Pioneers in non-ionicsNycomed launches the first non-ionic X-ray contrast medium - AMIPAQUEAMIPAQUE1974

OMNIPAQUE - a well documented productExperience across all indications and patient groupsExperience from over 200,000,000 examinations (2002) world-wideAvailable world-wideAvailable in a wide range of presentations

TRUST IN EXPERIENCE

OMNIPAQUE - a proven productOver 4,000 published papersMore than 35 doctoral theses on OMNIPAQUEThe gold standard against which other X-ray contrast media are evaluated

The concept of an ideal contrast medium is the driving force behind contrast media developmentThe diagnostic effect without adverse reactions

Main classes of X-ray contrast media

Transformation of ionic to non-ionic mediumEliminating carboxyl decreases neurotoxicityEliminating ions decreases osmotoxicityAdding hydroxyl groups decreases chemotoxicityAlmn T, Excerpta Medica ICS 816; 1989:25-45

History of X-ray contrast media- 1Wilhelm Conrad Rntgen discovers X-rays1895

History of X-ray contrast media- 2Registration of Nycomeds first X-ray contrast medium (CM) in Norway (Urotrast = licensee product)1934

History of X-ray contrast media- 3AMIPAQUE (metrizamide), the worlds first non-ionic low-osmolar X-ray CM, after an idea conceived by Torsten Almn

1974

purposeEnhancing too many structures in the body> increasing/creating contrast image through changes in:Consentrations in tissueAttenuation valueSignal quality.

Visualizing of functions:-Elimination ( kidney ,liver)-transport processes(bloodstream,CSF,intestinal,liver)-perfusion( all tissue)-permeability/barriers-metabolisme(MRS)

Classification: > Negative: gases ,air > Positive: Ba SO4, Iodinatediodinated : Oily, water Soluble.( ionic non ionic) Ionic :Monomer:Oral CholegraphicUro/angiographic agent

- Dimer:i.v cholegraphicAngiographicNon Ionic:Monomer:DAILY USE

Dimeric

BaSo4Insoluble sulfate for diagnosis GI tractUnabsorbtableAvailable as powder/ suspensionConcentration 1g/cc 2.5g/ccMust be changed if perforation is suspected.

Water soluble , almost always use Iodine element:High contrast densityLow toxicityNon ionic superior than ionic; better neural tolerance incidens of general reanctions( nausea,vomiting,allergy like, idiosyncratic reaction is far lower.Low osmolalityNo vascular pain, endothelial damage,distrurbance BBB

Molecular structureIodine content:46.6%Molecular weight: 821 dalton

Quantitative compositionPhysico-chemicalData on file 1980, Nycomed Amersham

Osmolality of contrast media formulations1001502002503003504002000160012008004000mOsm/kg H2Omg I/mlbloodionic monomersEivindvik K et al, Acta Radiol Suppl. 1995; 399:32-38

ViscosityPhysico-chemical1. Dyvik K et al, Acta Radiol suppl. 95; 399: 43-492. Rees CR et al, Cardiovasc Radiol 1988; 166: 53-56

Pharmacokinetics in humansDistribution half-life = 21.8 min (independent of dose)Elimination half-life = 121.2 min (independent of dose)No metabolites detectedAbout 99% of the contrast medium was excreted during the first 24 hours after injectionAakhus T et al, Acta Radiol 1980; Suppl 362: 131-134

A universal contrast medium

The Effects oc CMPrimaryThe only one effect is desired that is Attenuation of radiation.SecondaryAll other effects :Chemotoxicity:protein binding,effect cell membrane, enzym blocking, vasoactive substance release

Osmotoxicity: pain, vasodilatation.

Ion toxicity : high/low consentration ions interfering cellular function

Classification of adverse events:Mild:Does not require medical treatment,does not interferre th examinationIntermediate:Necessary medical treatment, examination delayed/affectedSerious:Necessary medical treatment & hospitalization,or will have permanensequelae.

Other classificatiosSystemic effectsRenal effectsCardiovascular & hematologic effectsCardiac effects

CardioangiographyConclusionHill et al.This study confirms in a large randomized trial of cardiac angiography that the incidence of adverse reactions of all types is significantly lower with OMNIPAQUE than with diatrizoate.Hill J et al, Am J Cardiol 1993; 72: 770-775

Cardioangiography / PTCAConclusionVacek et al.When contrast media like OMNIPAQUE or ioxaglate are to be used, the non-ionic contrast medium OMNIPAQUE is significantly safer than the ionic dimer ioxaglate.Vacek JL et al, Am J Cardiol 1990; 66: 1277-1278

Nephrotoxicity in renal insufficiencyHarris KG et al, Radiology 1991; 179: 849-852* p

SurveillanceConclusionKatayama et al.The use of non-ionic contrast media significantly reduces the prevalence of severe adverse reactions (at all levels of risk) and represents the most effective means of achieving greater safety in contrast media examinations.

Katayama et al, Radiology 1990; 175: 621-628

SurveillanceConclusionPalmerIt is safer to be at high risk and receive a non-ionic mediumthan to be at low risk and receive a conventional ionic medium.

Palmer, Australas Radiol 1988; 32: 426-428

SurveillanceConclusionWolf et al.The choice of contrast agent emerges as the most potent risk factor.Wolf et al, Invest Radiol 1991; 26: 404-410

Non-ionic is economicIt is simplistic to believe that it is just a matter of comparing the cost of a non-ionic agent to a comparable amount of ionic contrast.Conclusion from The Ontario Association of Radiologists in 1994.Report: The Use of Iondinated Contrast Media in Diagnostic Imaging.

... our data suggest that the use of a low-osmolality contrast agent in all patients could substantially reduce the number of moderate and severe reactions, at minimal incremental cost. Finding from a clinical trial (Steinberg EP et al, N Engl J Med 1992; 326: 425-430) comparing the cost-effectiveness of diatrizoate with OMNIPAQUE in 505 patients undergoing cardioangiography.

IV-54 1978 Indonesia stamp features a drawing of a patient having a cerebral angiogram. The right side of the stamp features a drawing of a pressure injector used to inject contrast media into patients' blood vessels. Stamps of this type are used to educate the public.

IV-56 1981 Algeria stamp was issued to announce an International Congress on Echinococcosis. The lung, liver, and brain are highlighted. This interesting stamp design also features barium in the small intestine.

Overhead 03 + Overhead 04The invention of non-ionic contrast media in 1969 changed the face of contrast enhanced x-ray imaging.Until then radiologists had no choice but to give their patients ionic contrast media - with their high osmolality, chemotoxicity and iontoxicity and associated risks and side effects.The introduction of a low-osmolar, non-ionic molecule was a quantum leap resulting in dramatically improved levels of patient safety and tolerability.Overhead 05Launched in 1982, OMNIPAQUE was our first ready to use non-ionic x-ray contrast medium.Since then it has become established as a world market leader with a proven record of both efficacy and safety.Omnipaque is branded Trust in Experience.Overhead 06 Scientific Documentation Service in Oslo has established and IMAG- database containing more than 4300 papers dealing with OMNIPAQUE per January 1998.Figures per 23.09.99, see table below:

To our knowledge, no other CM has been used for more doctorial theses.

Looking into different CM articles, OMNIPAQUE is the most common contrast medium used for comparative studies and therefore charachterized as the gold standard.Overhead 09Professor Torsten Almn recently commented: Only one contrast medium effect is desired and that is the attenuation of radiation on its way from a roentgen tube to a roentgen film. All other contrast media effects may be regarded as adverse eventsThis is the ideal - to which research has been directed at achieving since the introduction of iodinated contrast media about 70 years ago. The research has led to the development of the ionic monomeric, ionic dimeric and the non-ionic monomeric x-ray contrast media. In recent years also the non-ionic dimers (VISIPAQUE).Overhead 11These four types of CM have important differences in their chemical structure. Examples of those differences are presence of a carboxyl group in ionic CM (Figs. 1 and 2), absence of a carboxyl group in non-ionic CM (Figs. 3 and 4), presence of one iodinated benzene ring in monomers (Figs. 1 and 3) and presence of two iodinated benzene rings in dimers (Figs. 2 and 4).The presently used non-ionic monomers have at least four hydroxyl groups per molecule to achieve a high water solubility (Fig. 3), while the ionic CM have no hydroxyl except for ioxithalamate and ioxaglate with one hydroxyl group per molecule (Figs. 1 and 2).The ionic CM do not need hydroxyl groups to achieve water solubility, because they have a carboxyl group which strongly contributes to their water solubility. However, later experience from animal studies has shown that presence of several hydroxyl groups in a CM molecule may contribute both to a high water solubility and also to a low intravascular and subarachnoid toxicity.One may expect that CM with major differences in chemical structure also have important differences in their animal toxicity. Previous development of CM shows this to be true.Overhead 16Ionic monomer:-COO groups (carboxylic group) give the molecules its water solubility.Non-ionic monomer:1.Carboxylic group eliminated chemotoxicity is reduced decreased intravascular toxicity and particularly decreased subarachnoid neurotoxicity.

2.When the carboxylic group is eliminated accompanying cations are also eliminated osmolality and osmotoxicity of the CM solutions decrease.

3.COO is replaced with a slide chain containing OH-group(s) (hydroxyl groups) the higher the number of OH-groups and the more evenly distributed they are around the contrast medium molecule, the lower the chemotoxicity becomes. (Decreases both subarachnoid and intravascular toxicity of the CM.)

Although these non-ionic CM have half the osmolality of ionic CM, they remain hyperosmolar - with an osmolality up to 2 - 3 times that of blood.

Overhead 17

In addition to showing some milestones during the first 100 years of radiology, the following facts should be emphasized: The 2 elements used for X-ray CM, barium (Ba) and iodine (I), were introduced as early as in 1911 and the early 1920s, respectively. So far no other element have been found better.

Todays CM are chemically related to acetrizoate in that they are all based on triiodinated benzene rings. As such this group of compounds has been in use, however with great improvements since non-ionics were introduced in 1974, for over 50 years!

Work done in the 1960s on various salt/electrolyte mixtures has gained new relevance with the introduction of non-ionic dimers.Overhead 18In addition to showing some milestones during the first 100 years of radiology, the following facts should be emphasized:The 2 elements used for X-ray CM, barium (Ba) and iodine (I), were introduced as early as 1911 and the early 1920s, respectively. So far no other elements have been found better.Todays CM are chemically related to acetrizoate in that they are all based on triiodinated benzene rings. As such this group of compounds has been in use, however with great improvements since non-ionics were introduced in 1974, for over 50 years!Work done in the 1960s on various salt/electrolyte mixtures has gained new relevance with the introduction of non-ionic dimers.

ISOPAQUE: Ionic high osmolar CM - now withdrawn from the market.Overhead 19IMAGOPAQUE Available in Germany, Austria, Switzerland, Greece, Italy, Spain and France (IVEPAQUE). Approved for all examinations except myelography. Launched in countries where Schering has (had) licenseerights for selling OMNIPAQUE.AMIPAQUE Not available any longer.Overhead 03OMNIPAQUE is a non-ionic monomer (one benzene ring). The benzene ring is an aromatic carbon compound with three iodine atoms per molecule.OH groups give the molecule its water solubility less chemotoxicity. Not only the number of the OH-groups is of importance, but also how they are positioned.Each molecule contains 46.6% iodine.OMNIPAQUE does not dissociate (split) into electrically charged particles (ions) when dissolved in water. Does not conduct electric impulses.Overhead 04Description:* Iohexol (INN), N, N - bis (2,3 - dihydroxypropyl) - 5 [N - (2,3 -dihydroxypropyl)acetamido] -2,4,6-triiodoisopthalamide, is a triiodinated, non-ionic water solublecontrast medium.* Trometamol = Buffer. (It has the special property to keep a more or less constant pH.)* NaCaEDTA = A chelating agent (a stabilizer in order to prevent the release of freeiodine as a result of breakage of the organic bond caused by heavy metal catalysis).* HCL acid = pH adjustment* Water = solventOverhead 05Definition:Osmolarity =Number of particles in a certain volume (particles per liter)Osmolality =Particles per kiloIonic CM:Osmolality = 5-8 times higher than bloodNon-ionic monomeric CM: Osmolality = 2-3 times higher than bloodIsotonic dimeric CM: Osmolality = plasmaA certain amount of non-ionic CM injected into the blood stream will increase the blood-osmolality proportionally to the number of molecules.

By using the same amount of an ionic CM in which each molecule will dissociate into two particles, the increase in osmolality will be proportionally higher.Overhead 08Definition viscosity: A measure of the degree of friction between the individual (molecules) in a fluid.The friction is caused by the shape of the molecules in the solution and by the distribution of electrical charges on their surfaces.With increasing temperature each particle gets an increased movement causing less friction and thus decreased viscosity.Injection of contrast media at body temperature (37C) is also to prefer for the well-being of the patients.Overhead 02Following intravascular injection, OMNIPAQUE is distributed throughout the vascular system and into the extracellular interstitial fluid compartment (without crossing the cell membrane and without significant binding to plasma). Subsequently (and simultaneously) OMNIPAQUE is rapidly excreted unchanged by glomerular filtration (without tubular secretion or reabsorption).These two processes can be described as a two-compartment model, and both show an exponential kinetics pattern (this means i.a. that the distribution and elimination kinetics are independent of the dose administered).

Mathematical quantification of the pharmacokinetics are (conventionally) the so called half-lives. Distribution half-life is a value which is more theoretical than real (due to the fact that the CM is immediately excreted via kidneys when it reaches them with the blood stream - before it can be perfectly distributed in the extracellular compartment). This value can be calculated from extrapolating the curve of the CM blood concentration after the application, and it reflects the internal properties of the CM molecule (physiochemical properties, hydrophilicity, diffusability, protein binding, etc.) and the properties of the tissues as well.

The elimination half-life is the time (e.g. radioactive decay or elimination of OMNIPAQUE by the glomerular filtration) it takes to reach a blood concentration which is 50% of the concentration at the previous measurement. Typically elimination half life measurements will start at the point where the blood concentration reaches its maximum - which for injectables like CM is almost immediately after injection.

Distribution and elimination half-lives of the non-ionic CM are very similar.Overhead 03In the subsequent chapter we will present results from a selection of clinical trials conducted with OMNIPAQUE. These results include indications from which OMNIPAQUE is registered today, including intra-arterial, intravenous, children, body cavity and myelography use.

Main focus is on the adverse event profile, comparing OMNIPAQUE with other non-ionic monomers and particularly ionic products. Some efficacy data are also included.Overhead 07Cardiac adverse reactions were the most frequent adverse reactions, and OMNIPAQUE was associated with a significantly lower incidence of these reactions.

A limitation of this study is that patients were stratified based on renal rather than cardiac factors. However, the data suggest that the groups receiving OMNIPAQUE and diatrizoate were similar in all respects, thus lessening the importance of this stratification method.

Finally, the adverse experience rates in this study, which appeared to be higher than those previously reported, may have been related to both the prospective data collection and the greater number of azotemic patients included.Overhead 14As a consequence of OMNIPAQUEs reduced chemotoxic effect, this study emphasize that a non-ionic CM such as OMNIPAQUE causes a highly significant reduction in adverse and allergic phenomena when compared to ioxaglate.Overhead 24101 adult in-patients with high serum creatinine levels [range, 1.4 - 2.4 mg/dl (120 - 210 mmol/l)] undergoing contrast material-enhanced computer tomography were randomized to receive ionic or non-ionic contrast media in a uniform dose. Changes in serum creatinine level at 48 hours were measured.

All patients received 150 ml of either OMNIPAQUE 300 or Conray 282, 50 ml bolus were followed by a 100 ml drip infusion.

The precence of nephrotoxicity was defined by an increase of 25% or more in serum creatinine level within a 48-hour period.

7 of the 50 patients in the ionic group (14%) showed an increase in creatinine level of 25% or more by 48-hours, whereas only 1 of the 51 patients in the non-ionic group showed such an increase. The difference is statistically significant (p = 0.05).

In the subset of 25 patients with diabetes mellitus (9 in the ionic group, 16 in the non-ionic), 3 of the patients in the ionic group (33%) showed 25% or greater increase in creatinine level compared with none in the non-ionic group. The difference between the two groups was statistically significant (p < 0.05).

This study demonstrates a reduced propensity for exacerbation of renal insufficiency with intravenous administration of a low osmolality non-ionic contrast agent in a population of patients with impaired renal function. This effect also held for those with both impaired renal function and diabetes.Overhead 12Non-ionic CM also significantly reduce the prevalence of milder ADRs, such as nausea, vomiting, urticaria, itching and heat sensation, resulting in significantly improved patient comfort.

Although this study was limited to intravenous administration, we are convinced that a similar increase in safety would apply equally to other methods of contrast media administration. Of course, patients at risk must be identified before the contrast medium study, and all possible measures must be taken to deal effectively with spontaneous anaphylactoid reactions. The use of non-ionic contrast media, however, are the most effective means of increasing the overall safety of contrast medium studies.Overhead 19Non-ionic CM are safer for all groups and it is of interest that the results indicated that it is safer to be at high risk and receive a non-ionic CM than to be at low risk and receive a conventional ionic CM.

This survey has demonstrated the relative safety of non-ionic CM for intravenous use and confirms the previous clinical studies on smaller patient numbers.Overhead 23The most powerful risk factor is the contrast medium;

Those receiving ionic contrast media are at high risk and those receiving OMNIPAQUE are at low risk. The amount of risk reduction with OMNIPAQUE compared to an ionic CM regimen is estimated to 7.3 fold.

General comments: When you look at these results compared to other comprehensive studies (Katayama etc), the different results could be due to case mix, selectionof agent based on patient risk factor, criteria used for classifying a reaction and to the reporting methods.

ADRs in Wolfs study = 0.6%, Katayama = 3.1%, Palmer = 1.2%, with non-ionics.

Notice that these studies include other non-ionic CM than OMNIPAQUE.Overhead 04Regarding the first statement, reference is made to overhead number 02 and 03 (other arguments that must be taken into account prior to the choice of CM).

Regarding the second statement, this is from a cardio angiography study conducted by E. Steinberg, where he claims that:

-if the true incidences of a severe adverse reaction with an ionic CM is 5.5% and 3.6% when a low calcium-binding, high osmolality contrast medium is used [severe reactions are those that require intensive or prolonged therapy (such as myocardial infarction) as was the case in his study when a less strict definition of a severe reaction was used], then the use of a low-osmolality rather than a high osmolality contrast medium in all patients, 1200 at John Hopkins hospital per year, would result in 28 fewer severe reactions and 94 fewer moderate reactions per year. Contrast related costs would increase by only $32.333 per year once the costs with managing contrast related adverse reactions were taken into account.