Overview

Bortezomib is a reversible proteasome inhibitor, which is indicated for the treatment of multiple myeloma and mantle cell lymphoma by altering the regulatory proteins that control the progression of the cell cycle causing its arrest and apoptosis.^1,2 It has been found to significantly increase the patients' overall survival.³ In Malaysia, there are currently nine (9) bortezomib products registered with the Drug Control Authority (DCA) as parenteral formulations.¹

Peripheral neuropathy is a well-known adverse effect associated with bortezomib use.⁴ Recently, bortezomib has been associated with two other adverse effects related to peripheral neuropathy which are Guillain-Barré syndrome (GBS) and demyelinating polyneuropathy. GBS and demyelinating polyneuropathy are rare autoimmune disorders that affect the peripheral nerves and nerve roots, which may cause paralysis and difficulty breathing that eventually lead to death, if not treated.^2,5

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) has received information from the European Medicines Agency (EMA) on the risk of GBS and demyelinating polyneuropathy linked to bortezomib use.⁶

Based on all evidence from the literature and adverse event reports, including cases that involved a close temporal relationship and positive de-challenge, and in view of a plausible mechanism of bortezomib, the EMA concluded that a causal relationship between bortezomib and the risk of GBS and demyelinating polyneuropathy is at least a reasonable possibility.⁶ Following this conclusion, EMA has requested all product registration holders of bortezomib-containing products to update the package insert with the risk of Guillain-Barré syndrome and demyelinating polyneuropathy.

Adverse Drug Reaction (ADR) Reports

To date, NPRA has received 92 reports with 161 adverse events suspected to be related to bortezomib.⁷ There have been seven (7) reports of peripheral neuropathy and one (1) report on tingling sensation, but no reports of GBS or demyelinating polyneuropathy associated with bortezomib received so far. Other most frequently reported adverse events for bortezomib were diarrhoea (17), pneumonia (6), constipation (4), bronchitis (3), and thrombocytopenia (3).

Advice for Healthcare Professionals

• Carefully consider the risk of Guillain-Barré syndrome and demyelinating polyneuropathy in patients on bortezomib therapy, especially in patients with pre-existing severe neuropathy.
• Educate patients on the signs and symptoms such as weakness and tingling sensation in legs, spreading to upper body and arms, or loss of reflexes such as knee jerk.
• Consider dose reduction or withhold bortezomib therapy for patients with new or worsening peripheral neuropathy.
• Report all suspected adverse events associated with bortezomib to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (30)] has been issued for registration holders of bortezomib-containing products to update the local package inserts with this new safety information.

References:

1. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). Bortezomib local package insert [Internet]. Revision date: July 2019 [Cited on 2021 July 12]. Available from https://www.npra.gov.my.
2. Herráez-Albendea M, Amorós-Paredes A, Marta Arteta-Jiménez M. Guillain-Barré syndrome of a patient under bortezomib treatment. Farmacia Hospitalaria. 2020 [Cited 2021 July 12]; 44(2):77-78. Available from https://www.redalyc.org/jatsRepo/3659/365964755008/365964755008.pdf.
3. Xu Y, Zhao W, Tang Z, Li Z, Long Y, Cheng P et al. Guillain-Barré syndrome in a patient with multiple myeloma after bortezomib therapy: A case report. World Journal of Clinical Cases. 2019 [Cited 2021 July 12]; 7(18):2905-2909. Available from https://www.wjgnet.com/2307-8960/full/v7/i18/2905.htm.
4. Thawani S, Tanji K, De Sousa E, Weimer L, Brannagan T. Bortezomib-Associated Demyelinating Neuropathy—Clinical and Pathologic Features. Journal of Clinical Neuromuscular Disease. 2015 [Cited 2021 July 12]; 16(4):202-209. Available from https://journals.lww.com/jcnmd/Abstract/2015/06000/Bortezomib_Associated_Demyelinating.2.aspx.
5. The University of Chichago. Types of Peripheral Neuropathy - Inflammatory [Internet]. 2021 [Cited 2021 July 12 ]. Available from http://peripheralneuropathycenter.uchicago.edu/learnaboutpn/typesofpn/inflammatory/index.shtml.
6. European Medicines Agency. Annex I Scientific Conclusions and Grounds for the Variation to the Terms of the Marketing Authorisation(s) [Internet]. 2021 [cited 2021 July 12]. Available from https://www.ema.europa.eu/en/documents/scientific-conclusion/bortezomib-accord-h-c-psusa-00000424-202004-epar-scientific-conclusions-grounds-variation-terms_en.pdf.
7. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2021 [Cited 2021 July 12]. Available from https://www.npra.gov.my.

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.