In 2023, the National Agency for the Safety of Medicines and Health Products (ANSM) of France raised concerns about the safety of pseudoephedrine, an active ingredient in many nonprescription nasal decongestants, and initiated an Article 31 referral under Directive 2001/83/EC to the European Medicines Agency (EMA) for pharmacovigilance review. The referral was based on case reports of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) in individuals using pseudoephedrine-containing medicines. Following this, the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) conducted a comprehensive analysis of available data, including AE reports to EudraVigilance and worldwide scientific literature, to evaluate the risk of PRES and RCVS associated with pseudoephedrine. Between 2007 and 2023, 34 cases of PRES or RCVS were reported (18 cases from the European Economic Area [EEA]), which were assessed to be possibly or probably linked to pseudoephedrine. Most cases were resolved; 5 cases were associated with sequelae, and no cases were fatal [5]. Apart from the compilation and extensive review of this case series by PRAC, there were no additional epidemiologic data available that directly assessed the relationship between pseudoephedrine and these rare neurological events.

We sought to combine the PRAC-reviewed case series data with estimates of pseudoephedrine exposure to calculate an average annual reporting rate of PRES and RCVS potentially associated with pseudoephedrine use. This rate was defined as the total number of PRES and RCVS cases identified in the PRAC review divided by the estimated average number of individuals exposed to pseudoephedrine per year. We conducted a series of sensitivity analyses, varying key parameters, in order to compare a range of plausible annual reporting rates with the expected population background rate, derived from published epidemiologic studies of PRES and RCVS. To evaluate the effect of uncertainties on the annual reporting rate, we varied: (1) the estimated pseudoephedrine exposure; (2) the geographic scope; (3) the potential underreporting rate; and (4) the number of cases, focusing on subgroups of interest (Table 1).

The base-case scenario included all 18 cases from EEA countries identified between 2007 and 2023. The population prevalence of pseudoephedrine exposure was estimated to be 1.5% of the average annual EEA population during this period. This estimate applied the mid-point estimate of a study on nasal decongestants in France by Grimaldi-Bensouda et al., which estimated weekly pseudoephedrine use to be 1–2% of the population [6].

Due to differences in product availability across EEA countries, utilization patterns from Grimaldi-Bensouda et al. may not be generalizable to countries other than France. To account for country-specific variation in the use of pseudoephedrine-containing products, we modelled an alternative scenario using sales data from IQVIA Global OTC Insights, estimating exposure based on the number of packages of pseudoephedrine-containing products sold in 16 EEA countries between 2011 and 2022. We conservatively assumed that, on average, individuals experience four colds per year and purchased and completely used one packet of a pseudoephedrine-containing product per episode to calculate a sales-based estimate of the exposed population. This scenario included France and 15 other countries with pseudoephedrine sales data available, thereby minimizing the plausibly exposed population and maximizing the plausible estimated reporting rate calculated from sales data.

We also explored the impact of varying the geographic scope on reporting rates, given that EEA countries may vary with respect to the comprehensiveness of their national post-marketing surveillance systems as well as clinician awareness of PRES and RCVS. Of the 18 cases identified in EEA countries, 16 cases were reported from France. The French Pharmacovigilance system is a coordinated network of 31 centers, to which clinicians are required to report serious adverse reactions [7]. In addition, for over a decade, there has been education and specific efforts to identify neurovascular complications of vasoconstrictors in France [8]. Therefore, a scenario applying data solely from France was created to estimate the frequency of PRES and RCVS in which under-reporting would be minimized.

In general, adverse drug events are underreported to passive post-marketing surveillance systems. In a systematic review of underreporting, Hazell and colleagues estimated that the underreporting of AEs overall was approximately 95%, decreasing to 80% for serious and severe AEs [9, 10]. Although PRES and RCVS are considered severe AEs, often diagnosed and treated in hospital, we conservatively adjusted all scenarios to assume 95% underreporting.

After applying a series of plausible scenario parameters, the estimated annual reporting rates of PRES and RCVS after pseudoephedrine exposure ranged from 0.004 per 100,000 to a maximum adjusted annual reporting rate of 2.1 per 100,000 individuals (Fig. 1). Applying a 1.5% exposure estimate from Grimaldi-Bensouda et al. resulted in a higher reporting rate than any scenario using sales data. We then identified available data on the background population incidence of PRES and RCVS. A claims analysis of data from non-federal US hospitals reported 2096 cases of PRES among 7,581,668 hospitalizations over a 3-year period [11]. We extrapolated the expected annual incidence of PRES hospitalizations to be 2.3 per 100,000 adults in the USA. Two studies reported annual incidences of 0.30 and 0.45 RCVS hospitalizations per 100,000 adults per year in the USA using the same hospital system [12, 13].

Estimated base case and adjusted annual reporting rates of PRES and RCVS per 100,000 after pseudoephedrine use in the EEA. EEA European Economic Area, PRES posterior reversible encephalopathy syndrome, PSE pseudoephedrine, RCVS reversible cerebral vasoconstriction syndrome

Thus, even after adjusting for 95% underreporting, the estimated adjusted reporting rate of PRES and RCVS after pseudoephedrine use did not exceed the expected background population incidence of PRES and RCVS in any scenario. The sensitivity analysis scenario limited to France and adjusted for 95% underreporting resulted in the highest reporting rate (2.1 per 100,000 adults). The 16 cases reported from France exceeded the number reported in any other country. Elevated awareness and surveillance may have led to disproportionately high case counts, particularly of RCVS cases identified in France. In the past decade, there have been several studies conducted in France regarding RCVS [14,15,16,17] and the ongoing development of an international RCVS registry [18].