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

Pseudoephedrine, an alpha-adrenergic receptor agonist is used for the symptomatic relief of nasal or sinus congestion caused by common cold, flu, sinusitis, and other conditions.¹ This vasoactive agent functions as a decongestant by constricting dilated arterioles in the nasal mucosa, thereby reducing blood flow.^1,2

In Malaysia, all preparations containing ephedra alkaloids, including pseudoephedrine, are classified as Group C items, which can only be sold as dispensed medicines with an entry in the Prescription Book.^3,4 There are currently 62 pseudoephedrine-containing products registered with the Drug Control Authority (DCA).⁵ These registered products are all available in combination with antihistamines (e.g., loratadine, triprolidine, fexofenadine), analgesic (e.g., paracetamol), and/or antitussives (e.g., dextromethorphan).

Posterior Reversible Encephalopathy Syndrome (PRES) is a disorder manifests as vasogenic oedema primarily affecting the parieto-occipital regions, and is associated with the sudden onset of neurological symptoms such as encephalopathy, seizures, headache, altered mental status, focal neurologic deficit, and visual disturbances.^1,6

Reversible Cerebral Vasoconstriction Syndrome (RCVS) is a medical condition characterised by multifocal arterial constriction and dilation in the cerebral vasculature, which may be linked to non-aneurysmal subarachnoid haemorrhage.^1,7 The clinical manifestation of RCVS typically includes thunderclap headache (sudden severe pain with posterior onset followed by diffuse pain frequently accompanied by nausea, vomiting, photophobia, and phonophobia). RCVS may occur with or without the presence of ischaemia or other acute neurological symptoms.

In general, PRES and RCVS affects a wide age range, with a higher risk in the female population.^1,2,6-8 Similar patterns have also been observed in pseudoephedrine-associated cases, where all reported patients in published case reports were female, aged 18-58 years old.^2,8-10

 

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) has learned from the European Medicines Agency (EMA) regarding the risk of PRES and RCVS associated with the use of pseudoephedrine.¹¹

The EMA endorsed the recommendation to contraindicate pseudoephedrine-containing products in patients with (i) severe or uncontrolled hypertension or (ii) severe acute or chronic kidney disease or renal failure, as these are risk factors for developing PRES or RCVS.¹² The EMA also recommended updating the product information for all pseudoephedrine-containing medicines to include restrictions and warnings about the risks concerning PRES and RCVS.

This decision was based on the compatible and suggestive time to onset, biological plausibility, and the lacking of alternative aetiologies observed in some patients without any known risk factors for PRES and RCVS, following the EMA’s review of all available evidence, including post-marketing safety data.^1,12 The EMA also considered opinions from a diverse panel of medical experts, as well as input from patient and healthcare representatives.

During the review, the EMA conducted an analysis of case reports for PRES and RCVS available in the EudraVigilance (EV) database.¹ The reported time to onset ranged from 1 hour to 10 days. Most cases reported duration of pseudoephedrine use for within 1 week; of note, 5 reports documented prolonged or habitual pseudoephedrine consumption. While PRES and RCVS can be life-threatening and fatal, they are generally reversible or resolved with prompt diagnosis and management.^1,6,7 This was observed in the EV analysis, where more than half of the patients had favourable outcomes (recovered or showing signs of recovery), 5 recovered with sequalae, and no fatal cases were reported.¹

Overall, the number of case reports documenting PRES or RCVS in EV was not considered high relative to the high patient exposure to pseudoephedrine.¹ Risk factors for PRES and RCVS were present in most cases, including, but are not limited to, hypertension, renal disease, sepsis, autoimmune disease, acute kidney injury, concomitant use of certain medications, and history of migraine. There was also no data confirming a dose-response relationship.

The exact pathophysiology of pseudoephedrine-associated PRES and RCVS are not clearly elucidated.^1,2,6-10 PRES and RCVS can occur simultaneously and overlapping pathophysiological mechanisms have been proposed in the literature.^6,7 Potential mechanisms include abrupt fluctuations of blood pressure and dysfunction in cerebral vascular autoregulation, possibly induced by vasoconstriction.^6,7,13

 

Adverse Drug Reaction Reports

To date, the NPRA has received 220 reports with 442 adverse events suspected to be related to pseudoephedrine-containing products.¹⁴ The most frequently reported adverse events are pruritus (40 reports), rash (35), and dyspnoea (30). To date, no local reports of PRES or RCVS related to pseudoephedrine have been received. However, there were reports of seizure (2), hypertension (1), blood pressure increased (2), and headache (6). Considering the co-reported adverse events documented in these reports, the symptoms were not suggestive of PRES or RCVS.

 

Advice for Health Care Professionals

• While NPRA is still reviewing this safety issue, be aware that there have been post-marketing ADR reports of PRES or RCVS associated with the use of pseudoephedrine.
• It is important to obtain patient’s medical history (particularly severe or uncontrolled hypertension or severe renal disease) when considering prescribing pseudoephedrine-containing product and to prescribe it cautiously.
• Advise patients to monitor for signs and symptoms of PRES/RCVS, such as severe headache with a sudden onset, feeling sick, vomiting, confusion, seizures, and/or changes in vision. Remind them to stop taking pseudoephedrine and seek immediate medical attention if these symptoms occur.
• Early recognition of PRES/RCVS, prompt discontinuation of suspected drug, and initiation of appropriate treatment are crucial to reduce morbidity and mortality.
• Report all adverse events suspected to be related to the use of pseudoephedrine-containing products to the NPRA.

  

References:

1. European Medicines Agency (EMA). Assessment report [Internet]. 2023 Nov 30 [cited 2024 Apr 19]. Available from: https://www.ema.europa.eu/en/documents/referral/pseudoephedrine-containing-medicinal-products-article-31-referral-assessment-report_en.pdf
2. Farid H, Tatum JK, Wong C, Halbach VV, Hetts SW. Reversible cerebral vasoconstriction syndrome: treatment with combined intra-arterial verapamil infusion and intracranial angioplasty. AJNR Am J Neuroradiol. 2011 Nov-Dec;32(10):E184-7. Available from: https://doi.org/10.3174/ajnr.A2341
3. Pharmaceutical Services Programme. Poisons List First Schedule [Internet]. 2023 [cited 2024 Apr 19]. Available from: https://pharmacy.moh.gov.my/sites/default/files/document-upload/poisons-list-pua-306.2023-18.10.2023_2.pdf
4. Malaysia Regulatory Classification [Internet]. MIMS; 2024 [cited 2024 Apr 19]. Available from: https://www.mims.com/malaysia/viewer/html/poisoncls.htm
5. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Jul 17]. Available from: https://quest3plus.bpfk.gov.my/pmo2/index.php
6. Jeanneret V, Jillella DV, Rangaraju S, Groover O, Peterson R, Koneru S, Nahab F, Kase CS. PRES and RCVS: Two Distinct Entities or a Spectrum of the Same Disease? J Stroke Cerebrovasc Dis. 2022 Jun;31(6):106472. Available from: https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106472
7. Ribas MZ, Paticcié GF, de Medeiros SDP, de Oliveira Veras A, Noleto FM, Dos Santos JCC. Reversible cerebral vasoconstriction syndrome: literature review. Egypt J Neurol Psychiatr Neurosurg. 2023;59(1):5. Available from: https://doi.org/10.1186/s41983-023-00607-9
8. Dakay K, McTaggart RA, Jayaraman MV, Yaghi S, Wendell LC. Reversible cerebral vasoconstriction syndrome presenting as an isolated primary intraventricular hemorrhage. Chin Neurosurg J. 2018 Jun 4;4:11. Available from: https://doi.org/10.1186/s41016-018-0118-7
9. Zerbib Y, Gibert L, Bennis Y, Masmoudi K, Maizel J, Brault C. Posterior Reversible Encephalopathy Syndrome After Self-Medication With an Oral Decongestant: A Case Report. Front Med (Lausanne). 2022 Mar 7;9:837324. Available from: https://doi.org/10.3389/fmed.2022.837324
10. Ebbo M, Benarous L, Thomas G, Jourde N, Genot S, Bernit E, Veit V, Harlé JR, Schleinitz N. Syndrome d'encéphalopathie postérieure réversible induit par un décongestionnant nasal contenant de la pseudo-éphédrine [Posterior reversible encephalopathy syndrome induced by a cough and cold drug containing pseudoephedrine]. Rev Med Interne. 2010 Jun;31(6):440-4. French. Available from: https://doi.org/10.1016/j.revmed.2009.10.436
11. European Medicines Agency (EMA). PRAC recommends measures to minimise the risk of serious side effects with medicines containing pseudoephedrine [Internet]. 2023 Dec 1 [cited 2024 Apr 19]. Available from: https://www.ema.europa.eu/en/documents/referral/prac-recommends-measures-minimise-risk-serious-side-effects-medicines-containing-pseudoephedrine_en.pdf
12. European Medicines Agency (EMA). Pseudoephedrine-containing medicinal products - referral [Internet]. 2024 Jan 26 [cited 2024 Apr 19]. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/pseudoephedrine-containing-medicinal-products
13. Health Sciences Authority (HSA). Pseudoephedrine and the rare risk of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) [Internet]. 2024 Apr 29 [cited 2024 May 13]. Available from: https://www.hsa.gov.sg/announcements/safety-alert/pseudoephedrine-and-the-rare-risk-of-posterior-reversible-encephalopathy-syndrome-(pres)-and-reversible-cerebral-vasoconstriction-syndrome-(rcvs )
14. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Feb 29]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Wo Wee Kee

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