AEs and other safety issues

4.1 What should be done in case of extravasation of OMNIPAQUE?
Extravasation may lead to local reactions. This is usually a consequence of the osmolality and volume of contrast agent extravasated. Most injuries are minor. Severe injuries include skin ulceration, soft tissue necrosis, and compartment syndrome.

In the SPC, section 4.4 "Special warnings….." GEHC state: "Extravasation of contrast media occurs rarely and gives local pain and oedema, which usually recedes without sequale.. However, inflammation and even tissue necrosis have been seen. Elevating and cooling the affected site is recommended as routine measures. Surgical decompression may be necessary in cases of compartment syndrome."

Benson [11] warns that elderly and unconscious patients are at particular risk. In such cases, the use of non-ionic CM is advocated.

Where uncertainty about extravasation exists, an X-ray of the injection site will reveal the local presence of CM.

Literature on extravasation include a recommendation by ESUR [12] (or see the ESUR web site), in addition to other references [13,14].

4.2 Can a patient with iodine allergy be given OMNIPAQUE?
Please see section 4.4 '”Special warnings and special precautions for use”, where GEHC state “A positive history of allergy, asthma, or untoward reactions to iodinated contrast media indicates a need for special caution. Pre-medication with corticosteroids or histamine H₁ and H₂ antagonists might be considered in these cases.”.

Further, section 4.8 “Undesirable effects” advises on hypersensitivity: “Hypersensitivity reactions are rare and usually present as mild respiratory or cutaneous symptoms like dyspnoea, rash, erythema, urticaria, pruritus and angioedema. They may appear either immediately after the injection or up to a few days later.” and “Anaphylactoid reactions may occur irrespectively of the dose and mode of administration and mild symptoms of hypersensitivity may represent the first signs of a serious reaction. Administration of the contrast medium must be discontinued immediately and, if necessary, specific therapy instituted via the vascular access.”

Several large monitoring studies on AEs to CM have been carried out, and most quoted of these is the Katayama study [15], which monitored > 300,000 patients. He found that patients with allergies to any agent had an incidence of AEs of 23.35% with ionic and 6.85% with non-ionic CM. Patients with reactions to previous CM injection had AE incidences of 44.04% and 11.24%, with ionic and non-ionic CM respectively. Similar findings have been reported by Wolf [16] and Palmer et al. [17]. Finally, ESUR also has recommendations on this issue.

4.3 Request for information regarding delayed reactions to OMNIPAQUE.
Delayed reactions do occasionally happen with medications including CM. Hosoya et al. [18] gives an excellent overview of the occurrence of delayed reactions to CM, including >15000 patients presenting with such reactions. Brockow [19] also gives a good overview of the scope of both immediate and delayed reactions.

The mechanism behind delayed reactions is thought to be T-cell mediated.[20-22].

Finally, as shown by Choyke et al. [23] there seems to be an increased risk for delayed reactions in patients treated with interleukin-2.

4.4 A patient had an "allergic" reaction to a previous injection of OMNIPAQUE, what can we recommend if the patient needs another CM examination?
A history of serious reaction to OMNIPAQUE is a contraindication for repeated use. Hypersensitivity reaction to one product may predict similar reactions to other CM. Illustrating the complexity of the mechanism and recognition of hypersensitivity, the literature includes instances where a CM has been uneventfully administered to patients reporting prior reactions to the same agent. For further information, please refer to the warnings and precautions in the SPC, sections 4.4. and 4.8.

4.5 Can a patient who has had a CT with OMNIPAQUE have a coronary angiogram with VISIPAQUE later the same day?
Due to the risk of nephrotoxicity, repeated administration of (large doses of) any contrast medium is not generally recommended. If this is necessary, it may be useful to know that OMNIPAQUE is excreted by the kidneys, when renal function is normal, the elimination half-life of OMNIPAQUE is 2 hours i.e. every 2 hours the amount of OMNIPAQUE in the body decreases by half. Additionally, ensuring adequate hydration status and considered use of nephrotoxic medications or procedures may reduce the risk of renal insults.

If the patient suffers from a renal disease, a repeated administration is not recommended without further assessment.

4.6 What is the procedure for handling patients who are being treated with Metformin?
The SPC, section 4.4 “Special warnings…” GEHC write: “To reduce the risk of lactic acidosis, serum creatinine level should be measured in diabetic patients treated with metformin prior to intravascular administration of iodinated contrast medium.”

Depending on results of SCr measurements, the SPC gives recommendations for normal SCr/renal function, abnormal SCr/renal function and emergency cases.

See also recommendation on the ESUR Web site.

4.7 Information about for how long to stop breast feeding after using OMNIPAQUE.
According to SPC section 4.6 “Pregnancy and lactation” “Contrast media are poorly excreted in human breast milk and minimal amounts are absorbed by the intestine. Breast feeding may be continued normally when iodinated contrast media are given to the mother. The amount of iohexol in breast milk excreted in 24 hours after injection was 0.5% of the weight adjusted dose in a trial. The amount of iohexol ingested by the baby in the first 24 hours after injection corresponds to only 0.2% of the paediatric dose..”

Nursing mothers may pump breast milk for 1-2 days’ use prior to CM injection, and use this to feed their infants until 24 h after CM injection. Milk produced during this 24 h period should also be pumped, and discarded.

4.8 Some hospitals advise patients not to eat 12- 24 h before a CM examination. What do GEHC recommend?
With ionic HOCM there was a greater risk of AEs and the risk of vomiting and possible aspiration would be higher if patients had a full stomach. Clearly this was a concern if associated with anaphylactic reactions. This was translated into a "Nil by mouth" protocol within many radiology departments. With the introduction of LOCM the risk is less and there are currently NO such statements in SPCs of our CM.

Hydration of patients prior to administration of CM is, however, very important and forms part of the advice in the SPC which emphasises the importance of correct patient hydration both before and after administration of the CM (section 4.4 “Special warnings…”). Similar advice is also given by the ESUR guidelines. Oral or i.v. hydration is particularly important if the patient is at risk of renal insufficiency. A statement on this is part of the ESUR guidelines on prevention of contrast induced nephrotoxicity.