Outpatient fluoroquinolone use in relation to European Medicines Agency's recommendation: An Estonian nationwide drug utilization study.

PURPOSE: To determine possible changes in prescribing of fluoroquinolones in relation to the European Medicines Agency's (EMA) recommendation in October 2018. METHODS: We conducted a nationwide time-series study on outpatient use of fluoroquinolones during January 2016-June 2021 in Estonia. Joinpoint regression was used to identify change points over time. Several subgroup analyses by prescriber specialty, indication group, risk factors for tendon injury, aortic aneurysm/dissection or heart valve regurgitation/incompetence and the prescribing of other antibiotics were performed. RESULTS: During the study period 236 989 prescriptions of fluoroquinolones were dispensed to 142 659 persons. The number of episodes per month declined from 3780 (2.9/1000 inhabitants) to 2570 (1.9/1000 inhabitants). We identified three change points with four different trend segments: from January 2016 to November 2018 monthly percent change (MPC) -0.4%, from November 2018 to June 2019 MPC -2.5%, from June 2019 to July 2020 MPC 1.7% and from July 2020 to June 2021 MPC -3.3%. Prescribing for indications which were removed or restricted by EMA's recommendation comprised a small proportion of all fluoroquinolone episodes -2.8% and 6.3%, respectively. The risk factors for tendon injury and for cardiac disorders (aortic aneurysm/dissection or heart valve regurgitation/incompetence) were present in 46.4% and 57.8% episodes of fluoroquinolone users, respectively. No changes in the trend of prescribing to users with risk factors was detected. CONCLUSIONS: The EMA's recommendation may have contributed to the greater decline in the use of fluoroquinolones. However, there is still a high proportion of users with predisposing factors for tendon injury and serious cardiac disorders.

Pre-pregnancy counseling for women with epilepsy: Can we do better?

OBJECTIVE: For many women with epilepsy (WWE), decision making about pregnancy is difficult, due mainly to the potential teratogenic risks of anti-seizure medications (ASMs). Pre-pregnancy counseling is essential to minimize these risks. This study was conducted to assess the rate and effectiveness of pre-pregnancy counseling for women treated with valproate (VPA) in Estonia. METHODS: We used outpatient prescription data from the national health insurance provider to identify all women treated with VPA during 2011-2018 in Estonia. The personal medical documentation of women who became pregnant while on VPA treatment was reviewed. Pre-pregnancy counseling history and VPA-treatment indications were analyzed. RESULTS: Data from 141 women who became pregnant while on VPA treatment during 2011-2018 time period were analyzed. Of these patients, 77% had epilepsy and 19% psychiatric diagnoses. Pre-pregnancy counseling was recorded for 13% (n = 19) of women who later became pregnant. VPA monotherapy and the lack of VPA treatment indication were associated with the lack of counseling before pregnancy. CONCLUSIONS: This study revealed a significant deficit in pre-pregnancy counseling for WWE treated with VPA in Estonia. Awareness of the need for such counseling should be increased among medical specialists.

Trends in the use of hormonal contraception in Estonia 2005-2019 and the risk of arterial and venous thromboembolism: a population-based study.

PURPOSE: To describe trends in hormonal contraceptive use, incidence of thromboembolism and presence of risk factors for thromboembolism among the users in Estonia. MATERIAL AND METHODS: Data of 223 312 female patients aged 15-49 years in 2005-2019 from national health insurance databases was derived. Annual prevalence rates of hormonal contraceptive users, incidence rates of thromboembolism and prevalence rates of risk factors were calculated. RESULTS: Between 2005-2019 usage of progestogen-only contraceptives (POCs) increased steadily (from 24 to 135 users per 1000 population), whereas combined hormonal contraceptive (CHC) use declined (from 209 in 2012 to 161 users per 1000 population in 2019). During the study period, 390 cases of venous thromboembolism and 108 arterial thromboembolism coincided with hormonal contraceptive use. Incidence rate for venous thromboembolism was 5.0 (95% CI 4.5-5.5) and for arterial thromboembolism 1.4 per 10 000 person-years (95% CI 1.1-1.7) among hormonal contraceptive users. Age adjusted incidence of venous thromboembolism among CHC users was 5.8 (95% CI 4.1-8.2) times higher than in POC users. Among CHC users, 10.3% had more than one risk factor for thrombosis. CONCLUSIONS: In regards to the risk of thromboembolism, wider use of POCs and declining prevalence of CHCs in Estonia is positive trend. Still, women with history of thrombosis receiving CHC is a serious concern.

The COVID-19 pandemic and the use of benzodiazepines and benzodiazepine-related drugs in Estonia: an interrupted time-series analysis.

BACKGROUND: The COVID-19 pandemic has posed challenges that worsened people's mental health. We explored the impact of the COVID-19 pandemic on the mental well-being of the population, as indicated by the prevalence rates of benzodiazepine and benzodiazepine-related drug (BDZ) use. METHODS: This population-based, time-series analysis included all prescriptions of BDZs dispensed in Estonia between 2012 and 2021. The monthly prevalence rates of BDZ use were calculated. Autoregressive integrated moving average models with pulse and slope intervention functions tested for temporary and long-term changes in monthly prevalence rates after the onset of the COVID-19 pandemic. RESULTS: Throughout the 10-year study period, a total of 5,528,911 BDZ prescriptions were dispensed to 397,436 individuals. A significant temporary increase in the overall prevalence rate of BDZ use in March 2020 (2.698 users per 1000, 95% CI 1.408-3.988) was observed, but there was no statistically significant long-term change. This temporary increase affected all the examined subgroups, except for new users, individuals aged 15-29 years, and prescribing specialists other than general practitioners and psychiatrists. The long-term increase in BDZ use was confined to females aged 15-29 years (0.056 users per 1000 per month, 95% CI 0.033-0.079), while no significant change was observed among males of the same age (0.009 users per 1000 per month, 95% CI - 0.017 to 0.035). Among females aged 15-29 years, a significant long-term increase in BDZ use was observed for anxiety disorders (0.017 users per 1000 per month, 95% CI 0.010-0.023), depressive disorders (0.021 users per 1000 per month, 95% CI 0.012-0.030), and other mental and behavioral disorders (0.020 users per 1000 per month, 95% CI 0.010-0.030), but not for sleep disorders (- 0.008 users per 1000 per month, 95% CI - 0.018-0.002). CONCLUSION: The COVID-19 pandemic led to a short-term increase in BDZ use immediately after the pandemic was declared. In the long term, young females experienced a sustained increase in BDZ use. The prolonged effect on girls and young women suggests their greater vulnerability. These results underscore the need to effectively address the long-term effects of the pandemic among youth.

Compliance with Pregnancy Prevention Recommendations for Isotretinoin Following the Amendment of the European Union Pregnancy Prevention Program: A Repeat Study in Estonia.

BACKGROUND: Isotretinoin, indicated for severe acne, is a potent teratogen and therefore contraindicated in pregnancy. Thus, the pregnancy prevention program (PPP) for isotretinoin has been introduced. OBJECTIVES: The aim of this study was to assess the concomitant use of isotretinoin and effective contraception and the rate of potential isotretinoin-exposed pregnancies in females of childbearing age in 2017-2020 in Estonia. In addition, we aimed to evaluate whether compliance with the PPP has improved compared with the previous study conducted in Estonia covering the period of 2012-2016. METHODS: This retrospective, nationwide study using prescription and healthcare claims data included 2575 females aged 15-45 years who started using isotretinoin between 2017 and 2020. RESULTS: For 64.7% of females of childbearing age, no concurrent use of an effective contraceptive was detected while using isotretinoin. A moderately higher contraceptive coverage (35.3%) was observed compared with the previous study (29.7%) (p < 0.001). Complete contraception coverage was highest in females aged 30-39 years with an adjusted OR of 12.8 (p < 0.001) compared with the age group 15-19 years and 2.47 (p < 0.001) compared with the age group 20-29 years. 17 pregnancies coincided with the isotretinoin treatment-related period. The risk for potential isotretinoin-exposed pregnancy was 6.6 (95% CI 3.9-10.5) per 1000 treated females of childbearing age over the 4-year observation period. The risk for potential isotretinoin-exposed pregnancies per 1000 treated females was 1.0 in females aged 15-19 years, 11.6 in females aged 20-29 years, 8.8 in females aged 30-39 years, and 7.4 in females aged 40-45 years (p = 0.009). CONCLUSION: A slight improvement in complete contraceptive coverage during isotretinoin use has not resulted in a decrease in the risk of isotretinoin-exposed pregnancies. The contraceptive usage and risk for pregnancy vary greatly across age groups, suggesting the need for a more targeted approach to improve the effectiveness of the PPP.

An expert review of clozapine in Eastern European countries: Use, regulations and pharmacovigilance.

OBJECTIVES: To compare the prevalence, regulations, and pharmacovigilance practices of clozapine use in Eastern European countries (except Russia). METHODS: Questionnaires and data from administrative databases (2016 and 2021), package inserts and national guidelines were collected from 21 co-authors from 21 countries. Reports of clozapine adverse drug reactions (ADRs) sent to the global pharmacovigilance database (VigiBase™) were analyzed from introduction to December 31, 2022. RESULTS: Clozapine prescription among antipsychotics in 2021 varied six-fold across countries, from 2.8 % in the Czech Republic to 15.8 % in Montenegro. The utilization of antipsychotics in both 2016 and 2021 was highest in Croatia, and lowest in Serbia in 2016, and Montenegro in 2021, which had half the defined daily dose (DDD)/1000/day compared to the Croatian data. From 2016 to 2021, the prevalence of antipsychotic use increased in almost all countries; the proportion of clozapine use mainly remained unchanged. Differences were detected in hematological monitoring requirements and clozapine approved indications. Only a few national schizophrenia guidelines mention clozapine-induced myocarditis or individual titration schemes. The VigiBase search indicated major underreporting regarding clozapine and its fatal outcomes. By comparison, the United Kingdom had less than half the population of these Eastern European countries but reported to VigiBase more clozapine ADRs by 89-fold and clozapine fatal outcomes by almost 300-fold. CONCLUSION: Clozapine is under-utilized in Eastern European countries. Introducing individualized clozapine treatment schedules may help to maximize clozapine benefits and safety. Major improvement is needed in reporting clozapine ADRs and fatal outcomes in Eastern European countries.

Valproic acid prescription trends among females of childbearing age in Estonia: A 14-year nationwide prescription database study.

PURPOSE: Valproic acid (VPA) is a widely used anticonvulsant that is effective against most seizure types. Due to its teratogenic effects, its use should be avoided among females of childbearing age, unless other treatments are ineffective or not tolerated. This study aimed to determine the prevalence of VPA use in 2005-2018 in Estonia, with special attention to females of childbearing age. METHODS: In this retrospective nationwide population-based cohort study, outpatient prescription data from the national health insurance provider were used. Annual sex- and age-specific prevalence rates were calculated, and changes therein during the study period were evaluated. RESULTS: The annual rates of VPA use among females of childbearing age increased significantly in 2005-2014. After 2014, the increasing trend stopped; in 2014-2018, the prevalence rates declined slightly [prevalence rate ratio (PRR), 0.94; P = 0.136]. In males of the same age, the increasing trend continued (PRR, 1.08: P = 0.028). Among neurologists, the rate of VPA prescription to females aged <15 and 15-44 years decreased during 2014-2018 (PRR, 0.74; P < 0.001 and PRR 0.72; P < 0.001, respectively); no change in prescription frequency was seen among psychiatrists during this period. CONCLUSIONS: The increasing trend in VPA usage among females of childbearing age in Estonia stopped after 2014, when the European Medicines Agency's strengthened restrictions on VPA use in females were communicated extensively in Estonia. The level of awareness of VPA's harmful effects during pregnancy is lower in the psychiatric community.

Trends in opioid prescribing in Estonia (2011-2017).

Our objective was to examine the trends and variation in opioid prescribing in Estonia from 2011 to 2017. This retrospective cross-sectional study is based on a nationwide prescription medicines database. We stratified the analysis by treatment indication (cancer vs noncancer pain). Between 2011 and 2017, annual opioid prescribing rates increased by 67% (from 82.9 to 138.6 prescriptions per 1000 population). The annual number of prescriptions per patient did not change substantially (from 2.94 in 2011 to 2.87 in 2017), and was higher among cancer patients (5.07 vs 2.67 annual prescriptions per cancer and noncancer patients, respectively, in 2017). The use of the most potent opioids (morphine, fentanyl) was higher in noncancer than in cancer patients. The use of prescription opioids is low, and raises concern about the potential undertreatment of cancer pain, in parallel with misuse of opioids for either noncancer pain or diversion.

Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia in 2012-2016.

BACKGROUND: Isotretinoin is an effective treatment for severe acne; no alternative treatment has an equal therapeutic effect. The teratogenic effects of isotretinoin can be avoided, and numerous recommendations and regulations are in force to minimize the risk of pregnancy during treatment. OBJECTIVES: To describe isotretinoin prescription patterns for women aged 15-45 years, assess the concomitancy of isotretinoin and contraceptive use, and determine the rate of potential isotretinoin-exposed pregnancies in Estonia. METHODS: This retrospective, nationwide, population-based, cohort study derived data from national health insurance databases and included female patients aged 15-45 years in Estonia for whom one or more prescriptions for isotretinoin were dispensed between 2012 and 2016. The main outcome was the proportion of women who used systemic isotretinoin and had a concomitant record of (hormonal or intrauterine) contraception use covering the isotretinoin treatment period when pregnancy is contraindicated. RESULTS: Of the 2792 women aged 15-45 years filling an isotretinoin prescription, 15.7% (95% CI 14.4-17.1) had full and 13.9% (95% CI 12.7-15.3) partial (not covering the whole period during which pregnancy is contraindicated) contraceptive coverage. The risk for potential isotretinoin-exposed pregnancy was 3.6 (95% CI 2.0-7.0) per 1000 treated women over the 5-year observation period. The odds for full coverage with effective contraception increased with the age of the patient, with the duration of isotretinoin treatment and over the period of observation. CONCLUSION: Our study adds to the existing literature documenting limited compliance with pregnancy prevention programs for isotretinoin-containing products, and calls for program assessment to identify whether new measures should be taken or whether weaknesses in policy or implementation can be corrected.