Pseudoephedrine and the rare risk of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS)

Pseudoephedrine is a sympathomimetic agent widely used to relieve nasal congestion by vasoconstricting the blood vessels in the nasal passages. It is often combined with other active ingredients such as antihistamines and antipyretics to treat common cold or allergic symptoms. Pseudoephedrine-containing products have been registered in Singapore since 1989 and there are 31 products currently registered. Of these, one is a Prescription Only Medicine while the others are Pharmacy Only Medicines. A few overseas cases of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) have been reported with the use of pseudoephedrine. 

Postulated role of pseudoephedrine in causing PRES and RCVS1-3

The use of vasoactive agents such as pseudoephedrine has been postulated to play a contributory role in the development of PRES or RCVS, which are rare neurological conditions involving cerebral ischaemia. Although the pathogenesis of PRES and RCVS remains unclear, potential mechanisms include acute blood pressure changes and cerebral vascular autoregulation dysfunction, which could be induced by vasoconstriction.  

PRES typically presents with headaches, visual deficits, mental changes, seizures and brain oedema. Several risk factors have been identified, including immunosuppression, sepsis, pre-eclampsia, renal failure, autoimmune disorders and hypertension. Prognosis is generally favourable because clinical symptoms and imaging lesions are reversible in most patients. 

RCVS is characterised by cerebral vasoconstriction, which typically follows a self-limiting course in disease progression, although RCVS-like vasoconstriction may also be observed in PRES. Its symptoms include thunderclap headaches accompanied by other clinical manifestations such as seizures, encephalopathy, and focal neurological deficits. The majority of patients with RCVS have a favourable prognosis, whereby headaches and angiographic abnormalities resolve within days or weeks upon the identification and elimination of any precipitating factors.

International regulatory actions

The European Medicines Agency (EMA) and UK Medicines and Healthcare products Regulatory Agency (MHRA) have completed their safety assessments on the risk of PRES and RCVS associated with pseudoephedrine.^4,5 Their reviews considered information from post-marketing safety data and advice sought from their pharmacovigilance expert groups. The EMA acknowledged that while PRES and RCVS could lead to serious and life-threatening complications, these are rare conditions that generally resolve with prompt diagnosis and treatment. The UK MHRA’s review noted four reports of suspected PRES or RCVS with pseudoephedrine in the context of over 4 million packets sold in the UK in 2022 alone. Both agencies have contraindicated the use of pseudoephedrine in patients with severe or uncontrolled hypertension or severe renal disease, which are risk factors for PRES and RCVS, and recommended for the addition of warnings on these adverse events to the package inserts (PIs) or patient information leaflets (PILs) of pseudoephedrine-containing products. They have also recommended for healthcare professionals to advise their patients to stop using these products immediately and seek treatment if they develop symptoms of PRES or RCVS.

Local situation

To date, HSA has not received any local adverse event report of PRES or RCVS associated with pseudoephedrine despite its long history and widespread use. In March 2024, one of the product registrants issued a Dear Healthcare Professional Letter (DHCPL) to notify healthcare professionals about the risks of PRES and RCVS associated with the use of pseudoephedrine.⁶ HSA will work with the product registrants to strengthen the warnings on PRES and RCVS and their related symptoms in the PIs or PILs of pseudoephedrine-containing products registered locally. 

HSA’s advisory 

PRES and RCVS are rare and reversible conditions, and most patients fully recover with early recognition and appropriate treatment. Healthcare professionals are advised to take note of the advisories by the EMA and UK MHRA. They may also consider counselling their patients on symptoms that require immediate medical attention to facilitate the prompt detection of PRES and RCVS symptoms and the necessary medical intervention. These include sudden onset of severe headache, nausea, vomiting, visual disturbances, seizures and altered mental status. 

References

1. J. Stroke Cerebrovasc. Dis. 2022; 31: 106472

2. Front. Neurol. 2020; 11: 34

3. J. Neurol. 2023; 270: 673-88

4. https://www.ema.europa.eu/en/medicines/human/referrals/pseudoephedrine-containing-medicinal-products

5. https://www.gov.uk/drug-safety-update/pseudoephedrine-very-rare-risk-of-posterior-reversible-encephalopathy-syndrome-pres-and-reversible-cerebral-vasoconstriction-syndrome-rcvs

6. https://www.hsa.gov.sg/announcements/dear-healthcare-professional-letter/zyrtec-d---risks-of-posterior-reversible-encephalopathy-syndrome-and-reversible-cerebral-vasoconstriction-syndrome-associated-with-the-use-of-pseudoephedrine