Drug Safety最新文献

Background: The US Food and Drug Administration (FDA)-mandates Risk Evaluation and Mitigation Strategy (REMS) programs for certain drugs with serious side effects help ensure that the benefits of use outweigh the risks. REMS materials-including enrollment forms, fact sheets, and medication guides-inform patients and caregivers about drug risks and program requirements.

Objective: To explore how effectively REMS materials communicate drug risk information and program requirements to patients and caregivers and to identify patients' and caregivers' preferences for risk communication.

Methods: Interviews with patients and caregivers of patients prescribed REMS-covered drugs focused on REMS materials. Transcripts were coded manually, with answers to closed-ended questions tabulated in Excel.

Results: The study included 43 patients and six caregivers across eight REMS-covered drugs: alemtuzumab, ambrisentan, clozapine, isotretinoin, lenalidomide, pegvaliase, pomalidomide, and sodium oxybate. Most participants were female (N = 42, 86%), white/non-Hispanic (N = 40, 82%), and college educated (N = 37, 76%). The average age was 40 years, with 27 (55%) having annual family incomes over $100,000. Most participants learned about REMS-covered drugs via printed information (N = 36, 73%), mostly REMS materials; conversations with providers about drug risks and benefits (N = 29, 59%); and websites found on their own (N = 42, 86%). Nearly all participants (N = 47, 96%) felt well-informed about drug risks and benefits, and most participants taking self-administered drugs (N = 28, 67%) reported understanding safe use "very well." However, knowledge gaps emerged around REMS-related risks and reasons for safe use measures; some participants misunderstood REMS enrollment forms as legal protections, not safety measures. Patients also widely varied in their valuations of REMS materials, with some feeling informed and empowered and others confused or intimidated. Preferences for risk communication varied; most participants (N = 36, 73%) wanted to receive information verbally from providers, with several wanting visual aids, summaries, and other resources.

Discussion: Gaps in patients' and caregivers' understanding of REMS programs and drug risks highlight the merits of reviewing communication materials and strategies. Clear, concise, and comprehensive educational documents could promote understanding and adherence to REMS requirements.

Background: Sulfonylureas (SU) are widely used for diabetes management in older adults but can cause hypoglycemia, which may be worsened by drug interactions. We applied high-throughput data mining to identify medications that could increase hypoglycemia risk when taken with SU.

Methods: Using Medicare, MarketScan, and Optum Clinformatics (2003-2022), we identified patients aged ≥ 65 years who experienced a severe hypoglycemic event after at least 90 days on SU. We evaluated all medications dispensed in the 90 days before the event using a case-crossover (CCO) design. We adjusted for time-varying confounding and direct effect of the evaluated medications (precipitant) using a case-case time-control (CCTC) approach and metformin as control. We computed odds ratios (ORs) for its association with hypoglycemia. The false discovery rate (FDR) was controlled at 0.05 to adjust for multiple testing. To reduce confounding from other diabetes medications, we analyzed non-diabetes and diabetes medications separately.

Results: Among 1607 candidate drugs received before experiencing hypoglycemia, 86 non-diabetes medications showed a CCO OR ≥ 1.00. With metformin as control, sulfamethoxazole/trimethoprim (CCTC OR 1.76, p < 0.01, FDR q < 0.01) and metronidazole (CCTC OR 2.17, p < 0.01, FDR q = 0.04) were associated with severe hypoglycemia. Among 10 diabetes medications, insulin showed increased association (CCO OR 1.22, p < 0.01); however, once adjusted for the drug's direct effects, CCTC OR was 1.03 (p = 0.47, FDR q = 0.47).

Conclusions: Using a high-throughput data mining approach, we identified two antibiotics (sulfamethoxazole/trimethoprim and metronidazole) that may increase hypoglycemia risk in older adults on sulfonylureas. Given the exploratory nature of this study, these findings warrant further investigation.

Introduction: Sexual side effects of serotonergic drugs are well documented. However, observational evidence comparing specific antidepressants remains sparse.

Objective: The aim of this study was to compare the risk of developing healthcare-recorded sexual dysfunction among male patients after initiating treatment with citalopram, sertraline, venlafaxine, or mirtazapine.

Methods: We conducted a new-user, active comparator cohort study of adult males in Denmark who started treatment with any of the study drugs between 2001 and 2015, allowing multiple cohort entries per person. Data from Danish national healthcare registers included 170,580 new treatment episodes of citalopram, 67,721 of mirtazapine, 51,984 of sertraline, and 19,820 of venlafaxine. A separate analysis examined patients with prior depression-related hospital visits. Results were reported as incidence rates as well as unmatched and propensity score-matched hazard ratios.

Results: In our primary analysis with 1-year follow-up and washout periods, incidence rates ranged from 18.80 (95% CI 17.60-20.00) to 28.5 (95% CI 26.00-31.30) per 1000 person-years. Venlafaxine was associated with the highest risk of healthcare-recorded sexual dysfunction compared with citalopram (hazard ratio [HR] 1.27; 95% CI 1.02-1.46), which was particularly pronounced among those with previous hospital contact for depression (HR 1.93; 95% CI 1.14-1.27). No significant difference was observed for sertraline (HR 0.99; 95% CI 0.90-1.09), while mirtazapine demonstrated modest evidence of a lower risk relative to citalopram (HR 0.87; 95% CI 0.81-0.93). Findings remained consistent across all analyses.

Conclusions: The risk of developing sexual dysfunction varies across antidepressant treatment. Healthcare providers should discuss the potential for sexual side effects, particularly when multiple treatment options are available.

Background: Medicine shortages are an increasing threat to medicine safety and access. In Australia, a 7-month shortage of Coumadin 5-mg tablets (Dec 2022-Jul 2023) prompted Therapeutic Goods Administration (TGA) intervention via the Serious Scarcity Substitution Instrument (SSSI), allowing pharmacists to substitute 5-mg warfarin tablets with lower-strength tablets. Understanding the impact of this shortage on anticoagulant use and safety is essential for informing future regulatory responses.

Aims: The aim of this study was to assess the impact of the 2023 warfarin shortage in Australia on dispensing of warfarin and direct oral anticoagulants (DOACs), International Normalised Ratio (INR) testing, and adverse event reporting.

Methods: Monthly national dispensing data (January 2020-August 2024) were obtained from Pharmaceutical Benefits Scheme (PBS) Date of Supply data. INR pathology data were sourced from Services Australia. The TGA Medicines Shortages Database identified relevant shortage periods. Warfarin-related adverse events were extracted from the TGA Database of Adverse Event Notifications. Interrupted time series assessed changes in dispensing and INR testing trends over time.

Results: Warfarin dispensing declined by 1094 prescriptions per month prior to March 2023 (p < 0.0001). A short-term increase occurred in March 2023 (+ 8625 prescriptions; p = 0.0017) following implementation of the SSSI, although this was not sustained. At the warfarin strength level, dispensing rose for warfarin 1 mg and 2 mg but fell for 5 mg, with subsequent compensatory increases; 3 mg remained stable. DOAC dispensing increased steadily before March 2023 (+ 3771 prescriptions per month; p < 0.0001) but declined thereafter (- 3056 per month; p < 0.0001), most notably for rivaroxaban and dabigatran, while apixaban decreased non-significantly. INR testing briefly increased during the shortage and SSSI. A modest rise in haemorrhage-related adverse events was observed.

Conclusion: Warfarin supply was maintained during the 2023 shortage through strength-based substitution under the SSSI, with limited impact on DOAC dispensing.

BACKGROUND AND OBJECTIVES: SCORe of Toxic Epidermal Necrolysis (SCORTEN) and ABCD-10 have been developed as scoring systems for predicting mortality associated with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). These scores were developed based on a small number of patients; hence, their generalizability requires further exploration. The present study used three algorithms, including a machine learning method, to construct a mortality prediction model for SJS/TEN and to identify new candidate predictors of mortality from severe drug eruptions.

Methods: Data from 5966 patients with SJS or TEN were extracted from the Japanese Adverse Drug Event Report Database. A mortality prediction model was then constructed using stepwise regression, L1 regularized-logistic regression, and random forests based on the patient characteristics (e.g., age, sex, primary disease, adverse events, drug classification, route of administration) and outcomes (death).

Results and discussion: The mortality prediction models for SJS/TEN identified sex (men), primary disease (hyperlipidemia, diabetes mellitus, renal dysfunction, and malignant tumors), adverse events (renal dysfunction, liver dysfunction, respiratory dysfunction, bacteremia/sepsis, disseminated intravascular coagulation syndrome, shock, and multiple organ failure), number of concomitant drugs, and route of administration (injection) as common factors associated with mortality.

Conclusions: Our findings showed that sex, hyperlipidemia as the primary disease, number of concomitant drugs, use of antipyretic analgesics, and route of administration may be considered as predictors of mortality in patients with SJS/TEN. The external validity of these factors needs to be examined in the future.

Introduction: Medicinal plants are extensively utilized as dietary supplements to encourage disease prevention and to support the treatment of various health disorders. Unfortunately, several plants are known for mycotoxin contamination, which may overwhelm any beneficial effects the plants might have.

Objective: The purpose of the study was to determine the presence of ochratoxin A (OTA) and citrinin (CIT) in medicinal herbal products (MHP).

Methods: Sixty samples of different MHP types were purchased on the Czech market during 2020-2021. Both mycotoxins were determined using high-performance liquid chromatography with a fluorescence detector with immunoaffinity columns employed as a pretreatment.

Results: In total, 40% and 27% of samples were above the limit of quantification with the concentrations ranging up to 826.62 ng/g and 472.79 ng/g for OTA and CIT, respectively. The co-occurrence was confirmed in six MHP types.

Conclusions: MHP could be a significant source of OTA and CIT. To protect the health of MHP users, it is desirable to continue monitoring the presence of mycotoxins in MHP. During this study, new OTA regulations for herbs came into force in the EU.

Background: Adverse drug events (ADEs) are events occurring after the administration of a drug. Several authorities are involved in capturing these ADEs to improve pharmacovigilance. These ADEs are reported directly to healthcare professionals or via the telephone, online, or e-mail and are crucial for maintaining drug safety.

Objective: Patient-reported adverse drug events (ADEs) are collected using various tools, though not much is known with regard to the comparability of these different methodologies. It is known that telephone-based surveys result in a higher report rate, although it is not known if this has an effect on the type of ADEs that are reported. In this prospective study, we aimed to investigate if there are differences in the number, type, and severity of ADEs reported via telephone and online in an event monitoring setting.

Methods: Patients included in Dutch community pharmacies were asked whether they experienced any ADEs via telephone and online (Lareb Intensive Monitoring) surveys as part of the PREPARE study. The PREPARE study was a multicenter study, researching the effect of genotype-guided dosing on the incidence of clinically relevant adverse drug reactions. With the paired data acquired in the PREPARE study, we investigated differences in the number, type, and severity of the reported ADEs.

Results: Patients (N = 525) completed both the telephone and online surveys. Of the 525 patients who completed both surveys, 326 reported ADEs via telephone and 239 online. A visual comparison showed a similar distribution in the type of ADEs among the methods except for less commonly reported types of ADEs and cardiac disorders. The perceived severity of ADEs were proportionally reported as more severe during the telephone survey versus the online survey.

Conclusions: Our study showed a clear difference in the number of ADEs reported during telephone and online monitoring. Additionally, the differences in the type of ADEs and the severity distribution of both tools shows that the tools are not exchangeable (CT.gov identifier: NCT03093818).

Introduction: Opioid agonist treatment (OAT) reduces drug-related poisonings and injection-related infections among people with opioid use disorder (OUD). Despite buprenorphine-naloxone (BNX) and methadone (MET) both being first-line OAT options in Canada, their comparative effectiveness in preventing recurrent injection-related infections and poisonings remains unclear.

Objectives: This study compared the effectiveness of buprenorphine-naloxone and methadone in reducing recurrent risks of injection-related bacterial infections and opioid-related poisoning among people on OAT.

Methods: We used administrative health data from Québec, Canada to create our cohort of adult patients (aged 18-65 years) on OAT maintenance between 2014 and 2019. We applied a time-dependent Cox proportional hazards model for our time-varying exposure definition to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the recurrent risks of injection-related bacterial infections and opioid-related poisoning, adjusting for age, sex, socio-demographic, and clinical factors. We also compared the effectiveness of buprenorphine-naloxone and methadone during the OAT induction phase (i.e., first 30 days of treatment).

Results: The study population included 2010 patients (mean age: 41.21 years, 67.41% male). Compared to methadone, buprenorphine-naloxone was associated with 45% lower recurrent risk of opioid-related poisoning (HR: 0.55; 95% CI 0.35-0.86). Overall, the association between buprenorphine-naloxone and recurrent risk of injection-related bacterial infections suggested a weak protective effect (HR: 0.80; 95% CI 0.59-1.09). During the induction phase, there was limited evidence of differences between buprenorphine-naloxone and methadone for the recurrent risks of injection-related bacterial infections (HR: 0.91; 95% CI 0.51-1.60) and opioid-related poisoning (HR: 1.07; 95% CI 0.51-2.24).

Conclusion: Among patients in OAT maintenance, buprenorphine-naloxone was associated with lower risk of recurrent opioid-related poisoning compared to methadone, but not for injection-related infections. This advantage was not observed during induction, suggesting the need for improved treatment retention early in OAT.

Introduction: Opioids are the most frequently prescribed medications for managing moderate-to-severe pain and are associated with significant potential for harm. Several models have been developed to predict opioid-related harms (ORHs). This study aimed to describe and evaluate the methodological quality of predictive models for identifying patients at high risk of ORHs.

Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, we reviewed published studies on developing or validating models for predicting ORHs, identified through a literature search of Scopus, PubMed, Embase, and Google Scholar. The quality of studies was assessed using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). The models were assessed by area under the curve (AUC) or c-statistic, sensitivity, specificity, accuracy, and positive or negative predictive value. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024540456).

Results: We included 36 studies involving participants aged 18 years or older. The frequently modeled ORHs were opioid use disorder (12 studies), opioid overdose (8 studies), opioid-induced respiratory depression (6 studies), and adverse drug events (4 studies). In total, 16 studies (44.4%) developed and validated tools. Most studies measured predictive ability using AUC (31, 86.1%), and some only reported sensitivity (14, 38.9%), specificity (11, 30.6%), or accuracy (4, 11.1%). Of the 31 studies that reported AUC values, 29 (93.5%) had moderate-to-high predictive ability (AUC > 0.70). History of opioid use (66.7%), age (58.3%), comorbidities (41.7%), sex (41.7%), and drug abuse and psychiatric problems (36.1%) were typical factors used in developing models.

Conclusions: The included predictive models showed moderate-to-high discriminative ability for screening patients at risk of ORHs. However, future studies should refine and validate them in various settings before considering the translation into clinical practice.