In some instances, more than 10 retrieved ICSRs were found to probably refer to the same case.
FAERS, EVDAS were also queried for ICSRs concerning tadalafil based on the same criteria. Sanofi CHC’s global pharmacovigilance database was queried for any ICSRs concerning tadalafil as suspect drug. Data from FAERS, EVDAS and Sanofi CHC’s global pharmacovigilance database were downloaded as Microsoft Excel® files (ICSR line listings). The ISCR listing resulting from the SMARS website query was also transferred into Excel®. Excel® was used to organize, classify, tabulate and visualize retrieved ICSRs.
In line with the research questions, retrieved cases concerning sildenafil were included for further analysis only if they originated from Ireland, New Zealand, Norway, Poland or the UK. Cases concerning tadalafil were included for further analysis only if they originated from Poland or the UK. ICSRs concerning females, patients younger than 18 years of age, or describing use of sildenafil or tadalafil in patients with PAH (as defined in Appendix 2) were excluded from all analyses. Within the FAERS dataset, almost half of the retrieved, relevant ICSRs were suggestive for duplicates (i.e., ICSRs reporting the same country of origin, patient age and sex, suspect and concomitant drugs, ADRs and/or ADR onset dates, but received from different marketing authorization holders and with different Worldwide Unique Case Identification Numbers). Because full case information was not accessible through the FAERS Public Dashboard, definitive identification of case duplicates was not possible.
Therefore, suspected duplicates were not categorically excluded from the FAERS dataset. However, probable duplicates were flagged and the effect of excluding these cases on reporting patterns was explored in the country-specific analyses. In the EVDAS Level 1 retrievals, exact patient age and ADR onset dates are not provided at all, thereby prohibiting reliable identification of potential duplicates. There was no indication of the presence of duplicates in Sanofi CHC’s global pharmacovigilance database or, from the limited information available, in the SMARS dataset. Number of ICSRs and reporting rates over time The mode of dispensing of the suspect drug is not reported in the outputs of any of the queried databases and could also not be reliably established from the trade name of the suspect PDE5i, which was missing in approximately 52.5% of the relevant ICSRs of tadalafil retrieved from Sanofi CHC’s company database. This phenomenon started in 2014, likely as a consequence of the launch of generic sildenafil products, which led to the same ICSRs (e.g., those detected in the scientific literature) being reported multiple times by different marketing authorization holders.
| Product | Dosage | Quantity + Bonus | Price | |
|---|---|---|---|---|
| Cialis Generic | 10mg | 180 + 8 Pills | 236.88€ 225.60€ | |
| Cialis Generic | 20mg | 360 + 10 Pills | 427.34€ 406.99€ | |
| Cialis Generic | 60mg | 360 + 10 Pills | 570.52€ 543.35€ | |
| Tadalista Super Active | 20mg | 60 + 8 Pills | 230.32€ 219.35€ | |
| Cialis Generic | 20mg | 270 + 10 Pills | 335.21€ 319.25€ | |
| Cialis Generic | 40mg | 20 Pills | 59.47€ 56.64€ | |
| Cialis Generic | 40mg | 120 + 8 Pills | 206.98€ 197.12€ | |
| Cialis Generic | 60mg | 30 + 2 Pills | 85.33€ 81.27€ | |
| Cialis Generic | 2.5mg | 360 + 10 Pills | 260.03€ 247.65€ | |
| Cialis Generic | 2.5mg | 270 + 10 Pills | 199.64€ 190.13€ | |
| Tadalista Super Active | 20mg | 120 + 16 Pills | 382.15€ 363.95€ | |
| Cialis Generic | 20mg | 120 + 8 Pills | 188.15€ 179.19€ | |
| Cialis Generic | 20mg | 10 Pills | 31.49€ 29.99€ | |
| Tadalista Super Active | 20mg | 20 + 4 Pills | 92.35€ 87.95€ | |
| Tadalista Super Active | 20mg | 10 Pills | 55.64€ 52.99€ | |
| Cialis Generic | 2.5mg | 60 + 4 Pills | 83.43€ 79.46€ | |
| Cialis Generic | 60mg | 270 + 10 Pills | 443.96€ 422.82€ |
The distribution of the 790 cases across country and calendar year is shown in Table 6 (Table 5 and 6). Table 5: Sildenafil, FAERS: ICSRs by duplicate categorization and country.
Further 153 cases (14%) were from Norway, 76 cases (7%) from Poland, 45 cases (4%) from Ireland and 43 cases (4%) from New Zealand. The proportion of consumer cases ranged from 14% for Norway to 74% for New Zealand. 487 cases (45%) were serious, including 43 (4%) fatal cases. The proportion of serious cases ranged from 16% for Norway to 52% for UK (Table 1 and 2). Table 1: Sildenafil/EVDAS: ICSRs by reporter type and country.
Table 2: Sildenafil/EVDAS: ICSRs by seriousness and country. The distribution of the 1,080 included cases by country and calendar year is shown in Table 3. Approximately one third of the cases (324/1,095 cases) were reported in 2011 alone. Further investigation of this cluster revealed that 239 of these 324 cases (27 serious, 212 non-serious) were reported into EV by a single marketing authorization holder over a 2-day period. No such cluster in 2011 was apparent in FAERS.
A small subset of the serious cases could also be identified in FAERS, where they all had event onset dates and/or FDA receipt dates in 2009-2010. Together, these observations suggest that the case cluster seen in EVDAS for 2011 is due to delayed reporting of a batch of cases from earlier years (Table 3). Table 3: Sildenafil, EVDAS: ICSRs by country and calendar year. Shaded cells indicate the year of switch of prescription status in the respective country. Because relevant variables for identification of case duplicates such as exact patient age or ADR onset date are not available in the EVDAS Level 1 retrievals, reliable identification of duplicate ICSRs was not possible within this dataset. Table 6: Sildenafil, FAERS: ICSRs by country and calendar year. SMARS: The query of the New Zealand SMARS database revealed 43 cases, 37 of which were deemed relevant for this analysis. Further information on data retrieved from SMARS is presented in below section (Figure 3).
ICSR review did however reveal case clusters suggestive for possible duplicates. FAERS: The query of FAERS resulted in a total of 47,238 ICSRs with FDA receipt date ≥01 Jan 2010, of which 1,414 originated from one of the countries of interest. Of these, 624 cases, concerning children, females and/or treatment of PAH, were excluded. The remaining 790 cases were included in the analysis (Figure 2). Figure 2: Flowchart of ICSRs retrieved from FAERS. Figure 3: Flowchart of ICSRs retrieved from SMARS. In the following subsections, trends of specific countries over time are further described.
Countries are presented in chronological order of the switch of sildenafil to non-prescription status.
In the following analyses, the annual number of ICSRs and county-specific annual reporting rate is presented for the cases retrieved from EVDAS and FAERS. EVDAS data are stratified by seriousness and FAERS data are stratified by duplicate classification. In addition, potential changes in case characteristics over time are presented.
| Misconception | Reality | Source |
|---|---|---|
| OTC Tadalafil is completely safe | Not entirely, side effects and interactions possible | MHRA, NHS |
| Only prescribed meds work | OTC can be effective if used responsibly | Medical advice |
| It can cure all ED causes | It alleviates symptoms, not cures underlying causes | Urology guidelines |
| It’s addictive | No evidence of physical dependence | Clinical studies |
For New Zealand, ICSRs retrieved from SMARS are additionally presented.
Unknown delays between dispense, administration, ADR onset and ADR reporting also prohibited reliable classification of ICSRs as “prescription cases” vs. “non-Rx/OTC cases” based on ADR onset date or report date. Therefore, the annual number of ICSRs over time (i.e., pre and post non-Rx/OTC switch) was displayed and assessed per country, acknowledging that ICSRs reported after the non-Rx/OTC switch date would comprise an unknown mix of ADRs occurring in prescription and non-prescription settings. To crudely adjust for changes in patient exposure over time, country-specific, annual RR (number of ICSRs per million sold tablets) were calculated for Poland, UK, sublingual tadalafil Norway and Ireland for 2014-2024 on the basis of IQVIA sales data. For New Zealand, sales data were only available for 2016-2024 (Appendix 4).
These analyses were stratified by case seriousness (EVDAS and Sanofi CHC’s global pharmacovigilance database only) and duplicate classification (probable duplicate yes/no; FAERS only). ADR summary tabulations on MedDRA PT level were produced from the downloaded case listings and evaluated for any noteworthy trends in the distribution of ADRs over time that could indicate towards potential changes in the characteristics of the ICSRs received before and after the non-Rx/OTC switch. As possible indicators of change of patient characteristics or drug utilization over time, ICSRs were evaluated for changes of average patient age (FAERS only) and for evidence of concomitant use of contraindicated drugs (EVDAS, FAERS, SMARS and Sanofi CHC’s pharmacovigilance database; Appendix 3). Sildenafil is a medication primarily used to treat erectile dysfunction and pulmonary arterial hypertension. Sildenafil works by relaxing the muscles in the blood vessels of the penis, allowing increased blood flow during sexual stimulation, leading to an erection.
EudraVigilance: The query of EVDAS resulted in a total of 29,752 ICSRs concerning sildenafil with an EV Gateway receipt date ≥01 Jan 2010, of which 1,472 originated from one of the countries of interest. Of these, 392 cases, concerning children, females and/or treatment of PAH, were excluded. The remaining 1,080 cases were included in the analysis (Figure 1). Figure 1: Flowchart of ICSRs retrieved from EVDAS. Consistent with high exposure estimates for sildenafil in the UK (Section 3.1.2.3) as well as traditionally high spontaneous ADR reporting rates in the UK, 763 (71%) of the 1,080 cases included in the analysis were reported from the UK [5]. Since October, 2014 in New Zealand, pharmacists are supplying Sildenafil for the treatment of ED without prescription.
Number of ICSRs and reporting rates over time: The annual number of relevant ICSRs retrieved from EVDAS and FAERS, stratified by seriousness, are shown in Tables 7 and 8, respectively. There was no indication of a significant increase in the number of reports following the non-Rx/OTC switch in 2014.
Of the 790 relevant cases, 686 (87%) were tadalafil 2 5 mg from the UK, 54 (7%) from Poland, 20 (3%) from Norway, 18 (2%) from New Zealand and 12 (2%) from Ireland. Consistent with the regulatory reporting requirements for foreign ICSRs into FAERS, overall case numbers per country were lower than in EVDAS and all cases but one (99.9%) were serious. The proportion of consumer cases ranged from 15% for Norway to 72% for New Zealand (Table 4). Table 4: Sildenafil, FAERS: ICSRs by reporter type and country. In the FAERS case set, a high proportion of probable case duplicates (i.e., ICSRs reporting the same country of origin, patient age, suspect and concomitant drugs, ADRs and ADR onset dates but received from different marketing authorization holders and with different Worldwide Unique Case Identification numbers) was apparent: overall, 391 of the 790 relevant cases (49%) were categorized as probable duplicates of other cases included in the case set. Because most cases in EVDAS and FAERS were reported before 2016 whereas annual sales data were available only from 2016 onwards, calculation of meaningful reporting rates was not possible (Table 7 and 8).