Fertility, pregnancy and lactation

Contraception in males and females
Both male and female patients should take adequate contraceptive measures up to three months after the discontinuation of the therapy.

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 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-feeding
It 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).

Fertility
Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with vinflunine.
Effects on ability to drive and use machines

Javlor may cause adverse reactions such as fatigue (very common) and dizziness (common) which may lead to a minor or moderate influence on the ability to drive and use machines..Patients should be advised not to drive or use machines if they experience any adverse reaction with a potential impact on the ability to perform these activities (see section 4.8).

Undesirable effects

Summary of the safety profile

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 and anaemia; gastrointestinal disorders, especially constipation, anorexia, nausea, stomatitis/mucositis, vomiting, abdominal pain and diarrhoea, and general disorders such as asthenia/fatigue.

Tabulated list of adverse reactions

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 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
	Common	Infections (viral, bacterial, fungal)	7.6	3.6
	Uncommon	Neutropenic sepsis	0.2	0.2
Neoplasm benign, malignant and unspecified	Uncommon	Tumour pain	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	1.3	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
	Very common	Decreased appetite	34.2	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	4.4	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
	Uncommon	Tinnitus	0.9	0
Cardiac disorders	Common	Tachycardia	1.8	0.2
	Uncommon	Myocardial ischaemia	0.7	0.7
	Uncommon	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
	Common	Cough	2.2	0
	Uncommon	Acute respiratory distress syndrome	0.2	0.2
	Uncommon	Pharyngolaryngeal pain	0.9	0
Gastrointestinal disorders	Very common	Constipation	54.9	15.1
Gastrointestinal disorders	Very common	Abdominal pain	21.6	4.7

		Vomiting	27.3	2.9
		Nausea	40.9	2.9
		Stomatitis	27.1	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	28.9	NA
	Common	Rash	1.8	0
		Urticaria	1.1	0
		Pruritus	1.1	0
		Hyperhidrosis	1.1	0
	Uncommon	Dry skin	0.9	0
	Uncommon	Erythema	0.4	0
Musculoskeletal and connective tissue disorders	Very common	Myalgia	16.7	3.1
	Common	Muscular weakness	1.8	0.7
		Arthralgia	7.1	0.4
		Back pain	4.9	0.4
		Pain in jaw	5.6	0
		Pain in extremity	2.4	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	26.4	0.4
		Pyrexia	11.7	0.4
	Common	Chest pain	4.7	0.9
		Chills	2.2	0.2
		Pain	3.1	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
	Uncommon	Weight increased	0.2	0

aadverse reactions reported from post-marketing experience

bfrequency calculated on the basis of non-TCCU clinical trial

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 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 disorders

Constipation 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 disorders

Sensory 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 disorders

Cardiac 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 disorders

Dyspnoea 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 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 the national reporting system

listed in Appendix V

Overdose

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.

PHARMACOLOGICAL PROPERTIES
1. Pharmacodynamic properties
  
  Pharmacotherapeutic group: antineoplasic agents, vinca alkaloids and analogues, ATC code: L01CA05
  
  Mechanism of action
  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 efficacy and safety
  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 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 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).
  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.
PHARMACEUTICAL PARTICULARS
1. List of excipients
  
  Water for injections
2. Incompatibilities
  
  This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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.
  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.
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 after dilution of the medicinal product, see section 6.3.
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. Each vial contains either 2 mL (50 mg vinflunine), 4 mL (100 mg vinflunine) or 10 mL (250 mg vinflunine) of concentrate for solution for infusion.
  
  Pack size of 1 and 10 vials.
  
  Not all pack sizes may be marketed.
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. 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 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. 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.
    
    Disposal
    Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic medicinal products.
MARKETING AUTHORISATION HOLDER

PIERRE FABRE MEDICAMENT
Les Cauquillous 81500 Lavaur France
MARKETING AUTHORISATION NUMBER(S)

EU/1/09/550/001-012
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 September 2009 Date of the latest renewal: 16 May 2014
DATE OF REVISION OF THE TEXT

XX month YYYY

Detailed information on this medicinal product is available on the website of the European Medicines Agency .

ANNEX II

MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

FAREVA PAU FAREVA PAU 1
Avenue du Béarn F-64320 Idron France
CONDITIONS OR RESTRICTIONS REGARDING THE SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).
OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
- Periodic Safety Update Reports
  
  The marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) ) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web- portal.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
- Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

At the request of the European Medicines Agency;
Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time.

ANNEX III

LABELLING AND PACKAGE LEAFLET

LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

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. PHARMACEUTICAL FORM AND CONTENTS

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
Concentrate for solution for infusion 1 vial of 2 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 other routes.
Read the package leaflet before use.

6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Cytotoxic: Handle with caution

8. EXPIRY DATE

EXP:
Read the leaflet for the shelf life of diluted medicine.

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 medicinal product or waste material should be disposed of in accordance with local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

PIERRE FABRE MEDICAMENT
Les Cauquillous 81500 Lavaur France

12. MARKETING AUTHORISATION NUMBER(S)

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

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC: {number} SN: {number} NN: {number}

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

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
PACKAGE LEAFLET

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 because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor.
If you get any side effects talk to your doctor. This includes any possible side effects not listed in this leaflet. See Section 4.

What is in this leaflet
1. What Javlor is and what it is used for
2. What you need to know before you use Javlor
3. How to use Javlor
4. Possible side effects
5. How to store Javlor
6. Content of the pack and other 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. What you need to know before you use Javlor Do not use Javlor
if you are allergic to the active substance (vinflunine) or to other vinca alkaloids (vinblastine, vincristine, vindesine, vinorelbine),
if you have had (in the last 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

Warnings and precautions
Tell your doctor:
if you have liver, kidney or heart problems,
if you experience any neurological symptoms such as headaches, changed mental state which may lead to confusion and coma, convulsions, blurred vision and high blood pressure as you may need to stop taking this medicine,
if you are taking other medicines mentioned in “Using other medicines” below,
if you have constipation, or if you are treated with medicines 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, breast-feeding and fertility” 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.

Constipation is a very common side effect of Javlor. To prevent constipation you may be given laxatives.

Used in children and adolescents

Javlor is not intended for use in children and adolescents.

Other medicines and Javlor

Tell your doctor if you are taking, have recently taken or might take any other medicines.

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,
opioids, used to treat pain,
ritonavir, used to treat HIV infection,
doxorubicin and pegylated liposomal doxorubicin, used to treat some kinds of cancer,
rifampicin, used to treat tuberculosis or meningitis,
herbal preparation containing hypericum perforatum (St John’s wort) used to treat minor to moderate depression.

Javlor with food and drink
You should tell your doctor if you are drinking grapefruit juice since it may increase the effect of Javlor.
You should also drink water and eat high fibre foods.

Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before starting your therapy.

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.

You should not be given Javlor if you are pregnant, unless it is absolutely necessary. You must not breastfeed during treatment with 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.

Driving and using machines
Javlor may cause side effects such as tiredness and dizziness. Do not drive or use machines if you experience side effects that affect your ability to concentrate and react.
1. How to use Javlor Dose
  The recommended 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 starting 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 have moderate or severe kidney problems
if you have liver problems.

During treatment, your doctor may reduce the dose of Javlor, delay or interrupt the treatment if you experience certain side effects.
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 must not be given intrathecally (into the spine).
Javlor is a concentrate that has to be diluted before administration.
1. Possible side effects
  
  Like all medicines, this medicine can cause side effects, although not everybody gets them.
  
  Tell your doctor immediately if you develop any of the following serious side effects while being treated with Javlor:
fever and / or chills which could be signs of infection,
chest pain which could be sign of heart attack,
constipation that resists to laxative treatment,
headaches, changed mental state which may lead to confusion and coma, convulsions, blurred vision and high blood pressure, which could be sign of a neurological disorder such as “posterior reversible encephalopathy syndrome” (see section 2 “warnings and precautions”).

Other side effects may include:
Very common (may affect more than 1 in 10 people)
abdominal pain, nausea, vomiting
constipation, diarrhoea
inflammation of the mucosa of the mouth
tiredness, muscle pain
lack of sense of touch
weight decrease, decrease of appetite
loss of hair
reactions at injection site (pain, redness, swelling)
fever
low levels of white blood cells, red blood cells and/or platelets (seen in blood test)
low levels of blood sodium (hyponatraemia).

Common (may affect up to 1 in 10 people)
chills, excessive sweating
allergy, dehydration, headache, skin rash, itching
digestive problems, pain in the mouth, on the tongue and toothache, taste alteration
muscular weakness, pain in jaw, pain in extremity, back pain, pain in joints, muscular pain, bone pain, ear pain
dizziness, insomnia, transiant loss of consciousness
difficulties with body movements
fast heartbeat, raised blood pressure, reduced blood pressure
breathing difficulties, cough, chest pain
swelling of your arms, hands, feet, ankles, legs or other parts of your body
inflammation of the veins (phlebitis).

Uncommon (may affect up to 1 in 100 people)
visual disturbances
dry skin, redness of the skin
muscle contraction disorders
pain in the throat, gum disorders
weight increase
urinary problems
ringing or buzzing in the ears (tinnitus)
increase in liver enzymes (seen in blood test)
“Syndrome of inappropriate antidiuretic hormone secretion”, which is a condition that causes low levels of blood sodium
tumour pain.

Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
1. How to store Javlor
  
  Keep this medicine out of the sight and reach of children.
  
  Do not use this medicine 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.
  
  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
  
  Do not throw away any medicine via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
2. Content of the pack and other 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 Javlor 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 of concentrate. Each pack contains 1 or 10 vials.
Not all pack sizes may be marketed.

Marketing Authorisation Holder

PIERRE FABRE MEDICAMENT
Les Cauquillous 81500 Lavaur France
Manufacturer

FAREVA PAU FAREVA PAU 1
Avenue du Béarn F-64320 Idron France

For any information about this medicine, please contact the Marketing Authorisation Holder.
This leaflet was last revised in MM/YYYY
.

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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. 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 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. 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.

Disposal

Any unused medicinal 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.

Age (y)	Number of patients	Vinflunine (mg/m²)
[ 70 – 75 [	17	320
[ 75 – 80 [	15	280
≥ 80	14	250

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

Fertility, pregnancy and lactation

Effects on ability to drive and use machines

Undesirable effects

Table 4 Adverse reactions observed in patients with transitional cell carcinoma of the urothelium treated with vinflunine

Overdose

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacokinetic properties

Preclinical safety data

PHARMACEUTICAL PARTICULARS

List of excipients

Incompatibilities

Shelf life

Special precautions for storage

Nature and contents of container

Special precautions for disposal and other handling

MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

ANNEX II

MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

CONDITIONS OR RESTRICTIONS REGARDING THE SUPPLY AND USE

OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

Periodic Safety Update Reports

CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

Risk Management Plan (RMP)

ANNEX III

LABELLING AND PACKAGE LEAFLET

LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

2. STATEMENT OF ACTIVE SUBSTANCE(S)

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

5. METHOD AND ROUTE(S) OF ADMINISTRATION

6.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

12. MARKETING AUTHORISATION NUMBER(S)

13. BATCH NUMBER

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

4. BATCH NUMBER

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

PACKAGE LEAFLET

Package Leaflet: Information for the user

Javlor 25 mg/mL concentrate for solution for infusion

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

What is in this leaflet

What Javlor is and what it is used for

What you need to know before you use Javlor Do not use Javlor

Warnings and precautions

Used in children and adolescents

Other medicines and Javlor

Javlor with food and drink

Pregnancy, breast-feeding and fertility

Driving and using machines

How to use Javlor Dose

How Javlor is given

Possible side effects