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Sentences and sections with significant changes are given below in “track changes”:
4.2 Posology and method of administration
If on the day of infusion, in case ofthere is organ toxicity of Grade ³ 2 organ toxicity, 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 is was not modified in those 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
|
Level and
posology
|
Child Pugh Grade
|
Prothrombine time
|
|
Bilirubin
|
|
Transaminases
|
|
Gamma Glutamyl Transferases
|
|
Level 1
320 mg/m²
|
-
|
-
|
> 70% NV
|
and
|
> ULN and
£ 1.5xULN
|
and/or
|
> 1.5xULN and
£ 2.5xULN
|
and/or
|
> ULN and
£ 5xULN
|
|
Level 2
250 mg/m²
|
A
|
or
|
³ 60% NV
|
and
|
> 1.5xULN and
£ 3xULN
|
and
|
> ULN
|
and/or
|
> 5xULN
|
|
Level 3
200 mg/m²
|
B
|
or
|
³ 50% NV
|
and
|
> 3xULN
|
and
|
> ULN
|
and
|
> ULN
|
- 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 ³ 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 ³ 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.
NV: Normal Value ULN: Upper Limit of Normal
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 Gamma Glutamyl Transferases (GGT)>15xULN.
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 23 below:
Table 23: Dose adjustment due to toxicity in 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 ³ 38,5 °C)
|
|
Mucositis or Constipation Grade
2 ³ 5 days
or ³ 3 any duration
|
|
Any other toxicity Grade ³ 3
(except Grade 3 vomiting or nausea)
|
*National Cancer Institute, Common Toxicity criteria (NCI-CTC)
Elderly (> 65 years)
In the clinical studies, 103 patients ³ 75 years old and 374 patients ³ 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.
4.4 Special warnings and precautions for use
Elderly (≥ 75 years)
The recommended dose should be reduced in patients 75 years old and beyond (see section 4.2).
4.8 Undesirable effects
Table 3 Adverse reactions observed in patients treated 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)
|
8.06.9
|
3.32.7
|
|
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
|
hypersensitivityHypersensitivity
|
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
|
|
Nervous system disorders
|
Very common
|
Peripheral sensory neuropathy
|
10.29.8
|
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
|
2.01.8
|
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
|
2.72.2
|
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
|
22.221.6
|
4.94.7
|
|
Vomiting
|
27.3
|
2.9
|
|
Nausea
|
40.9
|
2.9
|
|
Stomatitis
|
26.9
|
2.7
|
|
Diarrhoea
|
12.9
|
0.9
|
|
Common
|
Ileus
|
2.62.7
|
2.2
|
|
Dysphagia
|
2.0
|
0.4
|
|
Buccal disorders
|
5.74.7
|
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
|
3.33.1
|
0
|
|
Pruritus
|
1.51.3
|
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
|
8.78.0
|
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
|
|
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
|
56.255.3
|
15.8
|
|
Injection site reaction
|
33.527.6
|
0.4
|
|
Pyrexia
|
10.9
|
0.4
|
|
Common
|
Chest pain
|
4.64.4
|
0.9
|
|
Chills
|
2.2
|
0.2
|
|
Pain
|
3.6
|
0.2
|
|
Oedema
|
1.41.3
|
0
|
|
Uncommon
|
Extravasation
|
0.7
|
0
|
|
Investigations
|
Very common
|
Weight decreased
|
24.0
|
0.4
|
|
Uncommon
|
Transaminases increased
|
0.60.4
|
0
|
|
Weight increased
|
0.2
|
0
|
Adverse reactions in other all indications
Adverse reactions occurring in patients with transitional cell carcinoma of the urothelium or and in patients with other disease than thise indication and potentially severe and or adverse reactions being that are a class effect of the vinca alkaloids are described below:
Blood and lymphatic system disorders
Grade 3/4 neutropenia was observed in 54.650.2% of patients. Severe anaemia and thrombocytopenia were less common (respectively 17.310.4 and 4.93.5%). Febrile neutropenia defined as ANC < 1,000/mm3and fever ³ 38.5°C of unknown origin without clinically microbiologically documented infection (NCI CTC version 2.0) was observed in 6.75.3% of patients. Infection with Grade 3/4 neutropenia is observed in 4.23.3% of patients.
Overall 6 7 patients (0.51.3% of the treated population) died from infection as a complication occurring during neutropenia
Gastrointestinal disorders
Constipation is a class effect of the vinca alkaloids: 15.312% of patients experienced severe constipation during treatment with vinflunine. Grade 3/4 ileus reported in 2.71.8% 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 0.20.1% 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 3.63.3% of the patients but was rarely severe (Grade 3/4: 0.41.2%).
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.
5.2 Pharmacokinetic properties
Pharmacokinetics in special populations
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
|
|
≥ 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 VFL 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).
6.3 Shelf life
Unopened vial: 3 years.
Diluted solution: Chemical and physical in-use stability has been demonstrated for the diluted medicinal product as follows:
- protected from light in polyethylene or polyvinylchloride infusion bag: for up to 6 days in a refrigerator (2 °C-8 °C) or for up to 24 hours at 25 °C;
- exposed to light in polyethylene or polyvinylchloride infusion set for up to 1 hour at 25 °C for up to 1 hour.
6.6 Special precautions for disposal and other handling
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).
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