The European Medicines Agency (EMA)’s Pharmacovigilance Risk Assessment Committee (PRAC) has recommended the suspension of the marketing authorizations for four linear gadolinium contrast agents because of evidence that small amounts of the gadolinium they contain are deposited in the brain.
The agents concerned are intravenous injections of gadobenic acid, gadodiamide, gadopentetic acid and gadoversetamide, which are given to patients to enhance images from magnetic resonance imaging (MRI) body scans.
The PRAC’s review of gadolinium agents found convincing evidence of accumulation of gadolinium in the brain from studies directly measuring gadolinium in brain tissues and areas of increased signal intensity seen on MRI scan images many months after the last injection of a gadolinium contrast agent.
The companies concerned by this review have the right to request the PRAC to re-examine its recommendations.
The PRAC’s final recommendations will be sent to the Committee for Medicinal Products for Human Use (CHMP) for its opinion. Further details will be published at the time of the CHMP opinion.
Although no symptoms or diseases linked to gadolinium in the brain have been reported, the PRAC took a precautionary approach, noting that data on the long-term effects in the brain are limited. Deposition of gadolinium in other organs and tissues has been associated with rare side effects of skin plaques and nephrogenic systemic fibrosis, a scarring condition in patients with kidney impairment. Furthermore, non-clinical laboratory studies have shown that gadolinium can be harmful to tissues.
The four agents recommended for suspension are referred to as linear agents. Linear agents have a structure more likely to release gadolinium, which can build up in body tissues. Other agents, known as macrocyclic agents, are more stable and have a much lower propensity to release gadolinium. The PRAC recommends that macrocyclic agents be used at the lowest dose that enhances images sufficiently to make diagnoses and only when unenhanced body scans are not suitable.
Some linear agents will remain available: gadoxetic acid, a linear agent used at a low dose for liver scans, can remain on the market as it meets an important diagnostic need in patients with few alternatives. In addition, a formulation of gadopentetic acid injected directly into joints is to remain available because its gadolinium concentration is very low – around 200 times lower than those of intravenous products. Both agents should be used at the lowest dose that enhances images sufficiently to make diagnoses and only if unenhanced scans are not suitable.
For those marketing authorizations recommended for suspension, the suspensions can be lifted if the respective companies provide evidence of new benefits in an identified patient group that outweigh its risks or show that their product (modified or not) does not release gadolinium significantly (dechelation) or lead to its retention in tissues.
Please refer to the following website in European Medicines Agency for details:
http://www.ema.europa.eu/../news_detail_002708.jsp&mid=WC0b01ac058004d5c1
In Hong Kong, there are nine registered pharmaceutical products which are gadolinium contrast agents, and are prescription only medicines, including Magnevist Inj (HK-32608) containing meglumine gadopentetate, Omniscan Inj 0.5mmol/ml (HK-43493) containing gadodiamide, Gadovist Inj 1mmol/ml (HK-51750) and Gadovist Inj 1mmol/ml (Prefilled Syringe) (HK-57330) containing gadobutrol, Primovist Prefilled Syringe Inj 0.25mmol/ml (HK-54116) containing sodium gadoxetate, Dotarem Inj 377mg/ml (Vial) (HK-41578) and Dotarem Prefilled Syringes, 377mg/ml (HK-41579) containing meglumine gadoterate, MultiHance Inj 334mg (China) (HK-55495) and MultiHance Inj 334mg (HK-57789) containing gadobenic acid (as meglumine gadobenate).
Related news was previously issued by the US FDA, Taiwan FDA, EMA and Health Canada, and was posted on the Drug Office website on 28 July 2015, 12 August 2015, 21 March 2016 and 7 January 2017 respectively. So far, the Department of Health (DH) has received seven cases of adverse drug reaction (ADR) in connection with GBCAs: two cases on Omniscan, three cases on Dotarem, and two cases on Gadovist. These reported ADR cases were not related to brain deposits.
DH will remain vigilant on the final opinion of the CHMP of EMA and conclusion of the reviews related to the risk of brain deposits conducted by US FDA and Health Canada, and any safety updates from other overseas drug regulatory authorities for consideration of any follow up action deemed necessary.
Ends/ Saturday, March 11, 2017
Issued at HKT 12:00
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