This information is an update to the NPRA Safety Alerts: Betamethasone (Systemic): Risk of Pheochromocytoma Crisis published on 6 April 2022.

Overview

Corticosteroids are anti-inflammatory drugs indicated for a wide range of conditions such as asthma and arthritis.¹ Among the corticosteroids available for systemic use include  betamethasone, dexamethasone, prednisolone, methylprednisolone, triamcinolone, and hydrocortisone²

Background of the 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.^3-5

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, and an update to the product information for all systemic betamethasone-containing products is warranted.⁶ On the other hand, Health Canada has also reviewed this safety issue and concluded that pheochromocytoma crisis is a class effect for all systemic corticosteroids.⁷

The exact pathophysiology of pheochromocytoma crisis induced by systemic corticosteroids 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 a few hours to a few days after systemic corticosteroid administration.^9-17 Once symptoms appeared, it has been observed that the patient's condition can deteriorate rapidly.⁹

Adverse Drug Reaction Reports¹⁸

The NPRA has received 1,174 reports with 2,153 adverse events suspected to be related to products containing systemic corticosteroids. No local cases of pheochromocytoma crisis following the use of systemic corticosteroids have been reported to the NPRA thus far. However, there were one (1) report of hypertension emergency, eight (8) reports of hypertension, and eight (8) reports of hypotension received by the NPRA.

Advice for Healthcare Professionals

• Pheochromocytoma crisis is associated with significant mortality. Administer systemic corticosteroids 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 corticosteroid 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 a 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 corticosteroids to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (6) Jld.1] has been issued for all registration holders of products containing corticosteroids for systemic use to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. NHS Inform. Corticosteroids [Internet]. 2022 [cited 2022 Jun 1]. Available from: https://www.nhsinform.scot/tests-and-treatments/medicines-and-medical-aids/types-of-medicine/corticosteroids
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2022 [cited 2022 Jun 1]. Available from: https://quest3plus.bpfk.gov.my/pmo2/index.php
3. Bartikoski SR, Reschke DJ. Pheochromocytoma crisis in the emergency department. Cureus. 2021;13(3): e13683. Available from: https://doi.org/10.7759%2Fcureus.13683
4. 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
5. 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
6. 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 Jun 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
7. Health Canada. Health Product InfoWatch. 2021 May [cited 2022 Jun 1]. Available from: https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/medeffect-canada/health-product-infowatch/may-2021/hpiw-ivps_2021-05-eng.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. Dong WY, Sun YK, Dong HS, Yang HK, Seok MS. Pheochromocytoma crisis after a dexamethasone suppression test for adrenal incidentaloma. Endocrine. 2010;37:213–219. Available from: https://doi.org/10.1007/s12020-009-9303-y
15. Chuen JY, Shin YN, Goh BKP. Pheochromocytoma multisystem crisis triggered by glucocorticoid administration and aggravated by citrate dialysis. A & A Case Reports. 2017;8(3):58-60. Available from: https://doi.org/10.1213/xaa.0000000000000423
16. Jee YA, Dong RK, Jong YO, Yang CH, Il SL, Tae JK, Bong RC. A case of recurrent glucocorticoid-induced pheochromocytoma crisis during the treatment of urticaria. Korean Journal of Medicine 88(5):564. Available from: http://dx.doi.org/10.3904/kjm.2015.88.5.564
17. Nobuyuki T, Toshio S, Kazuaki T, Hiroyuki Y, Yo M, Yutaka I, Reiko K, Seiji Y, Asuka A, Akira I. Steroid-induced crisis and rhabdomyolysis in a patient with pheochromocytoma: A case report and review. International Journal of Cardiology. 2011;146:41–45. Available from: http://dx.doi.org/ 1016/j.ijcard.2008.12.183    
18. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2022 [cited 2022 Jun 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