Regulatory action and moderate decrease in methylphenidate use among ADHD diagnosed patients aged five and under in Korea.

In December 2009, Korean regulatory agency announced that methylphenidate, a drug used to treat attention deficit-hyperactivity disorder (ADHD), should not be used in children aged five and under due to the risk of sudden cardiac death. This study examined the impact of regulatory action and prescribing patterns. We conducted a time series analysis using the Korea National Health Insurance Service database. Study subjects included children under 18years old with ADHD from January 2007 to December 2011. Contraindicated use of methylphenidate was defined as use of methylphenidate at least once in children aged five and under. We selected additional control points (2007, 2008, and 2010) and compared the methylphenidate use one year before and after each point. We calculated relative and absolute reductions, and 95% confidence intervals. The total number of ADHD patients was 376,298. Overall, there was a 70.87% relative reduction (95% CI: 63.33%-79.31%) and a 0.93% absolute reduction (95% CI: 0.51%-0.60%) of methylphenidate use. The relative and absolute reductions were 27.61% (95% CI: 24.76%-30.78%) and 0.31% (95% CI: 0.21%-0.41%) in 2007; 43.58% (95% CI: 38.02%-49.96%) and 0.35% (95% CI: 0.27%-0.43%) in 2008; 46.52% (95% CI: 38.86%-55.70%) and 0.21 (95% CI: 0.15%-0.27%) in 2009; and 10.20% (95% CI: 8.32%-12.50%) and 0.02% (95% CI: 0.02%-0.07%) in 2010. Korean regulatory action led to a moderate decrease in contraindicated methylphenidate use even after the steep decline before the regulatory action.

Prescribing patterns of the four most commonly used sedatives in endoscopic examination in Korea: propofol, midazolam, diazepam, and lorazepam.

As the sedative use increases due to the effectiveness and relatively safe profile, the abuse potential is also increasing. This study was conducted to examine the usage of four sedative agents in endoscopic examination and to compare the propofol use with the other three sedatives. Using National Health Insurance claims data from 2008 to 2012, we identified the number of cases of conscious sedation during endoscopy using one or more of the following agents: propofol, midazolam, diazepam, and lorazepam. The general characteristics of patients and medical service providers were analyzed, and the regional and annual distributions of frequency of use were compared. We also identified patient cases with excessive number of endoscopic examinations. Among the total of 3,156,231 sedatives users, midazolam was the most commonly used agent (n=2,845,250, 90.1%). However, the largest increase in patient number, which increased from 11,410 in 2008 to 28,170 in 2012, was observed with propofol. While the majority of patients received an annual endoscopy, we identified several suspected abuse cases of patients receiving endoscopies repetitively as many as 114 times in five years. The rise of sedative use in endoscopic examinations and several patient cases of repeated sedative administration suggest a potential risk for abuse. Medical service providers should be cautious when using sedatives and carefully review each patient's medical history prior to the procedure.

Prevalence of antibiotic use for pediatric acute upper respiratory tract infections in Korea.

This study was conducted to estimate the prevalence of antimicrobial prescribing for acute upper respiratory tract infections (URI) among pediatric outpatients and to identify the national patterns of its use from 2009 to 2011 in Korea. Using National Patients Sample database from 2009 to 2011, we estimated the frequency of antibiotics prescribing for URI in pediatric outpatients with diagnoses of acute nasopharyngitis (common cold), acute sinusitis, acute pharyngitis, acute tonsillitis, acute laryngitis/tracheitis, acute obstructive laryngitis/epiglottitis, and acute upper respiratory infections of multiple and unspecified sites. The proportions of each antibiotic class were calculated by year and absolute and relative differences were estimated. Also, we investigated daily amount of prescribed antibiotics per defined population according to the type of medical care institution, physician specialty, and geographic region. The overall antibiotic prescribing proportion was 58.7% and its annual proportion slightly decreased (55.4% in 2011 vs. 60.5% in 2009; adjusted odds ratio, 0.82; 95% confidence interval, 0.82-0.83). Variations by the type of medical care institution were observed. Tertiary hospitals (45.0%) were less likely to prescribe antibiotics than primary care clinics (59.4%), hospitals (59.0%), and general hospitals (61.2%); they showed different tendencies in choosing antibiotics. Variations by physician specialty and region were also observed. Prevalence of antimicrobial prescribing for pediatric URI is still considered higher than that of western countries and varies by the type of medical care institution, physician specialty, and geographic region.

Dramatic decrease in fluoroquinolones in the pediatric population in Korea.

PURPOSE: This study was performed to evaluate the change of prescribing patterns after the regulatory action regarding fluoroquinolones in pediatric patients. METHODS: We conducted a time series analysis using the Korea Health Insurance Review and Assessment Service National Patients Sample database. Study subjects consisted of pediatric patients under 18 years of age who were prescribed antibiotics at least once (ATC code, J01) before (January 2009-December 2009) and after implementation (January 2010-December 2011) of the regulation. The use of fluoroquinolones was defined as the use of the following antibiotics for at least once in pediatric patients: ofloxacin, ciprofloxacin, norfloxacin, lomefloxacin, levofloxacin, and gemifloxacin. We calculated the number of pediatric fluoroquinolone users for each month. The difference between proportions before and after the regulation was estimated as relative and absolute reduction of fluoroquinolone use. We calculated 95% confidence intervals (CI). RESULTS: We identified 4, 945, 169 antibiotic prescriptions in 484, 914 pediatric patients. During the 12-month period before implementation, percentage of fluoroquinolone use was 4.81% (95% CI: 4.70-4.91%, N = 8001). We observed a rapid decrease in the monthly number of fluoroquinolone users in pediatric population after the implementation of regulatory action. In the year after regulatory action, the percentage of fluoroquinolone use was only 0.26% (95% CI: 0.24-0.28%, N = 834). Overall, there was a 94.55% relative reduction (95% CI: 88.02-101.56%) in the use of fluoroquinolones. CONCLUSION: Korean regulatory actions regarding fluoroquinolones had an effect of reducing use in pediatric population.

New initiatives for pharmacovigilance in South Korea: introducing the Korea Institute of Drug Safety and Risk Management (KIDS).

PURPOSE: Pharmacovigilance plays a vital role in ensuring that patients receive appropriate medical products that are safe and effective. This paper aims to describe the history of pharmacovigilance in Korea and introduce the establishment and goal of the KIDS. METHODS: In Korea, the adverse drug reactions (ADR) reporting system was launched in 1988 by the Korea Ministry of Food and Drug Safety (MFDS) and spontaneous ADR reports have been collected from health care professionals and the general public. Although the ADR reporting system has begun, the reporting rate was very low in the first 10 years, and safety actions were done passively in response to the US Food and Drug Administration (FDA) or European Medicines Agency (EMA)'s safety alert and communications. RESULTS: Therefore, the Korea Institute of Drug Safety and Risk Management (KIDS) was established in April 2012 as a new initiative for pharmacovigilance. CONCLUSIONS: The KIDS will continue to contribute to the improvement of Korean pharmacovigilance by collecting, managing, and analyzing consumer-centered drug safety information.

Agreement of label information of cardiovascular drugs in pregnancy among Korea, the USA, the UK, and Japan.

Drug label is a common source of information; however, the content varies widely. This study aims to evaluate label information on cardiovascular drugs regarding pregnancy for their similarities in Korea, USA, UK, and Japan. Study drugs were selected as following (1) cardiovascular drugs according to the WHO ATC code (C01-C09) and (2) drugs currently marketed in all four countries were included. Evidence level was classified into five categories ('Definite', 'Probable', 'Possible', 'Unlikely', and 'Unclassified') and recommendation level was classified into four categories ('Contraindicated', 'Cautious', 'Compatible', and 'Unclassified'). Frequency and proportion were presented. Percent agreement and kappa coefficient with 95% confidence interval (CI) were calculated using SAS ver. 9.3. Total of 50 cardiovascular drugs were included. 'Unclassified' was represented the most in Korea, followed by Japan and UK (58%, 54%, and 46%, p<0.05). For recommendation level, the majority of drugs in all four countries were classified as 'contraindicated' or 'cautious'. Japanese labels had the largest proportion of 'contraindicated' level (62%), and Korea and UK followed (58%, 44%, p<0.05). Only in the USA, 10.0% of the drugs were 'compatible' whereas, there were none in Korea, UK, and Japan (p<0.01). Korea and Japan showed a substantial agreement in evidence and recommendation level (kappa=0.69, 0.67). Labels of cardiovascular drugs in pregnancy differed widely. Reliable safety information in pregnancy should be provided through regular updates.

Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study.

OBJECTIVE: To define the risk of intracranial haemorrhage among patients treated with antidepressants and non-steroid anti-inflammatory drugs (NSAIDs), compared with the risk among those treated with antidepressants without NSAIDs. DESIGN: Retrospective nationwide propensity score matched cohort study. SETTING: Korean nationwide health insurance database between 1 January 2009 and 31 December 2013. PARTICIPANTS: Patients who began receiving antidepressants for the first time (index date) without a history of having received a prescription for antidepressants during the preceding year. Patients who had been diagnosed as having cerebrovascular diseases within a year before the index date were excluded. MAIN OUTCOME MEASURE: Time to first hospital admission with intracranial haemorrhage within 30 days after drug use. Matched Cox regression models were used to compare the risk of intracranial haemorrhage among patients who were treated with antidepressants with and without NSAIDs, after propensity score matching with a 1:1 ratio. RESULTS: After propensity score estimation and matching in a 1:1 ratio, the cohort used in the analysis included 4,145,226 people. The 30 day risk of intracranial haemorrhage during the entire study period was higher for combined use of antidepressants and NSAIDs than for use of antidepressants without NSAIDs (hazard ratio 1.6, 95% confidence interval 1.32 to 1.85). No statistically meaningful differences were found in risk of intracranial haemorrhage between the antidepressant drug classes. CONCLUSIONS: Combined use of antidepressants and NSAIDs was associated with an increased risk of intracranial haemorrhage within 30 days of initial combination.

A comparison of risperidone and haloperidol for the risk of ischemic stroke in the elderly: a propensity score-matched cohort analysis.

OBJECTIVE: With an increase in antipsychotic use in the elderly, the safety profile of antipsychotics has been emphasized. Strong concerns have been raised about whether the risk of ischemic stroke differs between risperidone and haloperidol. This study compared the risk of ischemic stroke between elderly patients taking risperidone and haloperidol. METHOD: We conducted a retrospective cohort study using the Korea Health Insurance Review and Assessment Service database, applying a propensity-matched analysis. The cohort consisted of elderly patients who were newly prescribed haloperidol or risperidone between January 1, 2006 and December 31, 2009. Patients with prior cerebrovascular diseases (ICD-10, I60-I69), transient ischemic attack (ICD-10, G45), or cerebral tumors (ICD-10, C31) during 365 days prior to the initiation date were excluded. The study subjects were selected by propensity score matching. The outcome was defined as the first hospitalization for ischemic stroke (ICD-10, I63). Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence intervals (95% CI) for ischemic stroke with haloperidol compared with risperidone use. RESULTS: A total of 14,103 patients were included in the propensity-matched cohort for each drug. Overall, the incidence rate was higher for haloperidol users compared to the risperidone users (6.43 per 1000 person-years vs. 2.88 per 1000 person-years). A substantially increased risk was observed in haloperidol users (adjusted HR = 2.02, 95% CI, 1.12-3.62). CONCLUSIONS: The evidence showed that haloperidol should be prescribed in the elderly with caution.

Risk of ischemic stroke associated with the use of antipsychotic drugs in elderly patients: a retrospective cohort study in Korea.

OBJECTIVE: Strong concerns have been raised about whether the risk of ischemic stroke differs between conventional antipsychotics (CAPs) and atypical antipsychotics (AAPs). This study compared the risk of ischemic stroke in elderly patients taking CAPs and AAPs. METHOD: We conducted a retrospective cohort study of 71,584 elderly patients who were newly prescribed the CAPs (haloperidol or chlorpromazine) and those prescribed the AAPs (risperidone, quetiapine, or olanzapine). We used the National Claims Database from the Health Insurance Review and Assessment Service (HIRA) from January 1, 2006 to December 31, 2009. Incident cases for ischemic stroke (ICD-10, I63) were identified. The hazard ratios (HR) for AAPs, CAPs, and for each antipsychotic were calculated using multivariable Cox regression models, with risperidone as a reference. RESULTS: Among a total of 71,584 patients, 24,668 patients were on risperidone, 15,860 patients on quetiapine, 3,888 patients on olanzapine, 19,564 patients on haloperidol, and 7,604 patients on chlorpromazine. A substantially higher risk was observed with chlorpromazine (HR = 3.47, 95% CI, 1.97-5.38), which was followed by haloperidol (HR = 2.43, 95% CI, 1.18-3.14), quetiapine (HR = 1.23, 95% CI, 0.78-2.12), and olanzapine (HR = 1.12, 95% CI, 0.59-2.75). Patients who were prescribed chlorpromazine for longer than 150 days showed a higher risk (HR = 3.60, 95% CI, 1.83-6.02) than those who took it for a shorter period of time. CONCLUSIONS: A much greater risk of ischemic stroke was observed in patients who used chlorpromazine and haloperidol compared to risperidone. The evidence suggested that there is a strong need to exercise caution while prescribing these agents to the elderly in light of severe adverse events with atypical antipsychotics.