Pharmacoepidemiology, Volume 3, Issue 1 (March 2024) – 11 articles

In this cross-sectional descriptive study conducted in the Ratnapura district, Sri Lanka, we assessed the affordability of oral pediatric anti-infective medicines (OPAIMs). Using a modified WHO/HAI medicinal price methodology, we examined the availability, median price ratios (MPRs), mean percentage difference, and affordability of the standard treatment of the originator brand (OB) and lowest-priced generic (LPG) OPAIMs in 30 private and 2 state-owned pharmacies. The study revealed disparities in availability, with only 50% of private pharmacies offering all 11 medicinal drugs in their generic form. The MPRs of OPAIMs for OB and LPG varied, with three drugs exceeding the financially acceptable MPR of 2 (albendazole, amoxicillin, and erythromycin). The standard treatment with LPGs costs between 0.17 and 0.85 and between 0.06 and 0.28 days’ wages for the lowest daily salary of the private sector and unskilled public employees, respectively. We identified erythromycin and albendazole as having less than 50% availability in their generic form in private pharmacies. To address these findings, we recommend frequent pricing revisions based on exchange rates and associated costs, coupled with the establishment of a transparent scientific criterion to subsidize essential medicines deemed “unaffordable.” Failure to implement such measures amidst economic crises may adversely impact financial access to essential medications. Full article

Background: Hypertension is frequently studied in epidemiological studies that have been conducted using retrospective observational data, either as an outcome or a variable. However, there are few validation studies investigating the accuracy of hypertension phenotyping algorithms in aggregated electronic health record (EHR) data. Methods: Utilizing a centralized repository of inpatient EHR data from Singapore for the period of 2019–2020, a new algorithm that incorporates both diagnostic codes and medication details (Diag+Med) was devised. This algorithm was intended to supplement and improve the diagnostic code-only model (Diag-Only) for the classification of hypertension. We computed various metrics (sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)) to assess the algorithm’s effectiveness in identifying hypertension on 2813 chart-reviewed records. This pool was composed of two patient cohorts: a random sampling of all inpatient admissions (Random Cohort) and a targeted group with atrial fibrillation diagnoses (AF Cohort). Results: The Diag+Med algorithm was more sensitive at detecting hypertension patients in both cohorts compared to the Diag-Only algorithm (83.8 and 87.6% vs. 68.2 and 66.5% in the Random and AF Cohorts, respectively). These improvements in sensitivity came at minimal costs in terms of PPV reductions (88.2 and 90.3% vs. 91.4 and 94.2%, respectively). Conclusion: The combined use of diagnosis codes and specific antihypertension medication exposure patterns facilitates a more accurate capture of patients with hypertension in a database of aggregated EHRs from diverse healthcare institutions in Singapore. The results presented here allow for the bias correction of risk estimates derived from observational studies involving hypertension. Full article

Although statins have served as the cornerstone for pharmacological lowering of lipid levels in atherosclerotic cardiovascular disease (ASCVD) risk reduction, many patients are unable to achieve target doses of statin medication due to side effects or target levels of cholesterol reduction on statin monotherapy. The landscape of lipid-lowering strategies has expanded in recent years, with the emergence of therapies that make use of small interfering RNA (siRNA) and antisense oligonucleotides, in addition to traditional small-molecule agents. Non-statin therapies that have shown promising results in randomized controlled trials include adenosine triphosphate-citrate lyase inhibitors, proprotein convertase subtilisin/kexin 9 (PCSK9)-inhibiting antibodies and siRNA, omega-3 polyunsaturated fatty acids, and lipoprotein(a) gene-inhibiting siRNA and ASOs, in addition to older therapies such as ezetimibe. In contrast, cholesteryl ester transfer protein (CETP) inhibitors have shown less promising results in randomized trials. The purpose of this narrative review is to summarize the evidence for these medications, with a focus on phase III randomized trials. Full article

We described insulin glargine (originator) and insulin glargine-yfgn (biosimilar) treatment patterns, assessed effectiveness and safety outcomes, and identified reasons for switching back to the originator product from the biosimilar. This retrospective study included 328,463 Veterans 18 years of age and older who received one or more outpatient prescriptions for insulin glargine and/or insulin glargine-yfgn between 1 June 2021 and 31 December 2022. Patients were assigned to subgroups based on the initial prescription during the study period, prevalent versus incident use for originator insulin glargine, and prior versus no prior use of the originator before the biosimilar (i.e., prevalent originator non-switcher (n = 189,734), originator switch to biosimilar (n = 81,010), incident originator non-switcher (n = 49,401), and incident biosimilar (n = 8318)). There were no differences in the outcome of mean HbA1c (7.9% for all subgroups). There were also no differences in the unadjusted rates of hospitalization and/or emergency room visits for hyper- and hypoglycemia between the prevalent originator non-switcher and originator switched to biosimilar subgroups (p = 0.09 and 0.38, respectively) or the incident originator non-switcher and incident biosimilar subgroups (p = 0.054 and 0.61, respectively). Finally, none of the HbA1c or hyperglycemia outcomes adjusted for baseline characteristics were statistically different. Adjusted analyses for rates of hospitalization and/or emergency room visits for hypoglycemia could not be performed due to the low number of events. Overall, patients who received insulin glargine-yfgn had similar effectiveness and safety outcomes as patients who received the originator. Full article

Opioids are highly effective drugs but need close monitoring to avoid harm to patients. The aim of this study was to analyze how guideline recommendations are met for (i) the avoidance of the concomitant use of anxiolytics, hypnotics, or sedatives; (ii) the prescribing of laxatives in long-term opioid treatment; (iii) the co-prescribing of drugs to control the emetic effect of opioids; (iv) pretreatment with non-opioids; and (v) screening for depression when initiating opioids. The results are based on a routine data analysis of a large German health insurance fund. Different study populations of noncancer patients (18+ years old) treated with opioids were analyzed: 10.4% of the opioid recipients in 2021 received at least one concomitant prescription with anxiolytics, hypnotics, or sedatives; 69.3% of those with long-term opioid treatment received at least one laxative prescription. Of those with first-time opioid prescriptions, 4.8% received an antiemetic drug; 47.3% of those with a newly initiated opioid therapy received a non-opioid prescription within three months before the start of the opioid therapy; and 22.0% of patients with incident opioid prescription had at least one documentation of a depression diagnosis within three months of the first prescription. There is an urgent need to improve opioid prescribing to avoid risky combinations and adverse effects. Full article

Helicobacter pylori is a class I carcinogen that infects more than 100 million individuals in the United States. Antimicrobial therapy for H. pylori has typically been prescribed empirically rather than based on susceptibility testing. Until recently, therapeutic recommendations have generally ignored the principles of antibiotic stewardship. A combination of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin (triple therapy) remains popular despite increasing clarithromycin resistance and poor cure rates. Concomitant therapy (a PPI, amoxicillin, clarithromycin, and metronidazole) is recommended and widely used despite all patients receiving at least one unneeded antibiotic. In 2020, the Food and Drug Administration approved vonoprazan, amoxicillin, and clarithromycin triple therapy, which administers unneeded clarithromycin to >90% of patients (i.e., ~6 tons of unneeded clarithromycin/million treatments). In the late 1980s, the infectious disease community functionally transferred responsibility for the management of H. pylori to gastroenterology, which has managed the infection as another common gastrointestinal disease such as constipation. In 2022, both traditional and noninvasive molecular-based susceptibility testing for H. pylori became available in the United States. In order to reduce and prevent antibiotic misuse, the infectious disease community should reclaim responsibility for the management of this important infectious disease. Full article

Severe acute respiratory syndrome coronavirus 2 has infected millions of people, but about 20% of infected individuals do not develop symptoms. COVID-19 is an inflammatory disease that affects a portion of individuals infected with the virus and it is associated with liver injury and other complications, leading to hospitalization, critical illness, and death. Remdesivir is an antiviral agent used for the treatment of hospitalized patients with COVID-19 to improve the time to recovery, reduce the duration of mechanical ventilation, decrease the need for supplemental oxygen, and decrease the risk of mortality. Remdesivir-associated hepatotoxicity has been observed as increased transaminases more than five times the upper limit of normal in hospitalized patients with COVID-19, but causality has not been proven. It is generally difficult to distinguish between remdesivir-associated hepatotoxicity and COVID-19-induced hepatotoxicity. The purpose of this review is to evaluate the evidence for remdesivir-associated hepatotoxicity. Current evidence suggests that elevated liver enzymes in hospitalized COVID-19 patients are more likely to be due to the infection than remdesivir, and a 5-day course of remdesivir seems to be safe in regard to hepatotoxicity. Full article

Opioid use in women has increased by 300% since 1999, and opioid use disorder among pregnant women has quadrupled. The stigma of substance use disorder is a significant barrier to treatment, especially among women. The purpose of this study was to explore the experiences and perceptions of stigma among mothers and the underlying themes. (1) Background: To understand the stigmatization of women with substance use disorders, we interviewed mothers in recovery from opioid use disorder. (2) Methods: Qualitative methods and descriptive analysis was used to extrapolate themes related to the experienced stigma. (3) Results: A total of 20 mothers in recovery from opioid use disorder were interviewed and three main themes emerged from the data: internal stigma, external stigma, and healing from stigma. (4) Conclusion: The examination of stigma is important in reducing its effect on all individuals with substance use disorders, and it is important to understand gender inequities. Full article

Tofacitinib is a Janus kinase inhibitor (JAKi) that is used off-label for the treatment of alopecia areata (AA). Its boxed warning includes an increased risk of serious adverse events (SAEs) based on the results of a safety trial in rheumatoid arthritis (RA) patients taking the medication. The purpose of this study was to investigate the differences in patients’ characteristics and SAEs profiles between RA and AA populations taking tofacitinib. The cohorts were constructed using the TrinetX database to identify the patients who were prescribed tofacitinib for RA or AA between October 2012 and October 2023. A total of 22,873 patients were included in this analysis, with 21,080 individuals in the RA cohort and 1793 individuals in the AA cohort. After matching for age, sex, and race, each cohort had a sample size of 1482. Data on the patients’ sex, age, race, comorbidities, concomitant medications, and associated SAEs were collected. The cohorts were compared by calculating the odds ratios and tested for significance associations using Fisher’s Exact Tests. Both the RA and AA cohorts were predominantly female (RA 79%, AA 70%), with mean ages of 61 ± 14 years and 38 ± 19 years (p-value < 0.0001), respectively. Both the groups showed similar racial distributions. The RA cohort had increased rates of hypertension, obesity, type 2 diabetes mellitus, and nicotine dependence compared to those of the AA cohort (p-value < 0.0001). With the exception of cyclosporine and azathioprine, the percentage of concomitant medication use was higher in all the categories in the RA cohort than those in the AA cohort (p-value < 0.0001). Higher rates of adverse events were seen in the RA cohort across all the categories, except myocardial infarction, stroke, and lymphomas/hematopoietic malignancies. Our findings show that the SAEs on the boxed warning of tofacitinib should be strongly considered when being used off-label for the treatment of AA. Clinicians must carefully assess the individual patient factors when determining the appropriateness of tofacitinib use. Full article

Introduction: Calcineurin inhibitors (CNIs), ciclosporin and tacrolimus, are utilized primarily in organ transplantation and the treatment of autoimmune diseases. Since patients depend on these drugs over long periods, they face a potential risk of intoxication. This risk increases substantially when patients are overdosed or inadvertently exposed to cytochrome P450 (CYP) 3A4 inhibitors. Objectives: To analyze the utility of CYP inducers as a plausible treatment modality for acute CNI intoxication using real-world data from the WHO global pharmacovigilance database (VigiBase™) and supporting evidence from published data. Methodology: We explored all individual case safety reports (ICSRs) regarding CNI intoxications registered in VigiBase™. The queries “overdose” or “drug intoxication” were applied against the active ingredients “ciclosporin” and “tacrolimus”. Regarding the utility of CYP inducers, an extensive literature analysis was undertaken. We also report an index clinical case of a 60-year-old liver transplant patient that developed severe tacrolimus intoxication with multiple organ dysfunction at a peak concentration of 33.1 μg/L after a single dose of intravenous fluconazole. Results: Out of 143,710 documented ICSRs reported in VigiBase™ since 1992, 0.26% and 0.02% were registered as CNI overdoses and intoxications, respectively. The main etiological factor for CNI intoxication was the interaction with CYP 3A4 inhibitors (40.0% vs. case reports: 50.0%). The most commonly reported manifestation was acute kidney injury (36.7% vs. case reports: 46.3%). A total of 16.7% of intoxications led to fatal outcomes after drug withdrawal or dose reduction; however, in 43.0% of cases the exact actions undertaken were not reported. In peer-reviewed reports, 34 distinct clinical cases were treated with CYP inducers. Diverse pharmacoenhancement strategies with phenobarbital (5), phenytoin (23) and rifampicin (6) were described with a mean time of achieving the therapeutic target after 2.7 (±0.7), 3.1 (±0.5) and 4.6 (±1.0) days, respectively. In the index case, a therapeutic concentration of 4.9 [4–6 μg/L] was achieved after a 3-day regimen of rifampicin. Conclusion: In addition to general supportive treatment, the administration of phenobarbital, phenytoin, or rifampicin to reverse acute CNI intoxication is a viable treatment modality. The relatively long half-life of phenobarbital coupled with its exclusive renal elimination are potential pitfalls to reckon with. In spite of the favorable pharmacokinetic advantages of rifampicin, phenytoin offers a competitive pharmacodynamic advantage that is indisputable in patients with overt neurotoxicity. Full article

Background: The coronavirus pandemic has led to the creation of clinical guidelines by a large number of professional medical communities. However, the quality and methodology of development of Russian clinical guidelines has been little studied. The continued relevance of studying the use of DOACs (Direct oral anticoagulants) in patients with COVID-19 was the basis for conducting this study. Aim: The objective of this study was to assess DOAC consumption and expenditure in the Russian Federation during the COVID-19 pandemic and to analyze whether it was supported by the domestic evidence base for the use of DOACs in COVID-19 patients through identifying all publicly available Russian-produced CPGs (Clinical practice guidelines) for the treatment of COVID-19 and assessing their quality as the source of recommendations for the use of oral anticoagulants for the prevention of thrombotic complications in COVID-19 patients. We searched Russian databases for CPGs, published between 2020 and 2023. We identified seven relevant documents that met our inclusion criteria. Three authors analyzed Russian clinical guidelines using an AGREE II questionnaire. We calculated DOAC DDD (defined daily dose) consumption according to Russian clinical guidelines and DDD consumption in patients with COVID-19 for the period 2020–2022. Results: Seven clinical CPGs were analyzed with the AGREE II tool. It was revealed that experts gave the highest scores for the sections on scope and purpose (from 62.98% to 100%), and clarity of presentation (from 96.30% to 100%). The lowest scores were given for the sections on stakeholder involvement (33.33% to 64.81%), rigour of development (from 0% to 49.31%), applicability (from 23.61% to 50%), and editorial independence (from 0% to 50%). When comparing the total score, it was found that two clinical guidelines received the highest scores—ROPNIZ (Livzan), and ROPNIZ (Drapkina). The minimum score was registered with the NIIOZMM (Khripun) clinical guideline. No guideline received a total score of more than 70%. According to clinical recommendations, the consumption of apixaban and rivaroxaban is 15 DDD (30-day course of therapy), or 22.5 DDD (45-day course of therapy). Consumption of apixaban in the Russian Federation in 2020 and 2021 corresponds to the indicators presented in clinical recommendations (in 2020—26.59 DDD per patient with COVID-19; in 2021—15.75 DDD per patient with COVID-19), and in 2022—10.67 DDD, which is below the recommended values. In 2020, consumption of rivaroxaban in the Russian Federation was 26.59 which corresponds to data from clinical recommendations; in 2021, consumption decreased to 7.87 DDD; in 2022 it decreased to 5.48 DDD, which is 2.74 times less than recommended. Conclusions: Analysis of seven clinical recommendations revealed that such sections of clinical recommendations as scope, purpose, and clarity of presentation had the highest degree of assessment in accordance with AGREE II. The lowest scores were given for the sections on stakeholder involvement, rigour of development, applicability, and editorial independence. When comparing the total score, it was found that two clinical guidelines received the highest scores—the Russian Society for the Prevention of Non-communicable Diseases (Livzan), and the Russian Society for the Prevention of Non-communicable Diseases (Drapkina). The minimum score was registered with the Research Institute for Healthcare Organization and Medical Management of Moscow Healthcare Department clinical guideline. No guideline received a total score of more than 70%. During the pandemic, the highest DDD consumption of DOACs was in 2020, which exceeded the DOACs’ recommended DDD by Russian clinical guidelines. DOAC consumption had decreased by 2022. There was a decrease in the consumption of rivaroxaban, with an increase in apixaban’s share in the structure of DOAC consumption during the coronavirus pandemic. Obtained data indicate that in 2021 the apixaban consumption in the Russian Federation corresponded to the recommended DDD in the national guidelines, which indicates the most correct use of apixaban according to Russian GPGs. Full article