Overview

Iodinated contrast media (ICM) are medical imaging dyes used to enhance the ability for viewing the insides of various body parts such as blood vessels, tissues, and organs. ICM are generally used in radiographic procedures such as X-rays, computed tomography (CT) scans, and angiography.¹ Among ICM available for use include iohexol, iopamidol, iobitridol, iodixanol, iopromide, iomeprol, and amidotrizoic acid/meglumine.²

Hypothyroidism, or a decrease in thyroid hormone levels, may affect growth and development (including mental development) in infants and metabolic activity in children and adults.^3-4

Background of the Safety Issue

After considering the evidence from literature and post-marketing reports, the United States Food and Drug Administration (US FDA) has requested the product registration holders for the entire class of ICM injections to update the package inserts with risks of hypothyroidism and monitoring recommendations in children three (3) years of age or younger.¹

Hypothyroidism or transient thyroid suppression in paediatric patients after single and multiple administrations of ICM have been reported.¹ As ICM contains iodine, the mechanism of hypothyroidism following ICM administration could be related to the Wolff-Chaikoff effect and the escape phenomenon.⁵ Through an autoregulatory mechanism known as the Wolff-Chaikoff effect, a high amount of iodine intake acutely blocks the production of thyroid hormones within the thyroid follicles. In normal individuals, thyroid hormone production resumes after the body adapts to the transient Wolff-Chaikoff effect, which is called the escape phenomenon. However, certain vulnerable groups (especially babies with immaturity of these protective mechanisms) might develop an iodine-induced thyroid dysfunction due to a delayed “escape” from the Wolff-Chaikoff effect.^4-5

According to the safety review by the US FDA, the reported rate of hypothyroidism ranged from 1% to 15% following the use of ICM and tended to be higher in preterm newborns. The reported time interval between ICM administration and diagnosis ranged from 8.5 to 138 days, with most cases diagnosed within three (3) weeks. The review also found that this underactive thyroid was uncommon and most cases were transient subclinical hypothyroidism that did not require treatment. However, if the condition is not promptly identified and treated, the young patient might develop future cognitive and other developmental disabilities.¹

Adverse Drug Reaction Reports⁶

To date, the NPRA has received 1,244 reports with 2,278 adverse events suspected to be related to ICM. The most reported adverse events were pruritus (360), followed by rash (275) and urticaria (269). However, no local report of hypothyroidism has been received.

Advice for Healthcare Professionals

• Be aware of the risk of developing hypothyroidism following the use of ICM in children especially those of younger age, with very low birth weight, premature babies, or full-term babies with cardiac conditions (which usually require higher doses of ICM during invasive cardiac procedures) or other conditions that requiring admission to neonatal or paediatric intensive care units.
• Closely monitor babies and young children exposed to ICM, as signs of thyroid problems might not be visible. Consider performing blood tests to evaluate thyroid dysfunction, especially in high-risk patients during outpatient follow-up.
• If thyroid dysfunction is detected, promptly initiate treatment and monitor thyroid function to prevent future complications.
• Report all suspected adverse events associated with ICM-containing products to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (11) Jld.1] has been issued for all registration holders of products containing iodinated contrast media (ICM) to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. United States Food & Drug Administration (US FDA). FDA drug safety communication – FDA recommends thyroid monitoring in babies and young children who receive injections of iodine-containing contrast media for medical imaging. [Internet] 30 March 2022 [cited on 2022 Juy 12]. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-thyroid-monitoring-babies-and-young-children-who-receive-injections-iodine-containing
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2022 [cited 2022 Jul 12]. Available from: https://www.npra.gov.my
3. Health Canada. Summary Safety Review – Iodinated contrast medium: assessing the potential risk of decreased thyroid hormone production (hypothyroidism). [Internet] 24 Apr 2017 [cited on 2022 Jul 12]. Available at: https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00156
4. Singapore Health Sciences Authority (HSA). Safety Alerts – Iodinated contrast media and risk of hypothyroidism (particularly in infants). [Internet] 14 September 2018 [Cited on 2022 July 12]. Available at: https://www.hsa.gov.sg/announcements/safety-alert/iodinated-contrast-media-and-risk-of-hypothyroidism-(particularly-in-infants)
5. Kubicki R, Grohmann J, Kunz KG, Stiller B, Schwab KO, van der Werf-Grohmann N. Frequency of thyroid dysfunction in pediatric patients with congenital heart disease exposed to iodinated contrast media - a long-term observational study. J Pediatr Endocrinol Metab. 2020 Nov 26;33(11):1409-1415. Available from: https://doi.org/10.1515/jpem-2020-0032
6. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2022 [cited 2022 Jul 12]. Available from: https://www.npra.gov.my(access restricted)

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Written by: Wang Khee Ing
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr. Azuana Ramli