Summary Safety Review - Gadolinium-based Contrast Agents - Assessing the Potential Risk of Serious Adverse Reactions, Including Seizures, Encephalopathy, Coma and Death, with Intrathecal Use

Gadolinium-based contrast agents (Dotarem [gadoterate meglumine], Gadovist 1.0 [gadobutrol], Magnevist [gadopentetate dimeglumine], MultiHance [gadobenate dimeglumine], Omniscan [gadodiamide], Primovist [gadoxetate disodium] and ProHance [gadoteridol]) (GBCAs)

Serious adverse reactions, including seizures, encephalopathy (brain dysfunction), coma and death, with intrathecal (injection into the spinal canal) use

• Health Canada’s review found a possible link between the intrathecal use of GBCAs and serious adverse reactions, including seizures, encephalopathy, coma and death.

• Health Canada is working with manufacturers to update the product safety information in the Canadian product monograph (CPM) for all GBCAs to include the risk of serious adverse reactions, including seizures, encephalopathy, coma and death, with off label intrathecal use.

Health Canada reviewed the potential risk of serious adverse reactions, including seizures, encephalopathy, coma and death with the intrathecal use of GBCAs. The safety review was triggered by a labelling update in the United States for all GBCAs.

Gadolinium-based contrast agents are not authorized in Canada for intrathecal use. However, Health Canada is aware that they have been used off-label for this route of administration.

• Gadolinium-based contrast agents are authorized for use in magnetic resonance imaging (MRI) to make it easier to view certain body tissues and to help with the diagnosis of various conditions. They are authorized to be given into a vein (intravenously).

• Gadolinium-based contrast agents have been marketed in Canada for over 30 years. There are 7 GBCAs currently marketed under the following brand names: Dotarem, Gadovist 1.0, Magnevist, MultiHance, Omniscan, Primovist and ProHance. A generic version of Gadovist 1.0 is also available.

• From 2019 to 2024, approximately 2.5 million patients in Canada were given GBCAs. However, information on intrathecal usage is not available.

• Health Canada reviewed the available information from the Canada Vigilance database^a, the scientific literature, and clinical experts.

• Health Canada reviewed 22 cases (1 Canadian and 21 international) of serious adverse reactions, including seizures, encephalopathy, coma and death, in patients who were administered GBCAs intrathecally. Of the 22 cases, 18 (1 Canadian and 17 international) were found to be possibly linked, including 11 from the published literature^1-13. The remaining 4 cases could not be assessed due to missing clinical information.

• The dose given was reported in 15 of the 18 cases that were possibly linked to the intrathecal use of GCBAs, and ranged from 1.5 mmol to 12 mmol (median dose 3 mmol).

• All 18 cases that were possibly linked to the intrathecal use of GCBAs involved adult patients. In 17 (1 Canadian) of those cases, the patients recovered or were recovering. A death occurred in the remaining case.

• Health Canada also reviewed the findings from 28 published studies. There were no reports of seizures, encephalopathy, coma or death in patients administered GBCAs intrathecally.

• Health Canada’s review of the available information found a possible link between the intrathecal use of GBCAs and serious adverse reactions, including seizures, encephalopathy, coma and death.

• Health Canada is working with manufacturers to update the CPM for all GBCAs to include the risk of serious adverse reactions, including seizures, encephalopathy, coma and death, with off label intrathecal use.

• Health Canada encourages consumers and healthcare professionals to report any side effects related to GBCAs, and other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information involving GBCAs, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should new health risks be identified.

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international adverse reaction reports, and what is known about the use of GBCAs both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

1. Arlt S, Cepek L, Rustenbeck HH, et al. Gadolinium encephalopathy due to accidental intrathecal administration of gadopentetate dimeglumine. J Neurol. 2007;254(6):810-812. doi:10.1007/s00415-006-0439-x

2. Chang J, Mohan S. Severe adverse effects after intrathecal injection of gadolinium based contrast agent. Presented at: 2023 ACMT Annual Scientific Meeting; March 2023; San Diego, CA. J Med Toxicol. 2023;19:63-168. doi:10.1007/s13181-023-00930-w

3. Chauhan G, Upadhyay A. Gadolinium-based contrast agent-induced neurotoxicity: seeing is believing  BMJ Case Rep. 2021;14(1):e241372. doi:10.1136/bcr-2020-241372

4. Dworkin I, Rudd-Barnard G, Pangarkar S, et al. Pseudo-subarachnoid hemorrhage due to gadolinium extravasation following cervical interlaminar epidural steroid injection [abstract]. Pain Med. 2019;20(9):1850-1878. doi:10.1093/pm/pnz188

5. Padalia D, Reeves C, Galang E. Neurotoxic manifestations after intrathecal gadobutrol injection: a case report [abstract]. PM R. 2016;8(9 Suppl):S289. doi:10.1016/j.pmrj.2016.07.319

6. Park KW, Im SB, Kim BT, et al. Neurotoxic manifestations of an overdose intrathecal injection of gadopentetate dimeglumine. J Korean Med Sci. 2010;25(3):505-508. doi:10.3346/jkms.2010.25.3.505

7. Patel A, Zolyan A, Itrat A. Long-term sequela of intrathecal gadolinium extravasation: symptoms mimicking post-concussive syndrome. Cureus. 2021;13(3):e14084. doi:10.7759/cureus.14084

8. Provenzano D, Pellis Z, DeRiggi L. Fatal gadolinium-induced encephalopathy following accidental intrathecal administration: a case report and a comprehensive evidence-based review. Reg Anesth Pain Med. 2019;44(7):721-729. doi:10.1136/rapm-2019-100422

9. Sese D, Blaha T, Khurana R, et al. A leaky situation: gadolinium contrast induced neurotoxicity from intrathecal contrast. In: D45. Critical Care Case Reports: I (Don't) Want to Be Sedated—Neurocritical Care, Sedation, and Delirium. Am J Respir Crit Care Med. 2018;197(1):A6888. doi:10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A6888

10. Reeves C, Galang E, Padalia R, et al. Intrathecal injection of gadobutrol: a tale of caution. J Pain Palliat Care Pharmacother. 2017;31(2):139-143. doi:10.1080/15360288.2017.1313353

11. Samardzic D, Thamburaj K. Magnetic resonance characteristics and susceptibility weighted imaging of the brain in gadolinium encephalopathy. J Neuroimaging. 2015;25(1):136-139. doi:10.1111/jon.12067

12. Scarpiello S, Wang X, Iyer A, et al. A case report of gadolinium neurotoxicity. Neurology. 2021;96(15 Suppl):2704. doi:10.1212/WNL.96.15_supplement.2704

13. Sutherland E, Baird-Gunning J, Rudaks L, et al. Gadolinium encephalopathy presenting as status epilepticus following intrathecal injection. BMJ Neurol Open. 2021;3(Suppl 1):A1-A45. doi:10.1136/bmjno-2021-ANZAN.75

1. Canadian reports can be accessed through the Canada Vigilance Online Database.