Pseudoephedrine (PSE) is widely used as an oral decongestant treatment for nasal and sinus congestion, and over 400 products containing PSE alone or in combination with other medicines, such as analgesics, antihistamines and cough medicines are marketed in the European Union (EU) and the United Kingdom (UK) [1] . A review by the European Medicines Agency (EMA) has found that PSE-containing medicines are associated with risks of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS). PRES and RCVS are rare but serious conditions that affect the blood supply to the brain [2] . On 25 January 2024, EMA’s human medicines committee (CHMP) endorsed the measures recommended by the Pharmacovigilance Risk Assessment Committee (PRAC) to minimise the risks of (PRES) and (RCVS) for medicines containing PSE. PRAC recommended that there was a need to inform healthcare professionals (HCPs) as early as possible by Direct Healthcare Professional Communication (DHPC) and update the product information for PSE concerning potential risks for PRES and RCVS. No fatal cases of PRES or RCVS have been reported, and most of the cases resolved following discontinuation of the medicine and appropriate treatment [2] . In response to EMA recommendation, the European Commission issued a Decision on 27 March 2024 that Marketing Authorisation Holders should amend their respective centralised and national marketing authorisations for products containing PSE to include reference to contraindications and special warnings concerning PRES and RCVS [1] . The pack instructions to patients now state that PSE should not be used in patients with severe or uncontrolled hypertension and severe acute or chronic kidney disease or failure. However, a post-authorization safety study was conducted in 151 cardiology centres and 78 neurology centres in France to assess the risk of MI and stroke after the use of vasoconstrictors (oral PSE or nasal drugs with vasoconstricting agents) found no increase in these adverse cardiovascular outcomes [3] . Additionally, it is recommended that HCPs should counsel patients to discontinue the use of PSE promptly and seek medical assistance if they experience symptoms suggesting PRES or RCVS, such as sudden onset of severe headache, confusion, vomiting, visual disturbances or seizures [4] .

Considering the recent reviews by European regulatory authorities on the benefit-risk profile of PSE, it was considered useful to review the pharmacology of PSE relevant to any potential risk for the onset of PRES or RCVS.

The starting point for the literature was the references in the PRAC Rapporteur’s and Co-rapporteur’s updated assessment reports on the benefit-risk assessment of PSE in relation to PRES and RCVS [5] [6] . Citation reports for relevant articles in the PRAC report were made on the Web of Science.

This review will be divided into the following sections: Indications for treatment with PSE, Pharmacology of PSE, Role of sympathetic nervous system in nasal and cerebral circulations, Efficacy of PSE as a decongestant, Benefits of treatment with PSE, Posterior Reversible Encephalopathy Syndrome (PRES), Reversible Cerebral Vasoconstriction Syndrome RCVS, Benefit-Risk Assessment of PSE, Conclusions, References.

PSE is taken orally for the symptomatic treatment of congestion in the nasal cavity, paranasal sinuses and the Eustachian tube associated with acute upper respiratory tract viral infections (URTI) and allergic rhinitis [7] . Other indications include vasomotor rhinitis, and otitis media [8] . The main indications for treatment with PSE are nasal congestion associated with the common cold and flu and allergic rhinitis.

PSE is a stereoisomer of ephedrine and has a structure similar to noradrenaline [9] as illustrated in Figure 1 .

PSE is a sympathomimetic with a mixed mechanism of action with both direct and indirect effects on alpha and beta adrenergic receptors [8] as illustrated in Figure 2 . PSE exerts its indirect effects by inhibiting the uptake of noradrenaline [10] [11] and by displacing noradrenaline from sympathetic nerve endings [11] .

PSE can also directly stimulate alpha and beta adrenoceptors on blood vessels and cardiac beta receptors [11] . The cardiovascular effects of PSE are believed to be almost completely due to its actions on sympathetic nerve endings, causing noradrenaline release from the nerve endings and inhibiting uptake of noradrenaline into nerve endings, and PSE has little direct action on adrenoceptors. PSE acts on blood vessels via the release of noradrenaline, which acts on alpha 1 receptors to cause vasoconstriction. Noradrenaline also acts on beta receptors and causes an increase in heart rate by stimulation of beta 1 receptors.

Preclinical studies provide evidence that PSE acts via the release of noradrenaline from nerve endings. A study on anaesthetized rats reported that PSE caused a dose dependent increase in arterial blood pressure and heart rate and that these effects were abolished after destruction of the sympathetic nerve terminals with 6-hydroxydopamine (6-OHDA) pretreatment [11] . This demonstrates that in this model, the effects of PSE on the cardiovascular system are mediated entirely by its indirect actions, and that PSE does not have any direct effects on adrenoceptors on blood vessels or the heart. A similar result was found when using the rat anococcygeal muscle as PSE caused contraction of the muscle but this contractile response to PSE was abolished after destruction of sympathetic nerve terminals with 6-OHDA pretreatment [11] .

PSE acts by releasing noradrenaline from sympathetic nerves and therefore it is important to understand the effects of sympathetic nerve stimulation on nasal and cerebral blood vessels.

PSE has been used as a nasal decongestant since 1954 and has been available as an OTC product since 1960 [26] . The efficacy of PSE for symptomatic relief of nasal congestion associated with common cold/flu and allergic rhinitis is not questioned by regulatory authorities and there are many studies demonstrating efficacy of PSE alone or in combination with other medicines in these conditions [27] - [31] .

PSE-containing medicinal products are available in various oral dosage forms, alone and in combination with antihistamines, analgesics and/or cough suppressants.

PSE-containing medicinal products are mainly indicated for adults and adolescents from the age of 12 years, however, in some member states of the EU, there are some products indicated for children from 6 years of age. PSE is generally not recommended for children under 6 years since the efficacy and safety are not established in this age group.

Its oral adult single dose ranges from 30 to 120 mg as a hydrochloride or sulphate. Most commonly, a maximum intake of 180 mg to 240 mg of PSE daily is recommended by labels.

Nasal congestion is a common symptom associated with common cold/flu and allergic rhinitis [32] . Approximately 10% - 20% of the global population suffer from allergic rhinitis and upper respiratory tract viral infections such as the common cold/flu, which are the most common human diseases [33] . Viral infections and allergic responses in the nose cause inflammation and dilation of nasal airway blood vessels and swelling of nasal venous erectile tissue to cause nasal obstruction and difficulty breathing through the nose [34] [35] .

The major benefit of treatment with PSE in common cold/flu and nasal allergy is decongestion of blood vessels in the nasal airway, and because of the dense sympathetic innervation of these blood vessels and their great sensitivity to sympathomimetics, decongestion occurs with minimal effects on the cardiovascular system [20] .

Nasal congestion associated with common cold/flu and nasal allergy can affect quality of life in several different ways: by causing nasal obstruction, by congesting the ostia of the paranasal sinuses, by congesting the pharyngeal orifice of the pharyngotympanic tube (Eustachian tube).

Nasal congestion has a big impact on the quality of life, “Symptoms, such as nasal congestion, cause high rates of absenteeism as well as ‘presenteeism,’ where employees are present but underperforming” [32] . To better understand and appreciate the burden of allergy on the American population, a comprehensive national survey named “Allergies in America” was conducted in January 2006 and survey participants reported a “stuffed-up nose” to be the most bothersome symptom of nasal allergies, and nearly 80% of respondents listed a stuffed-up nose as “extremely” or “moderately” bothersome during a nasal allergy attack [32] . In a telephone survey on American patients with allergic rhinitis Shedden (2005) [36] reported that “Nasal congestion was the symptom that most adults and children wished to prevent, and it affected most respondents at work or school, had a notable emotional impact, and interfered with their ability to perform daily activities”.

Posterior reversible encephalopathy syndrome (PRES) is a “syndrome of diverse clinical symptoms including visual disturbance, headache, seizures and impaired consciousness. MRI shows oedema, usually involving the posterior subcortical regions. Triggering factors include hypertension, pre-eclampsia/eclampsia, renal failure, cytotoxic agents and autoimmune conditions. The mechanism underlying PRES is not certain, but endothelial dysfunction is implicated” [53] . Figure 3 summarises current knowledge about PRES as reviewed by Triplett et al. (2022) [53] .

PRES has a higher incidence in females and is found in 98% of women with eclampsia and is often associated with hypertension but is also found in patients with normal or even low blood pressure [54] .

The mechanisms and pathophysiology of PRES are unknown. However, cerebral endothelial damage and disruption of the blood-brain barrier are known to cause vasogenic oedema [55] . Immunogenic medications, particularly immunosuppressive medicines, are implicated in causing PRES [53] [56] . In a worldwide analysis

of medicines associated with PRES using the World Health Organisation pharmacovigilance database Balcerac et al. (2023) analysed 3,278 cases of PRES and identified 73 molecules statistically associated with PRES and found that “the main drug classes involved were antineoplastic and immunomodulating agents and the drugs with the greatest number of cases were tacrolimus, cyclosporin, bevacizumab, methotrexate, and vincristine” [56] and this supports an immunogenic mechanism for PRES. Nasal decongestants such as PSE were not listed amongst 73 medicines potentially associated with PRES based on disproportionality analysis of 3,278 cases reported to VigiBase, the World Health Organization pharmacovigilance database [56] .

Reversible Cerebral Vasoconstriction Syndrome (RCVS) is associated with sudden severe headache (thunderclap headache) and reversible multifocal cerebral vasoconstriction, and it is more prevalent in women as it often occurs shortly after pregnancy (puerperium) [57] . “The main precipitating factors described are: postpartum state, drugs with vasoactive properties, such as cocaine, marijuana, and heroin, catecholamine-secreting tumors, autoimmune disorders, such as systemic vasculitis, systemic lupus erythematous, antiphospholipid syndrome, blood transfusions, ginseng, sexual intercourse, temperature differences (baths too hot or too cold), air travel, Corona Virus Disease 2019 (COVID-19) infection and medications”. Figure 4 summarises current knowledge about PRES as reviewed by Ribas et al. (2023) [57] and Song et al. (2021) [58] .

Brain imaging shows that RCVS is accompanied by a “string of beads” appearance of cerebral vessels due to the alternating, simultaneous dilation and constriction, both of which (dilation and constriction) resolve completely within 3 months [59] [60] . The mechanism and pathophysiology of RCVS are unknown but “unpredictable and transient failure of regulation of cerebral arterial tone with sympathetic overactivity seems to have a role in the development of RCVS” [60] .

The main benefits of PSE are that it is a nasal decongestant in common cold/flu and allergic rhinitis. As detailed above, the efficacy of PSE as a nasal decongestant is proven and not contested.

This review focuses on the risk of PRES or RCVS associated with the use of PSE. The pathophysiology of PRES and RCVS is unknown, and cases of PRES and RCVS are associated with a very wide range of unrelated conditions, as illustrated in Figure 3 and Figure 4 . With such a wide range of conditions associated with PRES and RCVS it is likely that chance association of the conditions with PRES and RCVS is the reason for listing these conditions rather than any causal relationship. This may explain why PSE has been linked to cases of PRES and RCVS even when no other condition is recorded, although, as discussed below, only two cases with complete medical and medication histories can be identified with no other risks apart from taking PSE.

The PRAC Co-rapporteur’s updated assessment report on the benefit risk assessment of PSE in relation to PRES and RCVS (2023) [6] identified a total of 34 cases reported through 2023 from the worldwide medical literature and the Eudravigilance database, 18 cases from EU countries, in which “causal relationship between pseudoephedrine and posterior reversible encephalopathy syndrome (PRES)/reversible cerebral vasoconstriction syndrome (RCVS) is considered at least reasonably possible.”

Of the 34 cases, it was reported by the PRAC Co-rapporteurs that 5 cases had no other risk factor apart from exposure to PSE. However, examination of these cases shows that 3 cases had no information or had clearly incomplete information on medical history and/or concomitant medications, so they were not contributory to an assessment of risk factors (one physician reported case, [4] [61] [62] . For one of these 3 cases, the rapporteur’s summary of this case states: “Concomitant medication and patient history not reported, unknown”. The second case was an abstract of a poster presentation focusing on radiologic imaging which noted the patient did not have hypertension, but no other past medical history or medication history was described. The third case was a radiologic image-based case report which did not describe any past medical history or medication history. Therefore, these 3 cases should not be considered as scenarios where patients did not have risk factors but rather as incomplete information allowing assessment. Thus, only two remaining cases of the 5 cases considered by the rapporteur had no risk factors reported. Therefore, for nearly all of these cases, other risk factors apart from exposure to pseudoephedrine could be related to the adverse events of PRES/RCVS, and even in the remaining two cases, there could have been unreported risk factors apart from PSE.

It is important when considering the potential for a causal relationship between PSE and PRES/RCVS to take into consideration the population’s exposure to PSE.

In order to determine the use of PSE in the EU, data from IQVIA Consumer Health company was obtained for the year 2022 for the number of packs of PSE for mono and combination products which were sold OTC in 2022. In the 20 EU countries and the UK, a total of 72,507,672 packs of pseudoephedrine were sold in 2022.

The 72.5 million packs include tablets and syrups and is an underestimate of the total amount of PSE purchased as it does not include any PSE prescribed by physicians. Data was only available for 20 countries in the EU plus the UK, as the other countries did not have PSE available OTC. In 2023, the population of the 21 countries was 406,813,519. Over the 16-year period (2007-2023) that data for PRES/RCVS was gathered, the sales of OTC pseudoephedrine can be estimated as over 1.16 billion packs of pseudoephedrine and this resulted in only 18 reported cases of PRES/RCVS in the EU (plus UK) with only two of the cases with no other reported risk factors apart from intake of pseudoephedrine. With the small number of PRES/RCVS cases compared to exposure of the population to over 1 billion packs of pseudoephedrine, the risks for developing PRES/RCVS on exposure to pseudoephedrine are likely to be very low.

Hundreds of different PSE-containing products are taken by millions of people every day across the EU and UK, and it is estimated that more than 70 million packs of PSE products are taken every year.

PSE has sympathomimetic properties and, therefore, has the potential to cause vasoconstriction and tachycardia. However, the low OTC doses of PSE have little effect on the cardiovascular system.

Possible adverse effects of PSE in causing PRES and RCVS have recently been discussed by regulatory authorities, and warnings and contraindications have been added to patient instructions for the use of PSE products. PRES and RCVS are rare conditions of unknown etiology, and the number of cases involving the use of PSE and a possible link to the onset of PRES and RCVS are small, and it is difficult to link PSE as a definite cause of PRES and RCVS.

The opinion of the reviewer is that any causal relationship between the use of PSE and adverse events of PRES/RCVS is unlikely and that the benefits outlined in this review of PSE-containing medicines outweigh any risk associated with the onset of PRES and RCVS.

The author has no competing interests and has no financial or other interests in any pharmaceutical company. The author will receive payment from the Association of the European Self-Care Industry (AESGP) for time spent in the preparation of this manuscript, and this payment will also fund any publication charges for open access. The opinions expressed in this review are solely those of the author.

*Former Director of Common Cold Centre and Healthcare Clinical Trials (1988-2017).