Junko Abe

Analysis of the Interaction between Clopidogrel, Aspirin, and Proton Pump Inhibitors Using the FDA Adverse Event Reporting System Database

Clopidogrel is an antiplatelet agent widely used in combination with aspirin to limit the occurrence of cardiovascular (embolic/thrombotic) events. Consensus guidelines recommend proton pump inhibitors (PPIs) as a gastrointestinal (GI) prophylactic measure for all patients receiving dual antiplatelet therapy with clopidogrel and aspirin. The objective of this study was to analyze the effect of the simultaneous use of clopidogrel, aspirin, and PPIs on hemorrhagic and embolic/thrombotic events using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Reports of hemorrhagic and embolic/thrombotic events between 2004 and 2013 were analyzed with a reporting odds ratio (ROR) algorithm and logistic regression methods. The Medical Dictionary for Regulatory Activities Preferred Terms was used to identify such events. Regarding hemorrhagic events, the adjusted RORs of the concomitant use of aspirin and clopidogrel and those of PPIs prescribed with aspirin and clopidogrel were 4.40 (95% confidence interval [CI], 4.02-4.81) and 3.40 (95% CI, 2.84-4.06), respectively. For embolic/thrombotic events, the adjusted RORs of the concomitant use of aspirin and clopidogrel and those of PPIs prescribed with aspirin and clopidogrel were 2.37 (95% CI, 2.16-2.59) and 2.38 (95% CI, 2.00-2.84), respectively. Among patients included in the FAERS database, the concurrent use of aspirin and clopidogrel with PPIs reduced the adjusted ROR of GI hemorrhagic events. PPIs had little influence on the adjusted ROR of embolic/thrombotic events. These results support the use of PPIs as a preventive measure against GI hemorrhagic events for patients receiving clopidogrel and aspirin.

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:

Age-related trends in injection site reaction incidence induced by the tumor necrosis factor-α (TNF-α) inhibitors etanercept and adalimumab: the Food and Drug Administration adverse event reporting system, 2004-2015

Tumor necrosis factor-α (TNF-α) inhibitors are increasingly being used as treatment for rheumatoid arthritis (RA). However, the administration of these drugs carries the risk of inducing injection site reaction (ISR). ISR gives rise to patient stress, nervousness, and a decrease in quality of life (QoL). In order to alleviate pain and other symptoms, early countermeasures must be taken against this adverse event. In order to improve understanding of the risk factors contributing to the induction of ISR, we evaluated the association between TNF-α inhibitors and ISR by applying a logistic regression model to age-stratified data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The FAERS database contains 7,561,254 reports from January 2004 to December 2015. Adjusted reporting odds ratios (RORs) (95% Confidence Intervals) were obtained for interaction terms for age-stratified groups treated with etanercept (ETN) and adalimumab (ADA). The adjusted RORs for ETN* ≥ 70 and ADA* ≥ 70 groups were the lowest among the age-stratified groups undergoing the respective monotherapies. Furthermore, we found that crude RORs for ETN + methotrexate (MTX) combination therapy and ADA + MTX combination therapy were lower than those for the respective monotherapies. This study was the first to evaluate the relationship between aging and ISR using the FAERS database.

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.

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system

Doxorubicin (DOX) is an anthracycline widely used for the treatment of solid and hematological tumors. The aim of this study was to assess the adverse event profiles of conventional DOX and liposomal DOX. This is the first study to evaluate the effect of a liposomal formulation of DOX using spontaneous reporting system (SRS) databases. The SRS used was the US Food and Drug Administration Adverse Event Reporting System (FAERS). This study relied on definitions of preferred terms provided by the Medical Dictionary for Regulatory Activities (MedDRA) and the standardized MedDRA Queries (SMQ) database. We also calculated the reporting odds ratios (RORs) of suspected drugs (conventional DOX; PEGylated-liposome DOX; non-PEGylated-liposome DOX). The FAERS database contained 7,561,254 reports from January 2004 to December 2015. The number of reported AE cases for conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX was 5039, 3780, and 349, respectively. Conventional DOX and liposomal DOX have potential risks of causing myelosuppression, cardiotoxicity, alopecia, nausea, and vomiting, among other effects. The RORs (95% CI) from SMQ for haematopoietic leucopenia associated with conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX were 12.75 (11.89–13.68), 6.43 (5.81–7.13), and 14.73 (11.42–18.99), respectively. Liposomal DOX formulations were associated with lower RORs with regard to myelosuppression, cardiotoxicity, and alopecia than the conventional DOX was. The RORs (95% CI) for palmar-plantar erythrodysesthesia (PPE) associated with conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX were 6.56 (4.74–9.07), 64.77 (56.84–73.80), and 28.76 (15.77–52.45), respectively. This study is the first to evaluate the relationship between DOX liposomal formulations and their adverse event profiles. The results indicate that careful observation for PPE is recommended with the use of liposomal DOX, especially PEGylated-liposome DOX formulations.

Thromboembolic adverse event study of combined estrogen-progestin preparations using Japanese Adverse Drug Event Report database

Combined estrogen-progestin preparations (CEPs) are associated with thromboembolic (TE) side effects. The aim of this study was to evaluate the incidence of TE using the Japanese Adverse Drug Event Report (JADER) database. Adverse events recorded from April 2004 to November 2014 in the JADER database were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website (www.pmda.go.jp). We calculated the reporting odds ratios (RORs) of suspected CEPs, analyzed the time-to-onset profile, and assessed the hazard type using Weibull shape parameter (WSP). Furthermore, we used the applied association rule mining technique to discover undetected relationships such as the possible risk factors. The total number of reported cases in the JADER contained was 338,224. The RORs (95% confidential interval, CI) of drospirenone combined with ethinyl estradiol (EE, Dro-EE), norethisterone with EE (Ne-EE), levonorgestrel with EE (Lev-EE), desogestrel with EE (Des-EE), and norgestrel with EE (Nor-EE) were 56.2 (44.3–71.4), 29.1 (23.5–35.9), 42.9 (32.3–57.0), 44.7 (32.7–61.1), and 38.6 (26.3–56.7), respectively. The medians (25%–75%) of the time-to-onset of Dro-EE, Ne-EE, Lev-EE, Des-EE, and Nor-EE were 150.0 (75.3–314.0), 128.0 (27.0–279.0), 204.0 (44.0–660.0), 142.0 (41.3–344.0), and 16.5 (8.8–32.0) days, respectively. The 95% CIs of the WSP-β for Ne-EE, Lev-EE, and Nor-EE were lower and excluded 1. Association rule mining indicated that patients with anemia had a potential risk of developing a TE when using CEPs. Our results suggest that it is important to monitor patients administered CEP for TE. Careful observation is recommended, especially for those using Nor-EE, and this information may be useful for efficient therapeutic planning.