Pharmacokinetics of atorvastatin and sustained-release metformin fixed-dose combination tablets: two randomized, open-label, 2-way crossover studies in healthy male subjects under fed conditions

Two separate studies were conducted to establish bioequivalence (BE) for two doses of atorvastatin/metformin sustained-release (SR) fixed dose combination (FDC) versus the same dosage of the individual component (IC) tablets in healthy male subjects under fed conditions (study 1, BE of atorvastatin/metformin SR 20/500 mg FDC; study 2, BE of atorvastatin/metformin SR 20/750 mg FDC). Each study was a randomized, open-label, single oral dose, two-way crossover design. Serial blood samples were collected pre-dose and up to 36 hours post-dose for atorvastatin and 24 hours for metformin. Plasma concentrations of atorvastatin, 2-OH atorvastatin and metformin were analyzed using a validated liquid chromatography tandem mass-spectrometry. A non-compartmental analysis was used to calculate pharmacokinetic (PK) variables and analysis of variance was performed on the lognormal-transformed PK variables. A total of 75 subjects completed the study 1 (36 subjects) and study 2 (39 subjects). The 90% confidence intervals for the adjusted geometric mean ratio of Cmax and the AUC0-t were within the predefined 0.80 to 1.25 range. The number of subjects reporting at least one adverse event following FDC treatments was comparable to that following IC treatments. The two treatments were well tolerated. Therefore, atorvastatin/metformin SR 20/500 mg and 20/750 mg FDC tablets are expected to be used as alternatives to IC tablets to decrease the pill burden and increase patient compliance.

Erratum: Prescribing Patterns of Codeine among Children under aged 12 in Korea

Erratum agreed to by all authors, editor in chief, publisher, and scientific society.

Prescribing Patterns of Codeine among Children under Aged 12 in Korea

OBJECTIVE: Codeine may result in death or respiratory depression in children, particularly who are rapid metabolizer of CYP2D6, therefore it should be used cautiously among children under 12 years of age. This study was to investigate the prescribing pattern of codeine among children according to the age group, prescribed diagnosis, type of medical service and medical specialties. METHOD: We used Korea Health Insurance Review and Assessment Service-National Patient Sample (HIRA-NPS) database. Study subjects included inpatients or outpatients, who were prescribed codeine between January, 1, 2011 and December, 31, 2011. Contraindicated use of codeine was defined as the use of codeine at least one times under aged 12. Age groups were sub-classified according to the <2 years, 2-4 years, 5-8 years, and 9-11 years. Frequently prescribed diagnosis (ICD-10), type of medical service, and medical specialties were also described among codeine users under aged 12. RESULTS: Codeine users were 6,411 inpatients (9,958 prescriptions), and 3,397 outpatients (6,258 prescriptions), respectively. Codeine prescription under 12 years of age were 2.1% (210 prescriptions) among inpatients, and 12.3% (776 prescriptions) among outpatients (p-value<0.05). Outpatient prescriptions of codeine under 12 aged were issued mostly from primary care clinics and frequent diagnosis were unspecified bronchopneumonia (51.6%), and vasomotor rhinitis (23.7%). CONCLUSION: This study found prescribing of codeine under 12 aged is common in outpatient and primary clinics. Nationwide and community-based efforts should be needed to reduce inappropriate prescribing among children.

Agreement of Label Information on Anxiolytics and Antidepressants for Pregnant Women: Comparison among Korea, the USA, the UK and Japan / 대한정신약물학회지

OBJECTIVE: Anxiolytics and antidepressants are commonly used to treat depressive disorders in pregnant women. Specific and clear evidence is required when managing pregnant patients with such medications to ensure safety. However, information provided by approval label information is insufficient and often different among many countries. By analyzing label information of approval label and other references, this study aims to show the limitations and suggest appropriate directions for retrieving safety information. METHODS: We selected five anxiolytics and eleven antidepressants, which belongs to Korea drug classification codes 117 (psychotropic agents). We chose four countries, Korea, the United States of America (USA), the United Kingdom, Japan and collected safety information for pregnant women in label information. We evaluated the safety information based on recommendation level and evidence level. Then, kappa value and overall agreement were calculated using SAS 9.3. to assess data homogeneity. We further searched Reprotox and a textbook about contraindicated drugs in label information. RESULTS: Recommendation level and evidence level was different in each country. The number of commonly contraindicated drug in label information of four countries was none, and contraindicated drugs in labels were different respectively. Kappa value of evidence level between label information of Korea and Japan, the USA and Japan was 0.61, 0.43 respectively, corresponding to 'substantial agreement' and 'moderate agreement'. The overall agreement was 75%, 62.5% respectively. The information of label was different from that of other references, Reprotox and a textbook in terms of the clinical evidences and recommendation levels. CONCLUSION: Safety information of anxiolytics and antidepressants in label information needs to be updated on a regular basis both for health professionals and patients. With the implication of the inconsistent guidance for the safety information in pregnant women, reliable safety information in pregnant women would be needed.