UROGRAFIN Solution for infusion Ref.[49858] Active ingredients: Diatrizoic acid

Distribution

Plasma protein binding following intravenous injection amounts to less than 10%. A concentration corresponding to 2–3 g iodine/litre plasma can be expected 5 minutes after an intravenous bolus injection of 1 ml Urografin 60%/kg body weight. Over a period of 3 hours, the blood levels fall relatively quickly in the first 30 minutes, then with a half-life of 1–2 hours.

Amidotrizoic acid does not penetrate the erythrocytes, it is very quickly distributed in the extracellular space following intravascular administration but is not able to overcome an intact blood-brain barrier and is transmitted in only minimal amounts into breast milk.

Metabolism and elimination

At diagnostic doses, amidotrizoic acid undergoes glomerular filtration. About 15% of the dose is eliminated in chemically unchanged form with the urine within 30 minutes after the injection, and more than 50% within 3 hours; no metabolites could be demonstrated.

The kinetics observed on distribution and elimination of Urografin are unrelated to the dose within the clinically relevant range. This means that doubling or halving the dose results in blood levels and an eliminated amount of contrast medium in grams per time unit which are twice or half as high. Because of increased osmotic diuresis at twice the dose, however, the urinary concentration of contrast medium does not increase to the same extent.

Characteristics in patients

In impaired renal function amidotrizoate can also be eliminated extrarenally via the liver, although at a distinctly reduced rate. Renal contrast media can easily be removed from the body by extracorporeal haemodialysis. Regardless of the site of application, complete elimination within a short period of time is ensured even from tissues.

Systemic toxicity

Results from acute toxicity studies in animals show that there is no risk of acute intoxication following use of Urografin.

Experimental systemic tolerance studies with meglumine- or sodium amidotrizoate following repeated daily intravenous administration produced no findings which object to a single diagnostic administration to humans.

Reproduction

Reproduction-toxicological studies with meglumine- or sodium amidotrizoate gave no indication of a teratogenic or other embryotoxic potential following inadvertent administration of Urografin during pregnancy.

Genotoxic potential, tumorigenicity

Studies into genotoxic effects of amidotrizoate in vivo and in vitro gave no indication of a mutagenic potential.

Tumorigenicity studies have not been carried out.

Due to the absence of genotoxic effects and taking into account the metabolic stability, pharmacokinetics and the absence of indications of toxic effects on fast-growing tissues of amidotrizoate as well as the fact that Urografin formulations were only administered once, there is no evident risk of a tumorigenic effect on humans.

Local tolerance and contact-sensitizing potential

With the exception of an intramuscular local irritation study (Urografin 76%), animal experimental investigations into local tolerance of Urografin have not been carried out. However, local tolerance studies following paravenous, intraperitoneal and intravenous application as well as application into the oviduct have been carried out with meglumine amidotrizoate. Furthermore, the application sites were examined following repeated intravenous administration of meglumine- or sodium amidotrizoate in the systemic tolerance studies. The results from these studies are to be regarded as representative for Urografin.

These studies gave no indication that adverse local effects are to be expected in blood vessels, on mucous or serous membranes of humans. After inadvertent paravascular administration slight local intolerance reactions could occur. Animal studies, including the investigation into contact-sensitizing effect gave no indication of a sensitizing potential of amidotrizoate.