Preclinical - chemistry, pharmacology, toxicology, pharmaceutical issues (incl. packaging, stability/storage)

1.1 What are the storage conditions of OMNIPAQUE in warming cabinets?
SPC section 6.4 "Special precautions for storage" states: OMNIPAQUE should be stored at or below 30C protected from light and secondary X-rays. Furthermore, the product in glass vials and bottles can be stored at 37°C for up to 3 months prior to use.

The product in polypropylene (PP) bottles: 40, 50, 75, 100, 150, 175 and 200 ml volumes may be stored at 37°C for up to 1 month prior to use. The reason for the difference is that PP “breathes”, so that some water will actually evaporate and cause a concentration increase. No decay of any of the constituents has been demonstrated under these storage conditions.

1.2 Can OMNIPAQUE that has accidentally been frozen still be sold?
During the freezing/thawing process, glass vials may be broken or undergo non-detectable changes due to tensions in the glass wall resulting in leakage and possible contamination of the solution. GEHC, therefore do not permit the sale of contrast media in glass that has been frozen.

1.3 Can OMNIPAQUE be mixed with other drugs?
The SPC for OMNIPAQUE, in section 6.2 "Incompatibilities", states that “OMNIPAQUE should not be directly mixed with other drugs. A separate syringe should be used”.

When kept under the conditions described above, contrast agents are generally very stable compounds. However, there is a potential for interactions when drugs are administered together. For example, some drugs are stable only at very narrow pH ranges. In such instances, precipitation/crystallisation and oxidation (manifest as colour changes) have been reported. Therefore, contrast agents should not be mixed with other drugs for injection. For further info see refs. [1-4] and ESUR recommendation.

1.4 How much free iodine is there in OMNIPAQUE?
For specification limits, see table 1

Table 1 - OMNIPAQUE: Specification limits for inorganic iodide (NMT = no more than)

OMNIPAQUE Concentration	Glass/USB/SP
	Release	Shelf-life
180 mg I/ml	NMT 20 μg/ml	NMT 40 μg/ml
200 mg I/ml	NMT 20 μg/ml	NMT 45 μg/ml
240 mg I/ml	NMT 25 μg/ml	NMT 50 μg/ml
300 mg I/ml	NMT 30 μg/ml	NMT 60 μg/ml
350 mg I/ml	NMT 35 μg/ml	NMT 70 μg/ml

It should be emphasised that the actual, measured values for freshly manufactured product as well as for random reference samples stored for 3 years are consistently below these limits.

1.5 Can OMNIPAQUE be diluted and if so should it be diluted with saline or sterile water?
Generally, dilution of contrast media with saline or water is not recommended. There is little evidence supporting a need for this practice. Furthermore, dilution may alter the product properties: dilution of excipients may affect stability, and dilution with saline will render a non-ionic formulation ionic.

In specific cases, for oral or rectal use OMNIPAQUE may be diluted with sterile/tap water and used immediately. For recommendations on dilutions for oral and rectal use, see dosage tables in SPC, section 4.2 ”Posology and method of administration”.

Additionally, GEHC specifically warn against re-dispensing and/or re-sterilisation of the product following dilution, since both our glass and polypropylene vials/bottles are carefully selected and documented to ensure product stability.

1.6 What are the density values of OMNIPAQUE?
Regarding density/specific weight of our OMNIPAQUE formulations, see table below.

Concentration (mgI/ml)	Density (g/ml) 20°C	Density (g/ml) 37°C
180	1,2059	1,2059
240	1,2749	1,2749
300	1,3454	1,3364
350	1,4016	1,395

1.7 Is it acceptable to store OMNIPAQUE in a CT lab?
Protecting X-ray contrast media (CM) (incl. OMNIPAQUE) against radiation from X-ray equipment and daylight/sunlight during short time storage in X-ray labs is a well known precaution. [5]

Bottles filled with X-ray CM were stored for 3 days in a CT-lab to find out how secondary radiation affected CM stability. The CT scanner was used on average 7 h/day. It was shown that inorganic iodide increased only negligibly, while the product remained well within specifications. The quality and stability of the CM should thus not be influenced during a single working day.

In conclusion, X-ray CM may be kept in the X-ray room during one working day without any further precautions against radiation or daylight exposure.

However, long term storage in X-ray labs must be avoided.

1.8 How long after the bottle has been opened can OMNIPAQUE remain in a closed system (syringe and connector)?
GEHC has no guidelines to advise how long OMNIPAQUE can remain in a closed system. Conditions in such cases depend on the protocol and equipment used, and environment.

Two factors are important - sterility and contamination. GEHC can only guarantee that the CM in the vial/bottle is sterile and meets specifications before opening. Upon breaking of the seal, the contrast agent is exposed to environmental factors and thus beyond the control of GEHC. After a vial/bottle is opened it is intended to be used immediately. Once opened, contamination with microbiological material is to some degree inevitable (depending on environment). Since OMNIPAQUE (like all other CM) does NOT contain any preservatives / antimicrobial agents there is nothing to prevent growth. This also applies in closed systems.

1.9 Please provide data on serum protein binding for OMNIPAQUE, and its importance.
Iohexol has a serum protein binding of 1.5 % [6]. The technique used, however, has a lower level of accuracy of +2%, which means that essentially any values <2% are approximate values. For CM a lowest possible serum protein binding is desirable. The degree of protein binding parallels general toxicity of the CM.

All non-ionic CM bind to serum proteins (mainly albumin) <2%, while some ionic CM have considerably higher binding to serum albumin, (particularly ioxaglate 8%). Biliary CM (in use until the late 1980’s) had a protein binding >>90 % (essential for hepatic excretion), and were feared for their high incidence of serious and/or fatal ADRs.

Possible consequences of protein binding are:
1. Binding to enzymes affects enzyme function, as illustrated with the lysozyme model [6].
2. The stronger a substance tends to bind to serum protein, the more likely it will compete with other molecules attaching to the same binding site. Many therapeutics bind >>90% to serum albumin. Theoretically, CM with high protein binding, could detach bound therapeutics from the albumin, thus increasing the unbound fraction to a toxic level. This would NOT be the case with OMNIPAQUE.

1.10 Are there any precautions when using OMNIPAQUE in a patient undergoing haemodialysis?
In the SPC, section 4.4 “Special warnings…”, GEHC advise that patients on haemodialysis can be given OMNIPAQUE but that haemodialysis should be performed immediately after the imaging procedure. A warning is also given regarding the use of OMNIPAQUE (or any CM) in patients with renal impairment which is implied by the need for dialysis. Such patients are at risk from renal failure and all precautions to prevent such an outcome must be taken.

Haemodialysis or peritoneal dialysis completely eliminates the CM, but may take longer than via the normal GFR pathway. However, haemodialysis does not protect poorly functioning kidneys against CIN. Alternative imaging techniques should be considered. See also ESUR recommendations.