A Prospective Real-World Study of Bacillus clausii Evaluating Use, Treatment Habits and Patient Satisfaction in Italian Community Pharmacies: The PEGASO Study.

BACKGROUND: Ailments such as diarrhoea and antibiotic-associated gut symptoms are generally self-managed using probiotics. Real-world data on reasons behind self-medication with over-the-counter (OTC) products and patient-reported outcomes can be investigated strategically by the pharmacists. OBJECTIVE: This study evaluates the use of Bacillus clausii (Enterogermina®) at the Italian community pharmacies among self-medicating patients, their treatment habits and perceived benefits. DESIGN: This is a multicentre, prospective, non-interventional study which included two visits [at screening (T0) and end of the study (T1) when symptoms had subsided, ≤ 30 days from T0]. Patients who were already inclined to buy B. clausii were enrolled and instructed to complete a questionnaire at T0 and T1. The primary objective was to evaluate the reasons for taking B. clausii. Secondary objectives assessed treatment duration, perceived effectiveness, quality of life (QoL), treatment satisfaction and safety outcomes. RESULTS: Overall, 268 patients were enrolled; 99.6% of them were evaluated at T0 and 97.4% at T1, and safety was evaluated in 97.8% who had ≥ 1 dose of B. clausii. At T0, mean age was 50.7 years and majority were females (62.2%). In the interview, main reason stated for using B. clausii at T0 was diarrhoea (56.93%), followed by other gastrointestinal symptoms. Treatment duration was shorter in those with diarrhoea or abdominal pain versus those with constipation or abdominal tension. More than 90% perceived their symptoms to have improved or improved very much. Overall QoL improved in all the aspects measured. Treatment satisfaction was reported by nearly 90% of patients as satisfied, very satisfied or extremely satisfied. No adverse events were reported. CONCLUSION: This is the first pharmacy-based study in Italy that evaluated the real-world usage of an OTC probiotic containing B. clausii among self-medicating adults. Diarrhoea was the most common reason for use, with high-level of perceived effectiveness and patient satisfaction with B. clausii.

Safety of fexofenadine and other second-generation oral antihistamines before and after the removal of the prescription requirement in Italy and other European countries: A real-world evidence study and systematic review.

Background: The change from prescription to over-the-counter (OTC) status of oral antihistamines may raise concerns about drug safety due to the possibility of misuse/abuse. In most European countries, oral antihistamines are available without prescription, whereas in Italy, only <10-tablet packs are available OTC. Objectives: To evaluate the safety profile of fexofenadine after OTC switch in Italy in a real-world setting, and to compare its safety profile to that of other European countries where larger pack sizes are available. To compare the safety of fexofenadine, cetirizine, and loratadine in Italy. To examine safety/efficacy across Europe with a systematic review. Methods: This case-by-case analysis used the US Food and Drug Administration (FDA) adverse event reporting system (FAERS) to extract data of the adverse events (AEs) related to fexofenadine, loratadine and cetirizine in Italy January 2010-June 2020. The year 2016 was taken as the index date (removal of prescription requirement) for evaluation of the reporting trend of AEs of fexofenadine in Italy and make a comparison pre/post-OTC switch. A comparison of AEs with other European countries where fexofenadine is sold OTC in large packs >20 tablets (Belgium, Portugal, Switzerland, Finland, Hungary) was made. The rate at which an AE related to oral antihistamines occurred was estimated by calculation of the reporting rate (number of cases/[defined daily dose/1000 inhabitants per day]) on the basis of IQVIA sales data using the Italian Institute of Statistics database. A systematic review of the literature was also performed. Results: There were 3760 reports of AEs with a suspected association with fexofenadine; of these, eight were reported from Italy. There was a slightly increasing trend per year, in line with a general reporting trend of other drugs. In European countries where fexofenadine is available, the impact of OTC switch on AE reporting activity was negligible: from 2016, the reporting rate increased slightly and then normalized at 3.01, an incidence value similar to that recorded before the OTC switch (3.7 in 2015). Of 22 studies included in the systematic review, 18 (82%) positively evaluated the OTC use of oral antihistamines, confirming an acceptable safety/tolerability profile. Conclusion: There was no difference in number of AEs reported for fexofenadine pre/post-OTC switch, indicating a similar safety profile. Spontaneous reporting systems are a valuable source of real-world data and support the OTC provision of oral antihistamines in Europe and fexofenadine in Italy, in addition to supporting the use of larger pack sizes in Italy.

Kinetics of Intestinal Presence of Spores Following Oral Administration of Bacillus clausii Formulations: Three Single-Centre, Crossover, Randomised, Open-Label Studies.

BACKGROUND AND OBJECTIVE: Probiotics are live microorganisms that may provide benefits including the prevention of gastrointestinal disorders and other diseases. Enterogermina is a probiotic mix of spores from four strains of Bacillus clausii (O/C, T, N/R and SIN), available in several oral formulations. The objective of this analysis was to evaluate and compare the kinetic profiles of different formulations of Enterogermina-vial [E4 once daily (OD) and E2 twice daily (BID)], capsule [EC2 three times daily (TID)], oral powder for suspension (ES6 OD) and oral powder not requiring suspension (E6 OD) from two studies from 2012 (EUDRACT 2010-024497-19 and 2010-023187-41) and one study from 2016 (EUDRACT 2015-003330-27). METHODS: B. clausii spores were counted in homogenised faecal samples (results expressed as counts per gram) or after culture at 37 °C for 24-36 h (results expressed as colony-forming units). Kinetics were assessed by area under the concentration-time curve (AUC), maximum concentration (Cmax), time to maximum concentration (Tmax) and spore presence/persistence. RESULTS: In total, 22 subjects in each of the 2012 studies and 30 subjects in the 2016 study were randomised (mean age 25.0-33.8 years across studies). The mean (±SD) absolute faecal spore counts (in millions) expressed as AUC per hour were 270.7 ± 147.7 (E2 BID) and 213.8 ± 60.2 (E4 OD) in 2012 EGKINETIC4, 312.7 ± 218.0 (EC2 TID) and 319.0 ± 221.1 (ES6 OD) in 2012 EGKINETIC6, and 212.6 ± 118.0 (E6 OD) and 293.2 ± 247.2 (ES6 OD) in 2016 EGKINETIC6OP. The kinetic profiles of the different formulations of Enterogermina were similar, with superimposable AUC and daily curve profiles in each study up to the 8th day post dose. B. clausii spore presence/persistence in the intestine of healthy volunteers did not differ between the two formulations within each of the three studies. Enterogermina was well tolerated across all formulations and studies. CONCLUSION: These results show different formulations of Enterogermina had similar kinetic profiles within each study; however, they also showed that probiotics could be associated with high variability. The European Medicines Agency guidelines are the current bioequivalence reference, although only the Tmax parameter is used for high variability drugs. Due to the specific kinetics of probiotics, new parameters of bioequivalence could be necessary, considering, for example, variability via a parameter such as AUC. TRIAL REGISTRATION: EUDRACT 2010-024497-19, 2010-023187-41 and 2015-003330-27.