XENETIX

Training T. PEYROUX February 2005

Summary
f XENETIX: a new chemical concept f XENETIX: physicochemical features f XENETIX and clinical experience f XENETIX and handling optimization f XENETIX at a glance

Introduction (1)
f The ideal contrast agent should display:
{ an optimal diagnostic efficiency { an optimal safety osmolality viscosity { the highest biological inertia iodine content intrinsic features of the compound

f Benzene ring
I R1 R2

I R3

{ { { {

common structure to all nonionic monomers differenciation: R1, R2, R3 lateral side chains benzene ring: a very lipophilic and toxic structure hydrophobic interactions with biological media may occur (adverse effects)

Introduction (2)

f Aim: to prevent from hydrophobic interactions occurence

f How ?

by masking the lipophilic benzene structure by increasing the molecule's hydrophilicity

XENETIX: a new chemical concept (1)

Hydrophilicity concept

X 3 KEY STEPS:

{ Quantitative hydrophilicity { Qualitative hydrophilicity { Stabilized hydrophilicity

XENETIX: a new chemical concept (2)

f Quantitative hydrophilicity
Tri iodinated benzene ring

4-O 5-O
Lipophilic zone

iopro ide iopa idol iopentol iohe ol

6-O
Hydroxyl radical

Improved protection of biological media through increased numbers of

H radicals

XENETIX: a new chemical concept (3)

f Qualitative hydrophilicity

Lipophilic zone

Hydrophilic zone

Decreased accessibility of the tri iodinated benzene ring through optimal spatial distribution of the hydroxyl radicals

XENETIX: a new chemical concept (4)

f Qualitative hydrophilicity
Contact = interaction

Risk of molecular deformation

Accessibility to protein membranes available

The hydrophilicity must be stabilized

XENETIX: a new chemical concept (5)

f Stabilized hydrophilicity
hydroxyl radicals evenly distributed around the periphery of the molecule

Tertiary amides through binding of methyl groups preventing rotation = M RE RIGID M LECULE

XENETIX: a new chemical concept (6)

f Stabilized hydrophilicity
Protein or biological membrane No deformation of the hydrophilic covering

XENETIX
Less molecular deformation

Less interaction with biological media

Improved safety profile

XENETIX: physicochemical features (1)

f Osmolality (mOsm/kg H2O)

iodixanol 270 iohexol 240 XENETIX 250 iopamidol 250 iopromide 240

290 520 585 515 480

iohexol 300 XENETIX 300 iopamidol 300 iopromide 300

69 0 69 5 61 6 61 0

Iodixanol iohexol 350 XENETIX 350 iopamidol 370 iopromide 370

290 82 0 915 799 770

XENETIX: physicochemical features (2)

f Viscosity (mPa. sec, at 37C)
iodixanol 320 iohexol 350 XENETIX 350 iopamidol 370 iopromide 370 11.4 10. 5 1 0 9. 5 9. 5

iodixanol 270 iohexol 240 XENETIX 250 iopamidol 250 iopromide 240

5.8 3.2 4.0 3.0 2.8

iohexol 300 XENETIX 300 iopamidol 300 iopromide 300

5. 7 6. 0 4. 5 4. 6

XENETIX: physicochemical features (3)

f Hydrophilicity (log P octanol/water at 37C)

iohexol XENETIX iopamidol iopromide

- 2.51 - 2.62 - 2.42 - 2.5

XENETIX displays: a high hydrophilicity  a low osmolality  a low viscosity



XENETIX: the best compromise diagnostic efficiency/patient safety

XENETIX: clinical experience (1)

f Clinical safety and patients at risk
clcreat

31

21 patients (clcreat < 0ml/mn) requiring an angiography 2 groups (one requiring contrast agent, the other not requiring contrast agent) Xenetix 3 0: 1.9 ml/kg Creatinine clearance follow up, 2 days after the injection of Xenetix

(ml/mn)
30

29

29

enet c ntr l

(Deray G., Nephron ;1998)

XENETIX: clinical experience (2)

f Clinical safety and patients at risk

100 patients requiring a CT or an IVU examination Presenting either a normal renal function (group A, clcreat > 0ml/mn) or an impaired one (group B, clcreat < ml/mn) Xenetix 3 0: 1.3 ml/kg Creatinine clearance follow up, 3 days after the injection of Xenetix

clcreat (ml/mn) 74.3

73.3 72

36.6

38.1

38.9

Group A Group B

before inj.

at 48h

at 72h

(Louvel J.P., Eur. Radiol., 2000) XENETIX confirms its high safety profile by iv use in patients at risk

XENETIX: clinical experience (3)

f Clinical safety and patients at risk


50 patients enrolled for a CT examen in a double blind randomised clinical trial (25 p/Xenetix 300 25 p/Visipaque 320) Presenting with a pre existing renal failure (clcreat < 5ml/mn) Volume administered:  113 ml/Xenetix group  112 ml/Visipaque group Assessment criteria  Renal safety (creatininemia follow up at 3 days)  Image quality

XENETIX: clinical experience ( )

Results: XRenal
NS
Ser. Creat (mol/l)

safety
Number of patient with U Creat clear > 25 %

NS
n= 3 n=3

254 246 242

3 2.5 2
Visipaque 320 Xenetix 300
Visipaque 320

229

1.5 1 0.5
Xenetix 300

before inj.

D3

(Kolehmainen, Eur. Radiol., 2003)

XENETIX: clinical experience (5)

f Image quality

Good to excellent

96% 92% Visipaque 320 Xenetix 300

Average

3% 4% 4%

No imaging

XENETIX: clinical experience (6)

f Post marketing survey (France)

13 1 patients requiring a CT examination Xenetix 250, 300, 350: 98ml (12 250ml)
Adverse effects
in %
0.3 9 0.8

Image quality
in %
   
poo o f 6 X n t x 50 X n t x 300 X n t x 350 91 goo o x ll nt

v mt g t

0.5

cc

t t l

4.4

(Coulomb M., Journ Radiol, 1996)

    

0.2

94 96

     

d c

XENETIX: clinical experience (7)

f Post marketing survey (Germany) (Petersein J., Eur. Radiol., 2003)
n = 1 754 patients

297 children (age < 14) 1457 adults (age > 0: 30 505)
renal failure cardiac failure

in %
9

Patients at risk 1 risk (19 %) n = 17 797 (29 %) 2 risks (7 %) more than 2 risks (3%)

hypo or hypertonia coronary pathologies allergy dehydratation diabetes

24 27 2 2

(several items per patient)

XENETIX: clinical experience (8)

f Post marketing survey (Germany)
Contrast agent
Average volume: 100ml

Indication
in %
7

in %
2.5 5 3 9.5

1.5

91.5

80

Xenetix 250

Xenetix 300

Xenetix 350

CT

phlebo

DSA

angio

IVU

XENETIX: clinical experience (9)

f Post marketing survey (Germany)
Main adverse effects reported Adverse effects rate nausea urticaria 1390 patients in population at risk excluding warmth (701 patients) 2.3 % 1.5 % 1.1 % Adverse effects per subgroup children patients over 0 0. 5 % 1.85 % warmth sensation 0.3 % 0.1 % 1.3 %

XENETIX: clinical experience (10)

f Post marketing survey (Germany)
Image quality
10%

Diagnosti effi ien y

1%

90 %

99 %

goo to e ellent

fair

yes

no

XENETIX: handling optimization (1)

f FLAG LABEL
Description Additional label repeating basic information about product Detachable label to be stuck on patient record card and/or on a syringe

Advantages
Batch number Expiry date Name/ concentration

Product indentification right up to administration Accurate information on the product administered always possible Main label remains on bottle

XENETIX: handling optimization (2)

f MINI SPIKE
Description Device to take safely and easily contrast agent our of the bottle Contributes to contrast agent withdrawal free from bacterial contamination

Advantages Safety for the technician (no need to open the bottle) Improved handling No contrast agent waste
Fitted with air inlet

XENETIX: handling optimization (3)

f FILLING KIT
Description Device to fill the CT automatic injector easily and rapidly To be used with 500ml bottles

Advantages Patient line of the kit fitted with non return double valve to ensure highest security for the patient Kit partially kept in place, saving time and money

XENETIX at a glance (1)

f 3 concentrations available
{ XENETIX 250 { XENETIX 300 { XENETIX 350

XENETIX at a glance (2)

I CT

icati head hole body chest

ce trati 300 350 300 350 250 300 350 300 300 350 250

A era e

se ( l/k )

1.4 1 1.9 1.8 2 1.2 1 1. 1.7 2.1 3.1 2.2 2.8 1.8 3. 1.8 2.

IVU iv SA IA SA Angiography

rapid slo

peripheral lo er limbs abdominal cerebral

350 300 350 350 300 350 250

Angiocardiography Phlebography

XENETIX at a glance (3)

f How supplied ?
olu es* co ce tr tio s XENETIX 350 XENETIX 300 XENETIX 250 X X X X X X X X X X X X X X X X X X X X X X X X X X l l it l l it l l l l l l

* volume availability depends on country

XENETIX Available worldwide

E.U.
Austria Belgium Czech Rep. Denmark Finland France Germany Greece Hungary Ireland Italy Netherlands Portugal Spain Sweden UK

Europe
Croatia Macedonia Norway Russia Serbia Slovenia Switzerland Turkey

Americas
Argentina Brazil Chile Colombia Ecuador El Salvador Mexico Peru Uruguay Venezuela

Africa
Algeria Egypt Morocco South Afr Tunisia

Asia
China Hong Kong India Korea Malaysia Pakistan Philippines Singapore Tawan Thailand Vietnam

Middle East
Irak Isral Kuwat Lebanon Saudi Arabia U.A.E.

Oceania
New Zealand