Javlor 25 mg/ml concentrate for solution for infusion
- Name:
Javlor 25 mg/ml concentrate for solution for infusion
- Company:
Pierre Fabre Limited
- Active Ingredients:
- Legal Category:
Product subject to medical prescription which may not be renewed (A)
Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 07/10/15

XPIL
Package Leaflet: Information for the user
Package Leaflet: Information for the user
1. What Javlor is and what it is used for
1. What Javlor is and what it is used for
2. What you need to know before you use Javlor
2. What you need to know before you use Javlor
3. How to use Javlor
3. How to use Javlor
4. Possible side effects
4. Possible side effects
5. How to store Javlor
5. How to store Javlor
6. Content of the pack and other information
6. Content of the pack and other information

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1. NAME OF THE MEDICINAL PRODUCT
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
4. CLINICAL PARTICULARS
5. PHARMACOLOGICAL PROPERTIES
5. PHARMACOLOGICAL PROPERTIES
6. PHARMACEUTICAL PARTICULARS
6. PHARMACEUTICAL PARTICULARS
7. MARKETING AUTHORISATION HOLDER
7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER(S)
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
10. DATE OF REVISION OF THE TEXT
Pierre Fabre Limited

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Updated on 7 October 2015 PIL
Reasons for updating
- Addition of information on reporting a side effect.
Updated on 7 October 2015 PIL
Reasons for updating
- New PIL for new product
Updated on 7 October 2015 SPC
Reasons for updating
- Change to Section 4.8 – Undesirable effects - how to report a side effect
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Updated on 7 October 2015 SPC
Reasons for updating
- New SPC for new product
Legal category: Product subject to medical prescription which may not be renewed (A)
Updated on 18 July 2014 SPC
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 10 - Date of revision of the text
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Section 4.4
text added:
‘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.‘
Section 4.8
Table 4, updated (changes highlighted in blue): 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 |
|
|
Infections (viral, bacterial, fungal) |
|
|
||
Uncommon |
Neutropenic sepsis |
0.2 |
0.2 |
|
Neoplasm benign, malignant and unspecified |
|
Tumour pain |
|
|
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. |
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 |
Decreased appetite |
34. |
2.7 |
||
Common |
Dehydration |
4.4 |
2.0 |
|
Psychiatric disorders |
Common |
Insomnia |
5.1 |
0.2 |
Nervous system disorders |
Very common |
Peripheral sensory neuropathy |
11.3 |
0.9 |
Common |
Syncope |
1.1 |
1.1 |
|
Headache |
6.2 |
0.7 |
||
Dizziness |
5.3 |
0.4 |
||
Neuralgia |
|
0.4 |
||
Dysgeusia |
3.3 |
0 |
||
Neuropathy |
1.3 |
0 |
||
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 |
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 |
3.1 |
1.6 |
Vein thrombosis |
3.6 |
0.4 |
||
Phlebitis |
2.4 |
0 |
||
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 |
15.1 |
Abdominal pain |
21.6 |
4.7 |
||
Vomiting |
27.3 |
2.9 |
||
Nausea |
40.9 |
2.9 |
||
Stomatitis |
2 |
2.7 |
||
Diarrhoea |
12.9 |
0.9 |
||
Common |
Ileus |
2.7 |
2.2 |
|
Dysphagia |
2.0 |
0.4 |
||
Buccal disorders |
4.0 |
0.2 |
||
Dyspepsia |
5.1 |
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. |
NA |
Common |
Rash |
1. |
0 |
|
Urticaria |
1.1 |
0 |
||
Pruritus |
1.1 |
0 |
||
Hyperhidrosis |
1.1 |
0 |
||
Uncommon |
Dry skin |
0.9 |
0 |
|
Erythema |
0.4 |
0 |
||
Musculoskeletal and connective tissue disorders |
Very common |
Myalgia |
16.7 |
3.1 |
Common |
Muscular weakness |
|
0.7 |
|
Arthralgia |
|
0.4 |
||
Back pain |
4.9 |
0.4 |
||
Pain in jaw |
|
0 |
||
Pain in extremity |
|
0 |
||
Bone pain |
2.9 |
0 |
||
Musculoskeletal pain |
2.7 |
0.2 |
||
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 |
2 |
0.4 |
||
Pyrexia |
1 |
0.4 |
||
Common |
Chest pain |
4.7 |
0.9 |
|
Chills |
2.2 |
0.2 |
||
Pain |
3. |
0.2 |
||
Oedema |
1.1 |
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 |
aadverse reactions reported from post-marketing experience
bfrequency calculated on the basis of non-TCCU clinical trial
Section 4.8
The following paragraphs have been updated (changes highlighted in blue):
Blood and lymphatic system disorders
Grade 3/4 neutropenia was observed in 50.2%43.8% of patients. Severe anaemia and thrombocytopenia were less common (respectively 10.48.8 and 3.5%).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 5.3%2% of patients. Infection with Grade 3/4 neutropenia was observed in 3.3%2.8 % of patients.
Overall 7 8 patients (0.56% of the treated population) died from infection as a complication occurring during neutropenia.
Gastrointestinal disorders
Constipation is a class effect of the vinca alkaloids: 1211.8% of patients experienced severe constipation during treatment with vinflunine. Grade 3/4 ileus reported in 1.89% 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 0.16% patients. All resolved during the study.
Rare cases of Posterior Reversible Encephalopathy Syndrome have been reported (see section 4.4).
Cardiovascular disorders
Cardiac effects are a known class effect of the vinca alkaloids. Myocardial infarction or ischaemia were experienced by 0.65% 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 3.32% 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.
Section 10
DATE OF REVISION OF THE TEXT updated to
06/2014
Updated on 18 July 2014 PIL
Reasons for updating
- Change to warnings or special precautions for use
- Change to side-effects
- Change to date of revision
Updated on 16 June 2014 PIL
Reasons for updating
- Change to warnings or special precautions for use
- Change of contraindications
- Change to side-effects
- Change to drug interactions
- Change to information about pregnancy or lactation
- Change to information about driving or using machinery
- Change to date of revision
- Change to dosage and administration
- Change to improve clarity and readability
- Addition of information on reporting a side effect.
Updated on 15 June 2014 SPC
Reasons for updating
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.7 - Effects on ability to drive and use machines
- Change to section 4.8 - Undesirable effects
- Change to Section 4.8 – Undesirable effects - how to report a side effect
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 6.6 - Special precautions for disposal and other handling
- Change to section 9 - Date of renewal of authorisation
- Change to section 10 - Date of revision of the text
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
4.2 Method of administration
Intrathecal administration of Javlor may be fatal, moved to section 4.4
4.3 Contraindications
Lactation replaced with Breast-feeding
4.4 Special warnings and precautions for use
Subheading Others replaced with subheading Interactions
Sub-heading added:
Contraception
4.5 Interaction with other medicinal products and other forms of interaction
Replaced drugs with medicinal products
4.7 Effects on ability to drive and use machines
Added:
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.
Removed:
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable effects
Sub-headings added:
Summary of the safety profile
Tabulated list of adverse reactions
Added
Reporting of suspected adverse reactions
Reporting 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 Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
IMB Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie
5.1 Pharmacodynamic properties
Added:
antineoplasic agents,
Added:
Paediatric population
The 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).
6.6 Special precautions for disposal and other handling
Method of administration
Removed:
upper part of the forearm or central venous arm
Replaced with:
on a large vein preferably in the upper part of the forearm or using a central venous line.
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Added:
Date of the latest renewal: 16 May 2014
10. DATE OF REVISION OF THE TEXT
Updated revision date 05/2014
Updated on 30 July 2013 SPC
Reasons for updating
- Change to section 4.8 - Undesirable effects
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Updated on 3 August 2012 SPC
Reasons for updating
- Change to section 4.2 - Posology and method of administration
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.8 - Undesirable effects
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 6.4 - Special precautions for storage
- Change to section 6.6 - Special precautions for disposal and other handling
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Updated on 20 July 2012 PIL
Reasons for updating
- Change due to harmonisation of PIL
Updated on 22 November 2011 SPC
Reasons for updating
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.8 - Undesirable effects
- Change to section 5.2 - Pharmacokinetic properties
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Updated on 17 November 2011 PIL
Reasons for updating
- Change to side-effects
- Change to drug interactions
- Change to dosage and administration
Updated on 18 May 2011 SPC
Reasons for updating
- Change to section 4.2 - Posology and method of administration
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 6.3 - Shelf life
- Change to section 6.6 - Special precautions for disposal and other handling
Legal category: Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
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
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- 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) |
|
|
||
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 |
Nervous system disorders |
Very common |
Peripheral sensory neuropathy |
|
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 |
|
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 |
|
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 |
|
|
||
Vomiting |
27.3 |
2.9 |
||
Nausea |
40.9 |
2.9 |
||
Stomatitis |
26.9 |
2.7 |
||
Diarrhoea |
12.9 |
0.9 |
||
Common |
Ileus |
|
2.2 |
|
Dysphagia |
2.0 |
0.4 |
||
Buccal disorders |
|
0.2 |
||
Dyspepsia |
5.6 |
0.2 |
||
Uncommon |
Odynophagia |
0.4 |
0.2 |
|
Gastric disorders |
0.8 |
0 |
||