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, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Overview

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a class of medications indicated for the treatment of type 2 diabetes mellitus, as well as for reducing the risk of cardiovascular events and end-stage kidney disease.^1-3 They act by inhibiting SGLT2, a co-transporter primarily located in the proximal convoluted tubule (PCT) of the kidneys, leading to reduced reabsorption of renal glucose and sodium.^1-4

In Malaysia, the Drug Control Authority (DCA) has currently registered four types of SGLT2 inhibitors.⁵ These include 15 registered products containing dapagliflozin, 10 containing empagliflozin, 2 containing canagliflozin, and 2 containing luseogliflozin, available as single-ingredient products or as combination products with other drugs.

Lithium is used in the prophylaxis and treatment of mania or hypomania, as well as prophylaxis of bipolar disorder and recurrent unipolar depression.^6-8 The precise mechanism of lithium’s anti-manic effects remains unknown; however, lithium ions may act by competing with sodium ions at various sites in the body.⁶ Although lithium treatment has proven therapeutic benefits, its prolonged use is hindered by its narrow therapeutic index, elevated risks of toxicity, and association with several serious and sometimes irreversible adverse effects.⁸

At present, there is 1 product containing lithium (for therapeutic use) registered with the DCA.⁵

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) regarding the need to update the package inserts of all products containing dapagliflozin and empagliflozin to include the risk of decreased serum lithium concentration due to their drug interactions with lithium.^9-10 These regulatory actions were initially prompted by the EMA’s assessment of the periodic safety update reports (PSUR) for empagliflozin, which considered that this drug interaction cannot be excluded for other SGLT2 inhibitors due to the plausible mechanism.¹⁰ In addition, the United States Food and Drug Administration (US FDA) also evaluated this risk and the need for regulatory actions.¹¹ As a consequence, relevant regulatory updates have been reflected in the package inserts for the entire class of SGLT2 inhibitors approved in US (i.e., dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin) and lithium.¹²

The mechanism underlying the reduction in serum lithium concentration following co-administration of SGLT2 inhibitors with lithium can be explained as a pharmacokinetic interaction.^2,4,13 Lithium, predominantly excreted in the urine, can substitute for sodium and be reabsorbed in the PCT via sodium-transporting systems, presumably due to their atomic similarity.^4,5,8,13 Inhibition of SGLT2 likely leads to increased urinary excretion of lithium and decreased serum lithium concentration, which potentially reduce lithium’s therapeutic effectiveness.^4,10,13 While existing theoretical models suggest minimal involvement of SGLTs, a recent literature case report describing positive dechallenge and rechallenge with empaglifozin-induced reduction in serum lithium concentrations suggests a more substantial role of SGLT2 in lithium reabsorption.^4,8

Adverse Drug Reaction Reports

To date, the NPRA has received 509 reports with 874 adverse events suspected to be related to products containing dapagliflozin, empagliflozin, canagliflozin, and lithium.¹⁴ Among these, there have been no reported local cases of drug interactions involving lithium with dapagliflozin, empagliflozin, or canagliflozin. Of note, there have been no reported cases of drug interactions between luseogliflozin and lithium, either locally and globally.^14-15

Advice for Healthcare Professionals

• Be aware that concomitant use of an SGLT2 inhibitor (including dapagliflozin, empagliflozin, and canagliflozin) with lithium may decrease serum lithium concentrations.
• Inform patients or their caregivers to consult doctors if they encounter signs and symptoms of mental disorders aggravation.
• Monitor serum lithium concentration more frequently during treatment with an SGLT2 inhibitor, particularly following initiation or dose changes.
• If reduced serum lithium concentrations are detected, consider titrating the lithium dosage or switching to an alternative treatment.
• Report all adverse events suspected to be related to the use of all types of SGLT2 inhibitors and lithium to the NPRA.

Regulatory Actions

The NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (40) Jld.1] had been issued for all registration holders of products containing dapagliflozin, empagliflozin, canagliflozin, and lithium (for therapeutic use) to update the local package inserts and consumer medication information leaflets (RiMUP—Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

This directive does not apply to health supplement products that contain a relatively small amount of lithium as dietary supplements.

While there is currently insufficient evidence to warrant similar updates to the product information for luseogliflozin, the NPRA will continue to monitor the safety profiles of all SGLT2 inhibitors products.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). FORXIGA (dapagliflozin) [Package Insert]. QUEST3+ Product Search. 2023 May [cited 2024 Apr 12]. Available from: http://www.npra.gov.my.
2. National Pharmaceutical Regulatory Agency (NPRA). JARDIANCE (empagliflozin) [Package Insert]. QUEST3+ Product Search. 2023 Jul 17 [cited 2024 Apr 12]. Available from: http://www.npra.gov.my.
3. National Pharmaceutical Regulatory Agency (NPRA). INVOKANA (canagliflozin) [Package Insert]. QUEST3+ Product Search. 2023 Aug 24 [cited 2024 Apr 12]. Available from: http://www.npra.gov.my.
4. Armstrong GP. Empagliflozin-Mediated Lithium Excretion: A Case Study and Clinical Applications. Am J Case Rep. 2020 Jun 10;21:e923311. Available from: https://doi.org/ 10.12659/AJCR.923311
5. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Mar 13]. Available from: https://www.npra.gov.my
6. National Pharmaceutical Regulatory Agency (NPRA). LICONATE (lithium carbonate) [Package Insert]. QUEST3+ Product Search. 2018 Jun 6 [cited 2024 Apr 12]. Available from: http://www.npra.gov.my.
7. Tondo L, Alda M, Bauer M, Bergink V, Grof P, Hajek T, Lewitka U, Licht RW, Manchia M, Müller-Oerlinghausen B, Nielsen RE, Selo M, Simhandl C, Baldessarini RJ; International Group for Studies of Lithium (IGSLi). Clinical use of lithium salts: guide for users and prescribers. Int J Bipolar Disord. 2019 Jul 22;7(1):16. Available from: https://doi.org/10.1186/s40345-019-0151-2.
8. Shnaider A, Azab AN. Lithium-induced nephrogenic diabetes insipidus-a case report and discussion on the pathophysiological mechanism. Int. J. Nephrol. Kidney Fail. 2015;1(3). Available from: http://dx.doi.org/10.16966/2380-5498.113
9. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 2-5 May 2022 PRAC meeting [Internet]. 2023 Jan 31 [cited 2024 Apr 15]. Available from: https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-2-5-may-2022_en.pdf
10. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 29 Nov- 2 Dec 2021 PRAC meeting [Internet]. 2022 Aug 23 [cited 2024 Apr 15]. Available from: https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-29-november-2-december-2021_en.pdf
11. United States Food and Drug Administration (FDA). January - March 2022 | Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS) [Internet]. 2022 Jul 7 [cited 2022 Oct 28]. https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/january-march-2022-potential-signals-serious-risksnew-safety-information-identified-fda-adverse
12. United States Food and Drug Administration (FDA). Drug Safety-related Labeling Changes (SrLC). (dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, lithium carbonate, lithium citrate). [Internet] 2022 Oct 13 [cited 2024 Apr 15]. Available from: https://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/
13. New Zealand Medicines and Medical Devices Safety Authority (MEDSAFE). Starting empagliflozin or dapagliflozin in patients on lithium? Monitor lithium levels [Internet]. 2023 Mar 2 [cited 2024 Apr 15]. Available from: https://www.medsafe.govt.nz/profs/PUArticles/March2023/Starting-empagliflozin-or-dapagliflozin-in-patients-on-lithium.html
14. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Jan 22]. Available from: https://www.npra.gov.my (access restricted)
15. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2024 [cited 2024 Feb 6]. Available from: https://www.vigilyze.who-umc.org (access restricted)

Written by: Wo Wee Kee
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali