Javlor 25 mg/ml concentrate for solution for infusion

Change of IMB to HPRA and associated contact details

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	3.82.4	3.82.4
		Infections (viral, bacterial, fungal)	6.97.6	2.73.6
	Uncommon	Neutropenic sepsis	0.2	0.2
Neoplasm benign, malignant and unspecified	Not knownUncommon	Tumour paina	-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	1.83	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 appetiteAnorexia	34.42	2.7
	Common	Dehydration	4.4	2.0
Psychiatric disorders	Common	Insomnia	5.1	0.2
Nervous system disorders	Very common	Peripheral sensory neuropathy	11.39.8	0.9
	Common	Syncope	1.1	1.1
		Headache	6.2	0.7
		Dizziness	5.3	0.4
		Neuralgia	6.04.4	0.4
		Dysgeusia	3.31	0
		Neuropathy	1.38	0
	Uncommon	Peripheral motor neuropathy	0.47	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	1.13	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	3.13	1.68
		Vein thrombosis	3.63	0.4
		Phlebitis	2.42	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	15.13
		Abdominal pain	21.6	4.7
		Vomiting	27.3	2.9
		Nausea	40.9	2.9
		Stomatitis	26.97.1	2.7
		Diarrhoea	12.9	0.9
	Common	Ileus	2.7	2.2
		Dysphagia	2.0	0.4
		Buccal disorders	4.07	0.2
		Dyspepsia	5.16	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	28.79	NA
	Common	Rash	1.68	0
		Urticaria	1.13	0
		Pruritus	1.13	0
		Hyperhidrosis	1.1	0
	Uncommon	Dry skin	0.9	0
		Erythema	0.4	0
Musculoskeletal and connective tissue disorders	Very common	Myalgia	16.74	3.1
	Common	Muscular weakness	2.21.8	0.79
		Arthralgia	8.07.1	0.47
		Back pain	4.9	0.4
		Pain in jaw	3.35.6	0.0
		Pain in extremity	3.32.4	0
		Bone pain	2.94	0
		Musculoskeletal pain	2.70	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	27.66.4	0.4
		Pyrexia	10.91.7	0.4
	Common	Chest pain	4.74	0.9
		Chills	2.2	0.2
		Pain	3.61	0.2
		Oedema	1.13	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

 

 

 

 

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

"Phlebitis" and "Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)" have been added to the list of adverse reactions in section 4.8.

$04.       Clinicalparticulars$0$0 $0$04.2Posology and method of administration$0$0 $0$0Vinflunine treatmentshould be initiated under the responsibility of a physician qualified in theuse of anticancer chemotherapy and is confined to units specialised in theadministration of cytotoxic chemotherapy.$0$0 $0$0Posology$0$0 $0$0Recommendedco-medication $0$0In order to preventconstipation, laxatives and dietary measures including oral hydration arerecommended from day 1 to day 5 or 7 after each vinflunine administration (seesection 4.4).$0$0 $0$0Dose delay ordiscontinuation due to toxicity$0$0Dose adjustments due to toxicity $0$0 $0$0Table 2: Dose adjustments due to toxicity$0$0$0$0$0$0Toxicity$0$0$0$0Dose adjustment$0$0$0$0$0$0(NCI CTC v 2.0)*$0$0$0$0Vinflunine initial dose of 320 mg/m²$0$0$0$0Vinflunine initial dose of 280 mg/m²$0$0$0$0$0$0 $0$0$0$0First $0$0Event$0$0 $0$0$0$02^nd consecutive event$0$0$0$03^rd consecutive event$0$0$0$0First $0$0Event$0$0 $0$0$0$02^nd consecutiveevent$0$0$0$0$0$0Neutropenia Grade4$0$0(ANC< 500/mm³)>7 days$0$0$0$0 $0$0280 mg/m²$0$0 $0$0$0$0250 mg/m²$0$0$0$0Definitive$0$0Treatment discontinuation$0$0$0$0 $0$0250 mg/m²$0$0 $0$0$0$0Definitive$0$0Treatment discontinuation$0$0$0$0$0$0FebrileNeutropenia (ANC< 1,000/mm³ and fever ³ 38,5 °C)$0$0$0$0$0$0Mucositis orConstipation Grade 2 ³ 5 days or Grade ³ 3 anyduration¹$0$0$0$0$0$0Any other toxicityGrade ³ 3 (severe or life-threatening)$0$0(except Grade 3vomiting or nausea²)$0$0$0$0$0$0*National Cancer Institute,Common Toxicity Criteria Version 2.0 (NCI CTC v 2.0)$0$0¹ NCI CTC Grade 2 4 constipationis defined as requiring laxativesan obstruction or toxicmegacolon, Grade 3 as an obstipation requiring manual evacuationor enema, Grade 42 as an obstructionor toxic megacolon requiring laxatives. Mucositis Grade2 is defined as “moderate”, Grade 3 as “severe” and Grade 4 as“life-threatening”.$0$0² NCI CTC Grade 3 nausea isdefined as no significant intake, requiring IV fluids. Grade 3 vomiting as ³ 6 episodes in 24 hours over pretreatment; or need forIV fluids.$0$0 $0$0Special populations$0$0 $0$0Patients with hHepaticimpairment $0$0 $0$0 $0$0Patients with rRenalimpairment$0$0 $0$0Elderly patients(≥ 75 years)$0$0Table 3: Dose adjustments due to toxicity in renal impaired or elderlypatients$0$0$0$0$0$0Toxicity$0$0(NCI CTC v2.0)*$0$0$0$0Dose adjustment$0$0$0$0$0$0Vinflunine initial dose of280 mg/m²$0$0$0$0Vinflunine initial dose of250 mg/m²$0$0$0$0$0$0 $0$0$0$0First Event$0$0$0$02^nd consecutive event$0$0$0$0First Event$0$0$0$02^nd consecutive event$0$0$0$0$0$0Neutropenia Grade 4 $0$0(ANC< 500/mm³)> 7 days$0$0$0$0250  mg/m²$0$0 $0$0$0$0Definitive$0$0Treatment discontinuation$0$0$0$0225  mg/m²$0$0 $0$0$0$0Definitive$0$0Treatment discontinuation$0$0$0$0$0$0Febrile Neutropenia (ANC < 1,000/mm³ and fever ³ 38,5 °C)$0$0$0$0$0$0Mucositis orConstipation Grade 2 ³ 5 days or Grade ³ 3 anyduration¹$0$0$0$0$0$0Any other toxicityGrade ³ 3 (severe or life-threatening)$0$0(except Grade 3vomiting or nausea²)$0$0$0$0$0$0*National Cancer Institute,Common Toxicity Criteria Version 2.0 (NCI CTC v 2.0) $0$0¹ NCI CTC Grade 2 4 constipationis defined as requiring laxativesan obstruction or toxicmegacolon, Grade 3 as an obstipation requiring manual evacuationor enema, Grade 42 as anobstruction or toxic megacolon requiring laxatives.Mucositis Grade 2 is defined as “moderate”, Grade 3 as “severe” and Grade 4 as“life-threatening”.$0$0² NCI CTC Grade 3 nausea isdefined as no significant intake, requiring IV fluids. Grade 3 vomiting as ³ 6 episodes in 24 hours over pretreatment; or need forIV fluids.$0$0 $0$0Paediatric populations$0$0TUse in children– there is no relevant indication for use of Javlor in children thepaediatric population.$0$0 $0$0Method ofadministration$0$0Precautions to be taken before handling oradministering the medicinal product$0$0Javlor must be dilutedprior to administration. Javlor is for single use only.$0$0For instructions ondilution of the medicinal product beforeadministration, see section 6.6.$0$0 $0$0 $0$0Recommended co-medication$0$0In order to preventconstipation, laxatives and dietary measures including oral hydration arerecommended from day 1 to day 5 or 7 after each vinflunine administration (seesection 4.4).$0$0 $0$04.4     Special warnings and precautions for use$0$0 $0$0Gastrointestinal disorders$0$0 $0$0In case of Grade 2constipation, defined as requiring laxatives, for more than 5 days or moreor Grade ³ 3 of any duration, the dose ofvinflunine should be adjusted (see section 4.2). $0$0 $0$0In case of any Grade ³ 3 gastrointestinal toxicity (except vomiting or nausea) and or ofmucositis (Grade 2 for more than 5 days or more or Grade ³ 3of any duration) dose adjustment is required. Grade 2 is defined as “moderate”,Grade 3 as “severe” and Grade 4 as “life-threatening” (see Table 2 in section4.2). $0$0 $0$0 $0$0Posterior Reversible EncephalopathySyndrome (PRES)$0$0Cases of PRES have been observed afteradministration of vinflunine.$0$0The typical clinical symptoms are, with variousdegrees: neurological (headache, confusion, seizure, visual disorders),systemic (hypertension), and gastrointestinal (nausea, vomiting).$0$0Radiological signs are white matter abnormalitiesin the posterior regions of the brain. Blood pressure should be controlled inpatients developing symptoms of PRES. To confirm the diagnosis, brain imagingis recommended. $0$0Clinical andradiological features usually resolved rapidly without sequelae after treatment discontinuation.$0$0Discontinuation ofvinflunine should be considered in patients who develop neurological signs ofPRES (see section 4.8).$0$0 $0$0Elderly patients (≥ 75 years)$0$0The recommended dose should be reduced in patients 75years old and beyond (see section 4.2).$0$0 $0$04.6Fertility, pregnancy and lactation$0$0 $0$0Fertility $0$0Advice on conservation ofsperm should be sought prior to treatment because of the possibility of irreversibleinfertility due to therapy with vinflunine.$0$0 $0$0Contraception in males andfemales$0$0Both male and femalepatients should take adequate contraceptive measures up to three months afterthe discontinuation of the therapy. Advice on conservation of sperm should be soughtprior to treatment because of the possibility of irreversible infertility dueto therapy with vinflunine.$0$0 $0$0LactationBreast-feeding$0$0It is unknown if whether vinflunineor its metabolites are excreted in breast human milk. Dueto the possible very harmful effects on the infants, breast-feeding duringtreatment with vinflunine is contraindicated (see section 4.3). $0$0 $0$04.8Undesirable effects$0$0 $0$0Table 4 Adversereactions observed in patients with transitional cell carcinoma of theurothelium treated with vinflunine$0$0$0$0$0$0System Organ Class$0$0$0$0Frequency$0$0$0$0Adverse Reactions$0$0$0$0Worst NCI Grade per patient (%)$0$0$0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0All grades$0$0$0$0Grade 3-4$0$0$0$0$0$0Metabolismand nutrition disorders$0$0$0$0Very common$0$0$0$0AnorexiaHyponatraemia$0$0$0$034.439.8$0$0$0$02.711.7$0$0$0$0$0$0Anorexia$0$0$0$034.4$0$0$0$02.7$0$0$0$0$0$0Common$0$0$0$0Dehydration$0$0$0$04.4$0$0$0$02.0$0$0$0$0$0$0Nervoussystem disorders$0$0$0$0Very common$0$0Common$0$0$0$0Peripheral sensory neuropathy$0$0$0$09.8$0$0$0$00.9$0$0$0$0$0$0Syncope $0$0$0$01.1$0$0$0$01.1$0$0$0$0$0$0Headache$0$0$0$06.2$0$0$0$00.7$0$0$0$0$0$0Dizziness$0$0$0$05.3$0$0$0$00.4$0$0$0$0$0$0Neuralgia$0$0$0$06.0$0$0$0$00.4$0$0$0$0$0$0Dysgeusia$0$0$0$03.1$0$0$0$00$0$0$0$0$0$0Neuropathy$0$0$0$01.8$0$0$0$00$0$0$0$0$0$0Uncommon$0$0$0$0Peripheral motor neuropathy$0$0$0$00.7$0$0$0$00$0$0$0$0$0$0Rare$0$0$0$0Posterior ReversibleEncephalopathy Syndrome^a$0$0$0$00.03^b$0$0$0$00.03^b$0$0$0$0$0$0Neoplasmbenign, malignant and unspecified$0$0$0$0Not known$0$0$0$0Tumour pain^a$0$0$0$0-$0$0$0$0-$0$0$0$0$0$0^aadversereactions reported from post-marketing experience$0$0^bfrequencycalculated on the basis of non-TCCU clinical trial$0$0 $0$0Adverse reactions in all indications$0$0 $0$0Nervous systemdisorders$0$0Sensory peripheralneuropathy is a class effect of the vinca alkaloids. Grade 3 was experienced by0.1% patients. All resolved during the study.$0$0Rarecases of Posterior Reversible Encephalopathy Syndrome have been reported (seesection 4.4).$0$0 $0$05.       PHARMACOLOGICAL PROPERTIES$0$0 $0$05.1     Pharmacodynamic properties$0$0 $0$0Mechanism of action$0$0Vinflunine binds totubulin at or near to the vinca binding sites inhibiting its polymerisationinto microtubules, which results in treadmilling suppression, disruption ofmicrotubule dynamic, mitotic arrest and apoptosis. In vivo, vinfluninedisplays significant antitumor activity against a broad spectrum of humanxenografts in mice both in terms of survival prolongation and tumour growthinhibition.$0$0 $0$0Clinical trials efficacy and safety$0$0One phase III and twophase II trials support the use of Javlor for treatment of advanced ormetastatic transitional cell carcinoma of the urothelium as second-line therapyafter failure of a prior platinum-containing regimen.$0$0 $0$05.2 Pharmacokinetic properties$0$0 $0$0MetabolismBiotransformation$0$0All metabolitesidentified are formed by the cytochrome CYP3A4 isoenzyme, except for 4-O-deacetylvinflunine(DVFL), the only active metabolite and main metabolite in blood which is formedby multiple esterases. $0$0 $0$06.4Special precautions for storage$0$0 $0$0For storage conditions of thedilutedafter dilution of the medicinalproduct, see section 6.3.$0$0 $0$06.6     Special precautions for disposal and otherhandling$0$0 $0$0Disposal$0$0Any unused medicinal product or waste materialshould be disposed of in accordance with local requirements for cytotoxicmedicinal products.$0

$0Abbreviatedsummary of changes for Javlor SmPC dated 11/2011$0$0 $0$04.2Posologyand method of administration$0$0·Addition of monitoringplatelets and haemoglobin with a blood count.$0$0$0Addition of a table with dose delays ordiscontinuation due to toxicity (Table 1). This table also replaces thetext about treatment delays previously available. $0$0$0·For the table of doseadjustments due to toxicity, the definitions of the different CTC grades of constipation,nausea and vomiting have been added.$0$0$0Specialpopulations:$0$0$0Hepaticimpairment: No major changes, only re-wording$0$0$0$0o   Renalimpairment: Addition of one sentence: “Forfurther cycles, the dose should be adjusted in the event of toxicities, asshown in table 3 below”.$0$0o   Table3: This table is now for dose adjustments for both renal impaired andelderly patients. However, no major changes except addition of CTC definitionof severity grading.$0$0 $0$04.3     Contraindications$0$0·Further guidelines on baseline ANC: “BaselineANC < 1,500/mm³for the first administration,baseline ANC < 1,000/mm³ forsubsequent administrations.”$0$0 $0$04.4     Special warnings and precautions for use$0$0$0Hematologicaltoxicity:$0$0$0oLeucopoenia, anaemia andthrombocytopenia added as frequent adverse reactions. $0$0$0$0Change ofbaseline ANC similar to section 4.3$0$0$0Gastrointestinaldisorders:$0$0$0o   Furtherinformation on constipation and its management. $0$0 $0$04.5Interactionwith other medicinal products and other forms of interaction$0$0·Further details added regarding combination withdoxorubicin i.e. high risk of haematological toxicity.$0$0 $0$04.6Fertility,pregnancy and lactation$0$0·Change of title to include “Fertility”.$0$0 $0$04.8Undesirableeffects$0$0·Table 4,adverse reactions: Additions of rash and urticaria as common skindisorders and erythema as a very common musculoskeletal disorder. $0$0 $0$05.2 Pharmacokinetic properties$0$0$0Pharmacokinetics in specialpopulations, Renalimpairment:$0$0$0oFurther information added from the phase 1 study on patients with renalimpairment: the results indicate a reduction of vinflunine clearance with CrClis decreased. $0

 

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	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	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:

 

 

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