Coadministration of tizanidine and ciprofloxacin: a retrospective analysis of the WHO pharmacovigilance database.

PURPOSE: Tizanidine, an alpha-adrenergic substance with antinociceptive and antihypertensive effects, is extensively metabolized via cytochrome P450 (CYP) 1A2. Therefore, coadministration with potent CYP1A2 inhibitors, such as ciprofloxacin, is contraindicated. However, both drugs are broadly utilized in various countries. Their concomitant use bears an inherent high risk for clinically significant symptoms, especially in multimorbid patients experiencing polypharmacy. This study aims to investigate the impact of coadministration of tizanidine and ciprofloxacin using real-world pharmacovigilance data and to raise awareness of this potentially underestimated safety issue. METHODS: We conducted a retrospective study including Individual Case Safety Reports (ICSR) registered until March 1, 2017, in the World Health Organization (WHO) global database. Demographic data, drug administration information, the course of the adverse drug reaction (ADR), its severity, and outcomes were analyzed for cases reporting ciprofloxacin comedication. RESULTS: In 91 (2.0%) of the identified 4192 worldwide ICSR on tizanidine, coadministration of ciprofloxacin was reported. Most of the patients were female (n = 59, 64.8%) with a median age of 54 years (range 13-85 years). The countries contributing most reports were the USA (n = 54, 59.3%) and Switzerland (n = 16, 17.6%). ADRs reported most often affected the nervous system and the cardiac function, especially with large tizanidine doses or drugs with CNS and cardiovascular depressant effects. In two cases, a fatal outcome was reported. CONCLUSION: Despite the existing formal contraindication, the concomitant use of tizanidine and ciprofloxacin can be observed in real-world clinical practice. Reactions mainly affected the central nervous and the cardiovascular system resulting in potentially severe adverse effects. The concomitant use of tizanidine and ciprofloxacin should absolutely be avoided.

Development and validation of a clinical decision support system to prevent anticoagulant duplications.

BACKGROUND AND OBJECTIVE: Unintended duplicate prescriptions of anticoagulants increase the risk of serious adverse events. Clinical Decision Support Systems (CDSSs) can help prevent such medication errors; however, sophisticated algorithms are needed to avoid alert fatigue. This article describes the steps taken in our hospital to develop a CDSS to prevent anticoagulant duplication (AD). METHODS: The project was composed of three phases. In phase I, the status quo was established. In phase II, a clinical pharmacist developed an algorithm to detect ADs using daily data exports. In phase III, the algorithm was integrated into the hospital's electronic health record system. Alerts were reviewed by clinical pharmacists before being sent to the prescribing physician. We conducted a retrospective analysis of all three phases to assess the impact of the interventions on the occurrence and duration of ADs. Phase III was analyzed in more detail regarding the acceptance rate, sensitivity, and specificity of the alerts. RESULTS: We identified 91 ADs in 1581 patients receiving two or more anticoagulants during phase I, 70 ADs in 1692 patients in phase II, and 57 ADs in 1575 patients in phase III. Mean durations of ADs were 1.8, 1.4, and 1.1 calendar days during phases I, II, and III, respectively. In comparison to the baseline in phase I, the relative risk reduction of AD in patients treated with at least two different anticoagulants during phase III was 42% (RR: 0.58, CI: 0.42-0.81). A total of 429 alerts were generated during phase III, many of which were self-limiting, and 186 alerts were sent to the respective prescribing physician. The acceptance rate was high at 97%. We calculated a sensitivity of 87.4% and a specificity of 87.9%. CONCLUSION: The stepwise development of a CDSS for the detection of AD markedly reduced the frequency and duration of medication errors in our hospital, thereby improving patient safety.

Evaluation of Triple Whammy Prescriptions After the Implementation of a Drug Safety Algorithm.

BACKGROUND AND OBJECTIVE: The term triple whammy (TW) refers to the concomitant use of non-steroidal anti-inflammatory drugs, diuretics, and angiotensin system inhibitors; this combination significantly increases the risk of acute kidney injury (AKI). To prevent this serious complication, we developed an electronic algorithm that detects TW prescriptions in patients with additional risk factors such as old age and impaired kidney function. The algorithm alerts a clinical pharmacist who then evaluates and forwards the alert to the prescribing physician. METHODS: We evaluated the performance of this algorithm in a retrospective observational study of clinical data from all adult patients admitted to the Cantonal Hospital of Aarau in Switzerland in 2021. We identified all patients who received a TW prescription, had a TW alert, or developed AKI during TW therapy. Algorithm performance was evaluated by calculating the sensitivity and specificity as a primary endpoint and determining the acceptance rate among clinical pharmacists and physicians as a secondary endpoint. RESULTS: Among 21,332 hospitalized patients, 290 patients had a TW prescription, of which 12 patients experienced AKI. Overall, 216 patients were detected by the alert algorithm, including 11 of 12 patients with AKI; the algorithm sensitivity is 88.3% with a specificity of 99.7%. Physician acceptance was high (77.7%), but clinical pharmacists were reluctant to forward the alerts to prescribers in some cases. CONCLUSION: The TW algorithm is highly sensitive and specific in identifying patients with TW therapy at risk for AKI. The algorithm may help to prevent AKI in TW patients in the future.

Tackling alert fatigue with a semi-automated clinical decision support system: quantitative evaluation and end-user survey.

STUDY AIMS: Clinical decision support systems (CDSS) embedded in hospital electronic health records efficiently reduce medication errors, but there is a risk of low physician adherence due to alert fatigue. At the Cantonal Hospital Aarau, a CDSS is being developed that allows the highly accurate detection and correction of medication errors. The semi-automated CDSS sends its alerts either directly to the physician or to a clinical pharmacist for review first. Our aim was to evaluate the performance of the recently implemented CDSS in terms of acceptance rate and alert burden, as well as physicians' satisfaction with the CDSS. METHODS: All alerts generated by the clinical decision support systems between January and December 2021 were included in a retrospective quantitative evaluation. A team of clinical pharmacists performed a follow-up to determine whether the recommendation made by the CDSS was implemented by the physician. The acceptance rate was calculated including all alerts for which it was possible to determine an outcome. A web-based survey was conducted amongst physicians to assess their attitude towards the CDSS. The survey questions included overall satisfaction, helpfulness of individual algorithms, and perceived alert burden. RESULTS: In 2021, a total of 10,556 alerts were generated, of which 619 triggered a direct notification to the physician and 2,231 notifications were send to the physician after evaluation by a clinical pharmacist. The acceptance rates were 89.8% and 68.4%, respectively, which translates as an overall acceptance rate of 72.4%. On average, clinical pharmacists received 17.2 alerts per day, while all of the hospital physicians together received 7.8 notifications per day. In the survey, 94.5% of physicians reported being satisfied or very satisfied with the CDSS. Algorithms addressing potential medication errors concerning anticoagulants received the highest usefulness ratings. CONCLUSION: The development of this semi-automated clinical decision support system with context-based algorithms resulted in alerts with a high acceptance rate. Involving clinical pharmacists proved a promising approach to limit the alert burden of physicians and thus tackle alert fatigue. The CDSS is well accepted by our physicians.

Automation of the medication process in Swiss hospitals: results of a survey.

OBJECTIVES: Medication management is a core process in hospital administration. The safety, timeliness and efficiency of medication distribution may be improved by automating logistical and administrative aspects of the process. Forming an accurate high-level picture of current practices may help decision-makers to better advance the state of automation. This study aims to identify which systems for automating the medication process are currently in use in Swiss hospitals, and to what extent each system is used. METHODS: A 27-question survey was developed and distributed to Swiss Association of Public Health Administration and Hospital Pharmacists (GSASA) members. The survey focused on enterprise resource planning (ERP) systems, automation of in-hospital distribution and dispensing of pharmaceutical goods, bedside scanning, and the management of drug master data. RESULTS: The response rate was 98% (58/59 hospital pharmacies). All institutions had an ERP system in use, most frequently SAP (n=23, 39%). Electronic invoices from suppliers were fully processed by 37% and partially processed by 17% of respondents. Twenty-five percent of respondents reported performing bedside scanning for the purpose of medication administration. Automated medication distribution systems were available in 20 hospitals (34%), of which 13 were central robots and seven were decentralised systems. CONCLUSION: A considerable gap remains to achieve closed loop processes between multiple systems. The present results provide an inventory of existing systems and current trends for use by decision-makers in hospitals and hospital pharmacies.

Severe injection site reactions after subcutaneous administration of Sayana©.

PURPOSE: Sayana® was introduced as the first depot medroxyprogesterone acetate-containing contraceptive that is administered via subcutaneous injection. Within 10 months, the Regional Pharmacovigilance Centre (RPVC) Zurich received several anonymous reports of serious local reactions after Sayana® administration. In this retrospective study, individual case safety reports (ICSRs) on local adverse drug reactions (ADRs) related to Sayana® were analysed from the WHO pharmacovigilance database. METHODS: International, national and regional ICSRs during Sayana® administration up to 1 January 2016 were examined. Data on ADRs were retrieved from the WHO Global Database VigiBase™. Demographic data, drug administration information, duration of Sayana® treatment, latency time of the ADR, and its course, severity and outcomes were analysed. RESULTS: Worldwide, 398 ICSRs after Sayana® use were registered in the database. We identified 20 reported terms that were potentially used to describe a persistent lipodystrophy. When only cases containing one or more of these 20 reported terms were selected, 323 (81.2%) international ICSRs remained for analysis. Of those, 91.6% (n = 296) were categorised as serious. The majority of the reactions (n = 193, 54.4%) did not recover. In the 67 Swiss ICSRs, 77 ADRs were reported using 10 different terms including severe or persistent local reactions like lipodystrophy, atrophy or fat necrosis. Thirty-two patients (47.7%) did not recover. All 11 regional cases reported to the RPVC Zurich were categorised as serious ADRs. For the majority of the patients (n = 7, 63.6%) the interval between the application of Sayana® and development of the lipodystrophy was between 2 and 4 months. Most of the reactions were irreversible (n = 9, 81.8%). One patient underwent plastic surgery for artificial infill of the dent. CONCLUSIONS: Persistent local injection site reactions such as lipodystrophy, fat tissue necrosis or atrophy occur frequently after subcutaneous Sayana® use. These adverse drug reactions were recently integrated in the Swiss product information. Physicians and patients should be informed and advised about these potentially irreversible effects.

[Nalmefene and Opioid Withdrawal Syndrome: Analysis of the Global Pharmacovigilance Database for Adverse Drug Reactions]. / Nalmefen und Opioid-Entzugssyndrom: systematische Analyse der globalen PharmacovigilanceDatenbank.

Nalmefene (Selincro®) is a selective opioid receptor antagonist, licensed in April 2014 in Switzerland for the reduction of alcohol consumption in adults with a high drinking risk level. 200 reports of adverse drug reactions of nalmefene have been documented worldwide in the WHO global pharmacovigilance database between 7th March 1997 to 1st March 2015. In 21 cases (10,5%) nalmefene and an opioid were administered concomitantly, causing withdrawal symptoms. Until now, the regional pharmacovigilance center in Zurich received four cases of nalmefene combined with opioids. This combination should be avoided.