3.1 General Findings on ME ICSRs

Of the total of 9,662,345 ICSRs as provided by the EMA, there were 267,262 (2.8%) ICSRs containing information on at least one narrow ME, with a total of 300,324 reported MEs. The yearly proportion of ICSRs on MEs has been steadily increasing since 2004 (274 ICSRs; 1.1%) up to 2020 (27,549 ICSRs; 3.7%) as displayed in Fig. 2. In 2021, the number of ME-related ICSRs submitted to EudraVigilance (48,958 ICSRs) had almost doubled compared with 2020.

Fig. 2

Overview of all reports submitted to EudraVigilance (represented by the red bar chart, number of reports on the right y-axis) and the proportion of reports submitted mentioning a medication error (represented by the blue line chart, proportions noted on the left y-axis)

An overview of the most frequently reported MEs is displayed in Table 2. The five most frequently reported PTs for MEs account for more than half of all MEs, being “Inappropriate schedule of product administration” (52,646; 17.5%), “Incorrect dose administered” (32,379; 10.8%), “Wrong technique in product usage process” (26,831; 8.9%), “Medication error” (21,394; 7.1%) and “Product administration error” (16,538; 5.5%). Characteristics were separately provided for ICSRs noting “Inappropriate schedule of product administration” and “Incorrect dose administered” in Tables S1–S3 of the ESM.

Table 2 Overview of the 15 most frequently reported medication errors in the EudraVigilance database

The highest proportion of MEs was found in the age group 2 months to 2 years (12,694 ME ICSRs; 6.1% of 208,763 group total ICSRs), while the lowest proportion of MEs were found in the age group 18–64 years (94,979 ME ICSRs; 2.2% of 4,355,919 group total ICSRs), as seen in Table 3. The majority of ME-related ICSRs (215,133 ICSRs; 80.5%) had one drug marked as the main “suspect” within the corresponding ICSR (Table 3). The total amount of suspect drugs for MEs was 429,554, of which 353,852 (82.4%) could be mapped to an ATC code. A list of unmapped drugs within the entire EudraVigilance database is provided in Table S4 of the ESM.

Table 3 Count overview of suspect drugs reported in reports on MEs3.2 Person Characteristics

The ICSRs on MEs concerned more frequently female individuals (148,009; 55.4%) than male individuals (94,436; 35.3%), while sex was unknown in 24,817 (9.3%) ICSRs (Table 4). The median reported age was 50 years (interquartile range: 26–68 years) and the age category of 18–64 years (94,979 ICSRs; 35.5%) was most frequently reported within the ICSRs on MEs (Table 4). The age category was missing in 80,308 ICSRs (30.0%).

Table 4 EudraVigilance person characteristics of medication error-related reports3.3 Reporter and Reporter Country Characteristics

Most ICSRs on MEs were reported by healthcare professionals accounting for 155,711 (58.3%) ICSRs (Table 5). Additionally, a considerable amount of 103,128 (38.6%) ICSRs were submitted by consumers and non-healthcare professionals. Most ICSRs (98,716; 36.9%) originated from the USA. Countries from the European Union that reported most MEs were France (26,678 ICSRs; 10.0%), Germany (25,117 ICSRs; 9.4%) and Spain, (5,706 ICSRs; 2.1%). Many other countries from outside of Europe also submitted a considerable amount of ME ICSRs, such as the UK, Canada, Brazil, Japan, Australia and China (Table 5).

Table 5 EudraVigilance reporter and reporter country characteristics in ICSRs on medication errors3.4 Seriousness of Reported MEs

In 159,670 (59.7%) of the ICSRs, at least one category representing the seriousness of the reported ME was noted (Table 6). The most reported category was “Other medically important condition” for 108,557 (40.6%) ICSRs. The second most frequently reported category was “Hospitalisation” in 59,993 (22.4%) ICSRs. For 107,592 (40.3%) ICSRs, none of the seriousness categories was reported.

Table 6 Reported seriousness of the health outcomes for individual case safety reports including medication errors3.5 Identified SDRs and Subpopulation Differences

A total of 2221 drug-ME combinations were found, of which 847 (38.1%) met the criteria for disproportionality based on the entire EudraVigilance database (Table 7). The amount of SDRs was as low as 84 for the age group of 0-1 month and as high as 749 for female individuals. Most MEs were reported for the papillomavirus vaccine (human types 6, 11, 16, 18; ATC: J07BM01; 11,086 MEs), followed by infliximab (ATC: L04AB02; 9,236 MEs) and varicella, live attenuated (ATC: J07BK01; 5,623 MEs) as seen in Table 8. Sex-based subgroup SDRs showed minor differences between the sexes and also when compared with SDRs based on the overall EudraVigilance database, as shown in the SDR heatmap (Fig. 3 and ESM). When further analysing the heatmap of SDRs, the most distinct result in terms of age was found for etonogestrel (ATC: G03AC08), which showed an ROR of 60.4 (95% CI 14.4–252.8; three cases) for the age group 65–85 years. Of the total of 4501 MEs identified for etonogestrel, the most commonly reported ME was “Incorrect product administration duration” (2639 cases; 59%) as seen in the heatmap represented by Fig. 4 (and ESM).

Table 7 Amount of identified signals meeting the disproportionality criteria for the entire EudraVigilance database and groups based on sexes and age groupsTable 8 Thirty most reported drugs contributing to a signal of disproportionate reporting in relation to medication errorsFig. 3

Thirty most commonly reported drugs with their corresponding code from the Anatomical Therapeutic Chemical Classification System, associated with medication errors, ordered by the magnitude of disproportionality based on the values obtained when analysing the entire EudraVigilance database. Values of the reporting odds ratio are displayed where available for all the subgroups based on sexes and age groups. An empty cell signifies either no medication errors found or disproportionality criteria were not met. Interactive figure available in the ESM

Fig. 4

Fifteen most commonly reported medication errors highlighted and quantified for the 30 most commonly reported drugs associated with medication errors based on the entire EudraVigilance database. Values of the amount of reported cases are displayed where available. An empty cell signifies that the corresponding type of medication error was not reported for a drug. Interactive figure available in the ESM

Differences among age subgroups were also observed for vaccination against human papillomavirus (human types 6, 11, 16, 18; ATC: J07BM01), showing an ROR as low as 1.5 (95% CI 1.3–1.7; 314 cases) for the age group 3–11 years, a higher ROR of 23.8 (95% CI 18.2–31.2; 78 cases) for age group 2 months to 2 years, and an even higher ROR of 47.0 (95% CI 19.2–115.2; 7 cases) for the age group 65–85 years. The human papillomavirus vaccine was also the most commonly reported drug associated with MEs, accounting for 11,086 reported MEs, of which 6417 (58%) were attributed to “Inappropriate schedule of product administration”.

It was also notable that the SDR for the vaccine against herpes zoster (live attenuated; ATC: J07BK02) was stronger in all age groups, except age group 0–1 month, than for the entire EudraVigilance population. The ROR ranged between 45.9 and 79.1 among subgroups, while for the entire database the ROR was 36.4 (95% CI 35.2–37.7; 4,756 cases). For female individuals and male individuals, the ROR was lower, being respectively 26.6 (95%: 25.3–28.0; 1967 cases) and 30.4 (95% CI 28.3–32.6; 1028 cases). The most commonly reported ME was “Incorrect route of product administration” (1282 cases; 27.0%).

Analysis on age subgroups showed conspicuous SDRs for the age group 2 months to 2 years for the drugs oxycodone (ATC: N02AA05; ROR = 8.2; 95% CI 6.4–10.5; 73 cases), rivaroxaban (ATC: B01AF01; ROR = 10.7; 95% CI 4.7–24.1; 7 cases), and risperidone (ATC: N05AX08; ROR = 9.6; 95% CI 7.2–12.7; 57 cases). Very few SDRs for the most frequently reported drugs were found for the age group 0–1 months, but notably the SDR for paracetamol (ATC: N02BE01) stood out showing an ROR of 6.7 (95% CI 5.5–8.3; 100 cases). The most reported ME for oxycodone was “Accidental overdose” (847 cases; 35%), for risperidone “Inappropriate schedule of product administration” (469 cases; 22.3%), for rivaroxaban “Incorrect dose administered” (1377 cases; 34.6%) and for paracetamol “Accidental overdose” (1191 cases, 23%).

3.6 Type of MEs Among SDRs

Based on the results displayed in the heatmap in Fig. 4, several MEs stand out for a couple of drugs not yet mentioned above. For infliximab (ATC: L04AB02), there were 4707 out of a total of 9236 MEs (51%) attributed to “Inappropriate schedule of product administration”. The ME “Incorrect dose administered” accounted for 4836 (89%) out of 5433 MEs for ranitidine (ATC: A02BA02). The ME “Contraindicated product administered” was reported in a range of 1785–3323 MEs for (in ascending order) golimumab (ATC: L04AB06; 60.1% of MEs), certolizumab pegol (ATC: L04AB05; 78.3%), sulfasalazine (ATC: A07EC01; 89.6%), infliximab (ATC: L04AB02; 23.7%), hydroxychloroquine (ATC: P01BA02; 88.1%), adalimumab (ATC: L04AB04; 53.3%), tocilizumab (ATC: L04AC07; 88.0%) and abatacept (ATC: L04AA24; 87.9%).

3.7 Frequent MEs Among Frequently Reported Drugs and Strongest SDRs

Tables 9 and 10 display the top ten findings, not restricted to the EMA’s case count or ROR criteria, when ordering based on (A) the most frequently reported drugs in association with MEs and (B) the drugs with the highest lower boundary 95% CI of the ROR, accompanied by the top three MEs. A noteworthy result was the vaccine against coronavirus disease 2019 (ATC: J07BN01), which was the second most reported drug on MEs (10,150 ICSRs) in the database, predominantly because of the ME “Inappropriate schedule of product administration” (7510 cases; 74%). Another noteworthy result was etanercept (ATC: L04AB01) accounting for 8286 reported MEs, of which the most frequent ME was “Contraindicated product administered” (3135 cases; 37.8%). The drug with the highest lower boundary of the 95% CI of the ROR was sodium lauryl sulfoacetate, including combinations (ATC: A06AG11; 17 MEs; ROR with 95% CI 95, 48–189), with “Accidental device ingestion” (ten cases; 58.8%) being the most reported ME.

Table 9 Ten most reported drugs on MEs with the three most commonly reported ME type per drug, omitting the Preferred Term “Medication Error”Table 10 Drugs related to MEs ordered by descending lower boundary 95% CI of the ROR with the three most commonly reported ME type per drug, omitting the preferred term “Medication Error”