1.1
1.1
Headache
6.2
0.7
Dizziness
5.3
0.4
Neuralgia
6.0
0.4
Dysgeusia
3.1
0
Neuropathy
1.8
0
Uncommon
Peripheral motor
neuropathy
0.7
0
Eye disorders
Uncommon
Visual disturbance
0.4
0
Ear and Labyrinth
disorders
Common
Ear pain
1.3
0
Uncommon
Vertigo
0.9
0.4
Tinnitus
0.9
0
Cardiac disorders
Common
Tachycardia
1.8
0.2
Uncommon
Myocardial
ischaemia
0.7
0.7
Myocardial
infarction
0.2
0.2
Vascular disorders
Common
Hypertension
3.3
1.8
Vein thrombosis
3.3
0.4
Hypotension
1.1
0.2
Respiratory, thoracic
and mediastinal
disorders
Common
Dyspnoea
4.2
0.4
Cough
2.2
0
Uncommon
Acute respiratory
distress syndrome
0.2
0.2
Pharyngolaryngeal
pain
0.9
0
Gastrointestinal
disorders
Very common
Constipation
54.9
15.3
Abdominal pain
21.6
4.7
Vomiting
27.3
2.9
Nausea
40.9
2.9
Stomatitis
26.9
2.7
Diarrhoea
12.9
0.9
Common
Ileus
2.7
2.2
Dysphagia
2.0
0.4
Buccal disorders
4.7
0.2
Dyspepsia
5.6
0.2
Uncommon
Odynophagia
0.4
0.2
Gastric disorders
0.8
0
Oesophagitis
0.4
0.2
Gingival disorders
0.7
0
Skin and subcutaneous
tissue disorders
Very common Alopecia
28.7
NA
Common
Cutaneous reaction
3.1
0
Pruritus
1.3
0
Hyperhidrosis
1.1
0
Uncommon
Dry skin
0.9
0
Musculoskeletal and
connective tissue
disorders
Very common Myalgia
16.4
3.1
Common
Muscular weakness
2.2
0.9
Arthralgia
8.0
0.7
Back pain
4.9
0.4
Pain in jaw
3.3
0.0
Pain in extremity
3.3
0
Bone pain
2.4
0
8
Musculoskeletal
pain
2.0
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
27.6
0.4
Pyrexia
10.9
0.4
Common
Chest pain
4.4
0.9
Chills
2.2
0.2
Pain
3.6
0.2
Oedema
1.3
0
Uncommon
Extravasation
0.7
0
Investigations
Very common Weight decreased
24.0
0.4
Uncommon
Transaminases
increased
0.4
0
Weight increased
0.2
0
Adverse reactions in all indications
Adverse 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 disorders
Grade 3/4 neutropenia was observed in 50.2% of patients. Severe anaemia and thrombocytopenia were
less common (respectively 10.4 and 3.5%). Febrile neutropenia defined as ANC < 1,000/mm
3
and
fever ≥ 38.5°C of unknown origin without clinically microbiologically documented infection (NCI
CTC version 2.0) was observed in 5.3% of patients. Infection with Grade 3/4 neutropenia is observed
in 3.3% of patients.
Overall 7 patients (0.5% of the treated population) died from infection as a complication occurring
during neutropenia
Gastrointestinal disorders
Constipation is a class effect of the vinca alkaloids: 12% of patients experienced severe constipation
during treatment with vinflunine. Grade 3/4 ileus reported in 1.8% of patients was reversible when
managed by medical care. Constipation is managed by medical care (see section 4.4).
Nervous system disorders
Sensory peripheral neuropathy is a class effect of the vinca alkaloids. Grade 3 was experienced by
0.1% 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 3.3% 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.
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.
9
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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Vinca alkaloids and analogues, ATC code: L01CA05
Vinflunine 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 trials
One 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 and 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
10
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.
5.2 Pharmacokinetic properties
Vinflunine pharmacokinetics is linear in the range of administered doses (from 30 mg/m² to
400 mg/m
2
) in cancer patients.
Blood exposure to vinflunine (AUC), significantly correlated with severity of leucopenia, neutropenia
and fatigue.
Distribution
Vinflunine 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.
Metabolism
All 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.
Elimination
Vinflunine is eliminated following a multi-exponential concentration decay, with a terminal half-life
(t
1/2
) close to 40 h. DVFL is slowly formed and more slowly eliminated than vinflunine (t
1/2
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 impairment
No 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 impairment
A pharmacokinetic phase I study in patients with renal impairment is ongoing. An interim analysis on
13 patients with moderate impairment (40 ml/min ≤ CrCl ≤ 60 ml/min) and on 9 patients with severe
impairment (20 ml/min ≤ CrCl < 40 ml/min) indicated a decreased elimination of both vinflunine and
DVFL when CrCl is decreased. This was 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:
11
Age (y)
Number of
patients
Vinflunine (mg/m²)
[ 70 – 75 [
17
320
[ 75 – 80 [
15
280
≥ 80
14
250
Vinflunine clearance was significantly decreased in patients ≥ 80 years old as compared to a control
group of younger patients < 70 years.
Pharmacokinetics of vinflunine was not modified for patients 70 ≤ age < 75 years and 75 ≤ age < 80
years.
Based on both PK and safety data, dose reductions are recommended in the elder groups: 75 ≤ age <
80 years; and age ≥ 80 years.
For further cycles the dose should be adjusted in the event of toxicities (see section 4.2).
Others
According 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.
5.3
Preclinical safety data
Imaging distribution studies following radioactive vinflunine in rats, illustrated that the compound
levels in lungs, kidneys, liver, salivary and endocrine glands, and gastrointestinal tract were rapidly
higher than those in blood.
Preclinical data revealed moderate to severe neutropenia and mild anaemia, in all species tested, with
liver toxicity in dogs and rats (characterized by dose-dependent increases in liver transaminases and
hepatic necrosis/hepatocellular alterations at high doses). These toxic effects were dose-related and
fully or-partially reversible following a 1-month recovery period. Vinflunine did not induce peripheral
neuropathy in animals.
Vinflunine has shown to be clastogenic (induces chromosome breakage) in the
in vivo
micronucleus
test in rat as well as mutagenic and clastogenic in a mouse lymphoma assay (without metabolic
activation).
The carcinogenic potential of vinflunine has not been studied.
In the reproduction studies, vinflunine appeared to be embryolethal and teratogenic in rabbits and
teratogenic in rats. During the pre- and post-natal development study in rat, vinflunine induced
malformations of the uterus and vagina in 2 females, and adversely affected mating and/or ovule
implantation and markedly lowered the number of
concepti.
6.
6.1
List of excipients
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal product except those mentioned in
section 6.6.
6.3 Shelf life
Unopened vial
: 3 years.
12
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.
6.4
Special precautions for storage
Store in a refrigerator (2°C-8°C).
Store in the original package in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5
Nature and contents of container
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, containing either 2 ml (50 mg vinflunine, as ditartrate), 4 ml
(100 mg vinflunine, as ditartrate) or 10 ml (250 mg vinflunine, as ditartrate) of concentrate for solution
for infusion.
Pack size of 1 and 10 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
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. The use of gloves,
goggles and protective clothing is recommended.
If the solution comes into contact with the skin, the skin 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 . 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. Javlor is for single use only.
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.
After dilution of the Javlor concentrate, the Javlor 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.
-
upper part of the forearm or central venous arm
13
-
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 Javlor 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 product or waste material should be disposed of in accordance with local requirements for
cytotoxic medicinal products.
7.
Pierre Fabre Médicament
45, place Abel Gance
F-92100 Boulogne
France
8.
EU/1/09/550/001-012
9.
09/2009
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu
/.
14
ANNEX II
A.
MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH
RELEASE
B.
CONDITIONS OF THE MARKETING
15
AUTHORISATION
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Pierre Fabre Médicament Production
Etablissement Aquitaine Pharm International
Avenue du Béarn
F-64320 Idron
France
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the
Marketing Authorisation Application, is in place and functioning before and whilst the product is on
the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 4 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA.
16
ANNEX III
LABELLING AND PACKAGE LEAFLET
17
A. LABELLING
18
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Javlor 25 mg/ml concentrate for solution for infusion
vinflunine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
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)
3.
LIST OF EXCIPIENTS
Water for injections as excipient.
4.
1 vial of 2 ml
10 vials of 2 ml
1 vial of 4 ml
10 vials of 4 ml
1 vial of 10 ml
10 vials of 10 ml
50 mg /2 ml
100 mg /4 ml
250 mg /10 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use ONLY, after dilution.
Fatal if given by intrathecal route.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
19
Cytotoxic.
8.
EXPIRY DATE
EXP:
Read the leaflet for the shelf life of diluted product.
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements.
11.
Pierre Fabre Médicament
45, Place Abel Gance
F-92100 Boulogne
France
12.
EU/1/09/550/001 (box of 1 vial of 2 ml with grey stopper)
EU/1/09/550/002 (box of 10 vials of 2 ml with grey stopper)
EU/1/09/550/003 (box of 1 vial of 4 ml with grey stopper)
EU/1/09/550/004 (box of 10 vials of 4 ml with grey stopper)
EU/1/09/550/005 (box of 1 vial of 10 ml with grey stopper)
EU/1/09/550/006 (box of 10 vials of 10 ml with grey stopper)
EU/1/09/550/007 (box of 1 vial of 2 ml with black stopper)
EU/1/09/550/008 (box of 10 vials of 2 ml with black stopper)
EU/1/09/550/009 (box of 1 vial of 4 ml with black stopper)
EU/1/09/550/010 (box of 10 vials of 4 ml with black stopper)
EU/1/09/550/011 (box of 1 vial of 10 ml with black stopper)
EU/1/09/550/012 (box of 10 vials of 10 ml with black stopper)
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
20
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted
21
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Javlor 25 mg/ml sterile concentrate
vinflunine
IV use ONLY, after dilution
2.
METHOD OF ADMINISTRATION
See leaflet
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot:
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
50 mg/2 ml
100 mg/4 ml
250 mg/10 ml
6.
OTHER
22
B. PACKAGE LEAFLET
23
PACKAGE LEAFLET: INFORMATION FOR THE USER
Javlor 25 mg/ml concentrate for solution for infusion
vinflunine
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1.
What Javlor is and what it is used for
2.
Before you use Javlor
4.
Possible side effects
5.
How to store Javlor
6.
Further information
1.
WHAT JAVLOR IS AND WHAT IT IS USED FOR
Javlor contains the active substance vinflunine, which belongs to a group of anticancer medicines
called vinca alkaloids. These medicines affect cancer cell growth by stopping cell division, leading to
cell death (cytotoxicity).
Javlor is used to treat advanced or metastatic cancer of the bladder and urinary tract when a previous
therapy with platinum-containing medicines has failed.
2.
BEFORE YOU USE JAVLOR
Do not use Javlor
-
if you are allergic (hypersensitive) to the active substance (vinflunine) or to other vinca alkaloids
(vinblastine, vincristine, vindesine, vinorelbine),
- if you have had (within 2 weeks) or currently have a severe infection,
-
if you are breast-feeding,
-
if your levels of white blood cells and/or platelets are too low
Take special care with Javlor
Tell your doctor:
-
if you have liver, kidney or heart problems,
-
if you are taking other medicines mentioned in “Using other medicines” below,
-
if you have constipation, or if you are treated with drugs against pain (opioids), or if you have an
abdominal cancer, or if you had abdominal surgery,
-
if you would like to father a child (see “Pregnancy and breast-feeding” below).
Your blood cell counts will be checked regularly before and during your treatment, since low counts
of blood cells is a very common side effect with Javlor.
Javlor is not intended for use in children.
Using other medicines
24
3.
How to use Javlor
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription and herbal preparations.
In particular, you should tell your doctor if you are taking medicines containing any of the following
active substances:
-
ketoconazole and itraconazole, used to treat fungal infection,
-
ritonavir, used to treat HIV infection,
-
pegylated liposomal doxorubicin, used to treat some kinds of cancer,
-
rifampicin, used to treat tuberculosis or meningitidis,
-
herbal preparation containing hypericum perforatum (St John’s wort) used to treat minor to
moderate depression.
You should tell your doctor if you are drinking grapefruit juice.
You may be given laxatives to prevent constipation, which is a very common side effect of Javlor.
You should also drink water.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant or think you may be pregnant.
You should not be given Javlor if you are pregnant, unless it is absolutely necessary.
If you are a woman or a man of reproductive potential, you should use an adequate method of
contraception during treatment and for 3 months after your last dose of Javlor. If you would like to
father a child, seek advice from your doctor. You may want to seek counseling on sperm storage
before starting your therapy.
You must not breastfeed during treatment with Javlor
Driving and using machines
Javlor has not been studied for its possible effects on the ability to drive and use machines. If you
experience common side effects, such as dizziness or syncope, that affect your ability to concentrate
and react, do not drive or use machines.
3.
HOW TO USE JAVLOR
Dose
The usual dose in adult patients is 320 mg/m² body surface (this is calculated by the doctor based on
your weight and your height). The treatment will be repeated every 3 weeks.
Your doctor will adjust the dose of Javlor based on your age and physical conditions and in specific
situations::
-
if you had a previous irradiation of the pelvis.
-
if you experience certain side effects
-
if you have moderate or severe kidney or liver problems.
How Javlor is given
Javlor will be given to you by a qualified healthcare professional as an intravenous infusion (drip into
your vein) lasting 20 minutes. Javlor is a concentrate that has to be diluted before administration.
4.
POSSIBLE SIDE EFFECTS
25
Like all medicines, Javlor can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
very common: affects more than 1 user in 10
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
rare: affects 1 to 10 users in 10,000
very rare: affects less than 1 user in 10,000
not known: frequency cannot be estimated from the available data.
Very common side effects
-
abdominal pain, nausea, vomiting
-
constipation, diarrhoea
-
inflammation of the mucosa of the mouth
-
fatigue, muscle pain
-
weight decrease, loss of appetite
-
loss of hair
-
pain at the site of injection
-
decrease in the number of white blood cells (neutropenia) or red blood cells (anaemia) or platelets
-
fever.
Common side effects
-
fever with infection, chills, excessive sweating
-
allergy, dehydration, headache, cutaneous reaction, itching
-
digestive problems, paralytic intestine, pain in the mouth, on the tongue and toothache,
modification of the taste
-
muscular weakness, pain in jaw, pain in extremity, back pain, pain in joints, muscular pain, bone
pain
-
dizziness, insomnia, neurologic disorders, loss of consciousness
-
difficulties with body movements or sens of touch,
-
accelerated heartbeat, raised blood pressure, reduced blood pressure, vein thrombosis
-
breathing difficulties, cough, swelling (oedema), chest pain.
Uncommon side effects
-
increase of liver enzymes
-
generalized infection
-
visual disturbances, dry eye
-
vertigo, muscle contraction disorders
-
heart attack (myocardial infection, myocardial ischaemia)
-
acute respiratory distress, pain in the throat, gum disorders
-
renal failure
-
weight increase.
Cases of electrocardiography alterations have been observed after the administration of Javlor.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor. Your doctor may reduce the dose of Javlor or interrupt the treatment.
5.
HOW TO STORE JAVLOR
Keep out of the reach and sight of children.
Do not use Javlor after the expiry date which is stated on the vial label and the carton after EXP.
It is most unlikely that you will be asked to store this medicine yourself.
Storage conditions are detailed in the section intended for medicinal or heathcare professionals.
26
Unopened vials:
Store in a refrigerator (2°C-8°C).
Store in the original package in order to protect from light.
Diluted solution
The diluted solution should be use immediately
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Javlor contains
-
The active substance is vinflunine. Each 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).
-
The other ingredient is water for injections.
What Javor looks like and contents of the pack
Javlor is a clear, colourless to pale yellow solution. It comes in clear glass vials closed by a rubber
stopper containing 2 ml, 4 ml or 10 ml concentrate. Each pack contains 1 or 10 vials.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Pierre Fabre Médicament
45 place Abel Gance
F-92100 Boulogne
France
Manufacturer
Pierre Fabre Médicament Production
Etablissement Aquitaine Pharm International
Avenue du Béarn
F-64320 Idron
France
This leaflet was last approved in
{MM/YYYY}.
For any information about this medicine, please contact the Marketing Authorisation Holder.
<------------------------------------------------------------------------------------------------------------------------>
The following information is intended for medical or healthcare professionals only:
INSTRUCTION FOR USE
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. The use of gloves,
goggles and protective clothing is recommended.
27
If the solution comes into contact with the skin, the skin 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 . 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. Javlor is for single use only.
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.
Method of Administration
Javlor is for intravenous use ONLY.
After dilution of the Javlor concentrate, the Javlor 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.
o
upper part of the forearm or central venous arm
o
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 Javlor 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 product or waste material should be disposed of in accordance with local requirements for
cytotoxic medicinal products.
Storage conditions
Unopened vials
Store in a refrigerator (2°C-8°C).
Store in the original packaging in order to protect from light
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.
28
Source: European Medicines Agency
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