The NPRA has issued a new safety alert about this safety issue, see the NPRA Safety Alerts: Corticosteroids (Systemic): Risk of Pheochromocytoma Crisis issued on 19 July 2022. 

Overview

Betamethasone is a corticosteroid used to treat acute and chronic corticosteroid-responsive disorders including rheumatoid arthritis, bronchial asthma and dermatitis.^1-2

In Malaysia, there are currently seven (7) products containing betamethasone (systemic) that had been registered with the Drug Control Authority (DCA). Of these, five (5) products are in parenteral form and two (2) products are in oral form.³

Background of Safety Issue

Pheochromocytoma is a rare and often undiagnosed catecholamine-secreting tumour that grows in adrenal glands, specifically from the cells known as chromaffin cells. The clinical presentations of pheochromocytomas are widely variable but typically include hypertension, palpitations, sweating, and headache. On rare occasions, patients may experience sudden surges in catecholamine release and develop haemodynamic instability, which may lead to end-organ damage or dysfunction. This emergency situation is known as pheochromocytoma crisis.^4-6

Based on evidence from literature reports, including two describing a positive rechallenge with betamethasone, the European Medicines Agency (EMA) concluded that there is a close temporal relation between systemic betamethasone use and pheochromocytoma crisis. Additionally, considering the literature reports of pheochromocytoma crisis in association with other corticosteroids suggesting a class effect, and the serious and potentially life-threatening nature of the condition, an update to the product information for all systemic betamethasone-containing products is warranted.⁷

The exact pathophysiology of pheochromocytoma crisis induced by systemic betamethasone use has not been fully elucidated. However, several mechanisms have been postulated, including corticosteroids’ ability to enhance the action of catecholamines on peripheral vessels and the heart, eventually causing vasculopathy, tissue necrosis, and haemorrhage. Another hypothesis suggests that increased corticosteroid receptor expression may alter the sensitivity of pheochromocytomas to corticosteroids and subsequently cause catecholamine synthesis and release.^8-9

The onset of pheochromocytoma crisis has been reported ranging from 12 hours to two (2) days after betamethasone administration.^8-13

Adverse Drug Reaction Reports¹⁴

The NPRA has received seven (7) reports with 16 adverse events suspected to be related to systemic betamethasone-containing products, which include palpitations (2) and diaphoresis (1). No local cases of pheochromocytoma crisis following the use of systemic betamethasone have been reported to NPRA thus far.

Advice for Healthcare Professionals 

• Pheochromocytoma crisis is associated with significant mortality. Administer systemic corticosteroids like betamethasone to patients with suspected or identified pheochromocytoma only after an appropriate risk/benefit evaluation.
• Consider the diagnosis of pheochromocytoma crisis in any patient developing hypertensive crisis, cardiac failure, tachycardia, headache, and abdominal or chest pain after systemic corticosteroids administration. Prompt confirmation of the diagnosis followed by optimal management is essential to improve patient survival.
• Patients with pheochromocytoma crisis should be managed in an intensive care environment to enable appropriate monitoring and circulatory support and general supportive care. In each case, tailor specific treatment decisions to reflect which organ systems are involved.
• The role of emergency surgery without prior medical stabilisation in pheochromocytoma crisis is controversial but is widely agreed to carry significant risks. In almost all cases, it would be appropriate to attempt surgery only after medical stabilisation has been achieved.
• Report all suspected adverse events associated with products containing systemic betamethasone to the NPRA.

References: 

1. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). DIPROSPAN (betamethasone) Injection (5ml) [Package Insert]. 2021 Aug [cited 2022 Mar 1]. Available from: http://www.npra.gov.my (access restricted)
2. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). YSP Betamethasone Tablet 0.5mg [Package Insert]. 2017 Mar [cited 2022 Mar 1]. Available from: http://www.npra.gov.my (access restricted)
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2021 [cited 2022 Mar 1]. Available from: https://www.npra.gov.my
4. Bartikoski SR, Reschke DJ. Pheochromocytoma crisis in the emergency department. Cureus. 2021;13(3): e13683. Available from: https://dx.doi.org/10.7759%2Fcureus.13683
5. Whitelaw BC, Prague JK, Mustafa OG, Schulte KM, Hopkins PA, Gilbert JA, McGregor AM, Aylwin SJB. Phaeochromocytoma crisis. Clinical Endocrinology. 2014;80:13–22. Available from: https://doi.org/1111/cen.12324
6. Meijs AC, Snel M, Corssmit EPM. Pheochromocytoma/paraganglioma crisis: case series from a tertiary referral center for pheochromocytomas and paragangliomas. Hormones (Athens). 2021;20(2):395–403. Available from: https://dx.doi.org/10.1007%2Fs42000-021-00274-6 
7. European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation(s) – Betamethasone [Internet]. 2021 Oct [cited 2022 Mar 1]. Available from: https://www.ema.europa.eu/en/documents/psusa/betamethasone-cmdh-scientific-conclusions-grounds-variation-amendments-product-information-timetable/00000391/202101_en.pdf 
8. Dupont MF, Battista MC, Comeau E, Chababi MA, Perron P, Chamberland M. Corticosteroid-induced case of a lightning pheochromocytoma crisis: Insight into glucocorticoid receptor expression. Integrative Cancer Science and Therapeutics. 2016;3(1):345-348. Available from: http://dx.doi.org/10.15761/ICST.1000167 
9. Rosas AL, Zaluska AAK, Papierska L, Bass BL, Pacak K, Eisenhofer G. Pheochromocytoma crisis induced by glucocorticoids: a report of four cases and review of the literature. European Journal of Endocrinology. 2008;158(3):423–429. Available from: https://doi.org/10.1530/EJE-07-0778 
10. Langton K, Gruber M, Masjkur J, Steenblock C, Peitzsch M, Meinel J, Lenders J, Bornstein S, Eisenhofer G. Hypertensive crisis in pregnancy due to a metamorphosing pheochromocytoma with post-delivery Cushing's syndrome. Gynaecological Endocrinology. 2017;34(1):1-5. Available from: https://doi.org/10.1080/09513590.2017.1379497 
11. Rashid-Farokhi F, Cheraghvandi A, Masjedi MR. Pheochromocytoma crisis due to glucocorticoid administration: a case report and review of the literature. Arch Iranian Med. [Internet] 2009 [cited 2022 Mar 1];12 (2):190-194. Available from: https://pubmed.ncbi.nlm.nih.gov/19249894/ 
12. Tomoyasu M, Mori Y, Fukase A, Kushima H, Hirano T. Pheochromocytoma presenting with severe hyperglycemia and metabolic acidosis following intra-articular glucocorticoid administration: a case report. Journal of Medical Case Reports. 2019;13:3. Available from: https://doi.org/10.1186/s13256-018-1945-z 
13. Taimur SDM, Karim MR, Rahman MH, Gomes HI, Salahuddin M, Farzana I, Fahmida AS. Pheochromocytoma with hypertensive crisis due to glucocorticoid administration: a case report and review of the literature. Bangladesh Journal of Medical Science. 2011;10(3), 213–215. Available from: https://doi.org/10.3329/bjms.v10i3.8369 
14. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2022 [cited 2022 Mar 1]. 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: Ng Chiew Seng

Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr Azuana Ramli