Natsumi Ueda

Evaluation of Dabigatran- and Warfarin-Associated Hemorrhagic Events Using the FDA-Adverse Event Reporting System Database Stratified by Age

Dabigatran and warfarin are oral anticoagulant drugs widely used for the prevention of stroke in patients with atrial fibrillation. The objective of this study was to evaluate the interaction between aging and dabigatran- and warfarin-induced gastrointestinal (GI) and nervous system hemorrhage using data available in the FDA Adverse Event Reporting System (FAERS) database. We analyzed reports of hemorrhagic events in the GI and nervous system recorded in the FAERS database between 2004 and 2014 using an adjusted reporting odds ratio (ROR). We demonstrated that dabigatran-associated GI hemorrhage was significantly increased in patients over the age of 80 years. The RORs of dabigatran increased with increasing age, although aging had little effect on warfarin-associated GI hemorrhage. The ROR for anticoagulant-associated nervous system hemorrhage was not significantly affected by aging, as compared to GI hemorrhage. Our results indicate that the excretion of dabigatran may be affected by aging, as compared to warfarin, likely due to renal function decline. Our results emphasize the need for physicians to closely monitor GI bleeding in aging patients, because it is closely related to renal function deterioration.

Time-to-Onset Analysis of Drug-Induced Long QT Syndrome Based on a Spontaneous Reporting System for Adverse Drug Events

Long QT syndrome (LQTS) is a disorder of the heart’s electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal. There have been no previous reports on the time-to-onset for LQTS based on data from spontaneous reporting systems. The aim of this study was to assess the time-to-onset of LQTS according to drug treatment. We analyzed the association between 113 drugs in 37 therapeutic categories and LQTS including TdP using data obtained from the Japanese Adverse Drug Event Report database. For signal detection, we used the reporting odds ratio (ROR). Furthermore, we analyzed the time-to-onset data and assessed the hazard type using the Weibull shape parameter. The RORs (95% confidence interval) for bepridil, amiodarone, pilsicainide, nilotinib, disopyramide, arsenic trioxide, clarithromycin, cibenzoline, donepezil, famotidine, sulpiride, and nifekalant were 174.4 (148.6–204.6), 17.3 (14.7–20.4), 52.0 (43.4–62.4), 13.9 (11.5–16.7), 69.3 (55.3–86.8), 54.2 (43.2–68.0), 4.7 (3.8–5.8), 19.9 (15.9–25.0), 8.1 (6.5–10.1), 3.2 (2.5–4.1), 7.1 (5.5–9.2), and 254.8 (168.5–385.4), respectively. The medians and quartiles of time-to-onset for aprindine (oral) and bepridil were 20.0 (11.0–35.8) and 18.0 (6.0–43.0) days, respectively. The lower 95% confidence interval of the shape parameter β of bepridil was over 1 and the hazard was considered to increase over time.Our study indicated that the pattern of LQTS onset might differ among drugs. Based on these results, careful long-term observation is recommended, especially for specific drugs such as bepridil and aprindine. This information may be useful for the prevention of sudden death following LQTS and for efficient therapeutic planning.

Hyperglycemic adverse events following antipsychotic drug administration in spontaneous adverse event reports

BackgroundAntipsychotics are potent dopamine antagonists used to treat schizophrenia and bipolar disorder. The aim of this study was to evaluate the relationship between antipsychotic drugs and adverse hyperglycemic events using the FDA Adverse Event Reporting System (FAERS) database. In particular, we focused on adverse hyperglycemic events associated with atypical antipsychotic use, which are major concerns.FindingsWe analyzed reports of adverse hyperglycemic events associated with 26 antipsychotic drugs in the FAERS database from January 2004 to March 2013. The Standardized Medical Dictionary for Regulatory Activities Queries (SMQ) preferred terms (PTs) was used to identify adverse hyperglycemic events. The number of adverse hyperglycemic reports for the top eight antipsychotic drugs, quetiapine, olanzapine, risperidone, aripiprazole, haloperidol, clozapine, prochlorperazine, and chlorpromazine was 12,471 (28.9%), 8,423 (37.9%), 5,968 (27.0%), 4,045 (23.7%), 3,445 (31.5%), 2,614 (14.3%), 1,800 (19.8%), and 1,003 (35.7%), respectively. The reporting ratio increased with co-administration of multiple antipsychotic drugs. For example, adverse hyperglycemic events represented 21.6% of reports for quetiapine monotherapy, 39.9% for two-drug polypharmacy, and 66.3% for three-drug polypharmacy.ConclusionAntipsychotic drug polypharmacy may influence signal strength, and may be associated with hyperglycemia. After considering the causality restraints of the current analysis, further robust epidemiological studies are recommended.

Stevens–Johnson syndrome and toxic epidermal necrolysis: The Food and Drug Administration adverse event reporting system, 2004–2013

StevenseJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are severe cutaneous adverse reactions, are associated with fatal disorders.1 Although many causes of SJS/TEN have been proposed, their pathogenesis is not fully understood. Hypersensitivity to medications accounts for the majority of cases of SJS/ TEN.2 Several research groups have presented reports on drugs implicated in SJS/TEN (selective cyclooxygenase-2 inhibitors, lamotrigine, anti-epileptic drugs, sulfonamide antibiotics, and allopurinol, etc.).3,4 SJS associated with Mycoplasma pneumoniae infection is observed mainly in children,5,6 while another group reported the effects of the genetic background of patients.7 The relationship between aging and SJS/TEN is still not clear. Since SJS/TEN are very rare diseases,1 the implementation phase of epidemiologic research is fraught with difficulties. The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) is the largest and most well-known database worldwide, and it reflects the realities of clinical practice.8 FAERS, therefore, is one of the primary tools used in pharmacovigilance. We examined the incidence of SJS/TEN in the FAERS database from January 2004 to March 2013. To extract case reports of SJS/ TEN from the FAERS database, SJS/TEN were coded according to the terminology preferred by the Medical Dictionary for Regulatory Activities 16.0. We used the following three preferred terms to match SJS and TEN: SJS/PT10042033, oculomucocutaneous syndrome/PT10030081, and TEN/PT10044223. To detect SJS/TEN incidences, we calculated the reporting odds ratio (ROR), which is established for pharmacovigilance by using a disproportionality analysis.8 The ROR is an applicable technique that allows for adjustment through logistic regression analysis and offers the advantageous possibility of controlling for covariates.9 We refined the results with a dedicated correction to detect possible confounders present in the database. The reports were stratified by age as follows: 17 years, 18e39 years, 40e59 years, 60e79 years, and 80 years. The RORs were adjusted for gender, reporting year, and stratified age group. The following logistic model was used:

Analysis of licorice-induced pseudoaldosteronism in the Japanese Adverse Drug Event Report database

We analyzed the association of age, sex, and dosage with licorice‐associated pseudoaldosteronism using spontaneous adverse event reports.

[Adverse Event Trends Associated with Over-the-counter Drugs: Data Mining of the Japanese Adverse Drug Event Report Database].

Over-the-counter (OTC) drugs play an important role in self-medication. To ensure patient safety, pharmacists should ask patients to pay attention to possible adverse events (AE) associated with OTC drugs and educate patients about the symptoms related to those AEs. The aims of the present study were as follows: (1) to assess the tendency of AEs to occur with OTC drug use in Japan; (2) to detect a safety signal for OTC drugs using the reporting odds ratio (ROR); and (3) to evaluate clustery features, which include suspected drugs and therapeutic classifications, and safety signal indices (number of reports and the ROR), using cluster analysis. The number of reports of AEs following use of combination cold remedy, antipyretic and analgesic remedy, and herbal medicine was 1007, 566, and 221, respectively. We set the cluster number at five; clustery features obtained were as follows: (1) high reporting rate for skin and subcutaneous tissue disorder AEs was the largest group related to combination cold remedy; (2) high reporting rate for nervous system disorder AEs including dizziness was the second largest group. The same medicinal ingredient may demonstrate similar tendencies of the occurrence of AEs and similar clustery features in the Japanese Adverse Drug Event Report database. Our analysis of AEs associated with OTC drugs may be useful for pharmacists and patients alike. Further studies are required to draw better-informed conclusions.

Evaluation of Drug-Induced Photosensitivity Using the Japanese Adverse Drug Event Report (JADER) Database

Drug-induced photosensitivity (DIP) refers to the development of cutaneous disorders caused by the combined effects of different medications and light. The aim of this study was to obtain new information on drug risk comparisons and on DIP onset profiles, including seasonal variations, for clinically used prescription drugs. We analyzed reports of DIP recorded in the Japanese Adverse Drug Event Report (JADER) database using a reporting odds ratio (ROR). We also used Weibull proportional-hazards models for each drug to examine the patterns of DIP. The JADER database contains 430587 reports recorded from April 2004 to November 2016. The ROR values (95% confidence interval [CI]) of losartan/hydrochlorothiazide (HCTZ), valsartan/HCTZ, and ketoprofen were 214.5 (162.1-283.9), 104.7 (66.3-165.5), and 117.9 (76.6-181.5), respectively. For time-to-onset analysis, the median durations (interquartile range) for DIP caused by losartan/HCTZ, valsartan/HCTZ, and ketoprofen were 56 (41-78), 49 (38-88), and 8 (2-14) days, respectively. The lower limit of the 95% CI for the Weibull shape parameter β value for losartan/HCTZ was greater than 1. More than half of the reports of DIP onset following the administration of ketoprofen were recorded within 10 d of treatment initiation. The seasonal variation of photosensitivity reactions was shown to follow an annual sinusoidal pattern with a peak in April and May. Based on the results, losartan/HCTZ, valsartan/HCTZ, and ketoprofen should be used carefully in clinical practice to avoid DIP.

Contraceptives as possible risk factors for postpartum depression: A retrospective study of the food and drug administration adverse event reporting system 2004-2015.

Postpartum depression is a mood disorder that commonly affects women during the early postpartum period. The objective of this study was to analyse the association of postpartum depression with drugs (including contraceptive devices and implants) with spontaneously reported adverse events reported in the US Food and Drug Administration Adverse Event Reporting System database.

Analysis of polypharmacy effects in older patients using Japanese Adverse Drug Event Report database

Population aging is a global phenomenon, and choosing appropriate medical care for the elderly is critical. Polypharmacy is suspected to increase the risk of adverse events (AEs) in older patients. We examined the AE profiles associated with polypharmacy and aging using the Japanese Adverse Drug Event Report (JADER) database. We attempted to mitigate the effect of patient-related factors using a multiple-logistic regression technique and data subsetting. We selected case reports for AEs as specified in the Medical Dictionary for Regulatory Activities (MedDRA). The association between polypharmacy and “renal disorder” or “hepatic disorder” was evaluated using reporting odds ratio (ROR) and adjusted for covariates using multiple-logistic regression. For renal disorder, advanced polypharmacy showed higher adjusted RORs, because the value of administered drugs group [1.82 (1.76–1.88), ≥ 10] was higher than that of the number of administered drugs group [1.27 (1.24–1.31), 5–9]. The lower limit of the 95% confidence interval (CI) of adjusted ROR for age (≥ 60 years) was > 1 for renal disorder. For hepatic disorder, the adjusted RORs were as follows: 1.17 (1.14–1.20) for the number of administered drugs group (5–9) and 1.14 (1.11–1.18) for the number of administered drugs group (≥ 10). The adjusted RORs of hepatic disorder compared to those of renal disorder had lower adjusted RORs related to the increase in the number of administered drugs. Therefore, elderly individuals should be closely monitored for the occurrence of renal disorder when they are subjected to polypharmacy. This approach might apply to the simultaneous evaluation of the AE risk of polypharmacy and aging.