BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions associated with fatal disorders. Although many causes of SJS/TEN have been proposed, the time-to-onset for SJS/TEN and the relationship between aging and SJS/TEN are still not clear. Therefore, the aim of this study was to determine the relationship between aging and SJS/TEN using the Japanese Adverse Drug Event Report (JADER) database and analyze the time-to-onset profile of SJS/TEN.MethodsWe analyzed reports of SJS/TEN recorded in the JADER database between 2004 and 2015 using an adjusted reporting odds ratio (ROR). We also used Weibull proportional hazards models for each drug to examine the expression patterns of SJS/TEN. We selected the drugs according to the number of the reports associated with SJS/TEN.ResultsThe JADER contained 330,686 reports from April 2004 to April 2015. The adjusted RORs for patients in the 0–19-, 20–39-, 60–79-, and ≥ 80-year-old groups from all data extracted from the JADER database were 1.33 (95 % confidence interval [CI], 1.21–1.45), 1.78 (95 % CI, 1.65–1.93), 0.71 (95 % CI, 0.66–0.75), and 0.72 (95 % CI, 0.66–0.79), respectively. The adjusted ROR tended to be higher in patients aged 0–19 years, particularly in patients using antipyretic analgesics, such as loxoprofen or acetaminophen. More than half of the cases of SJS/TEN onset following administration of loxoprofen and acetaminophen occurred within 4 days of the initiation of treatment. The median times-to-onset were 3 days for loxoprofen and 2 days for acetaminophen. The scale parameter α values of loxoprofen and acetaminophen were 9.44 and 6.17, respectively. The upper 95 % CIs of shape parameter β values for the drugs were all less than 1, with the exceptions of those for carbamazepine, ACE inhibitors, and corticosteroids.ConclusionsOur results suggested that monitoring of younger patients who frequently use antipyretic analgesics is important. These drugs should be used and monitored within the first 2–3 days of treatment in the Japanese population.

BackgroundDrug-induced gingival hyperplasia (DIGH) causes problems with chewing, aesthetics, and pronunciation, and leads to the deterioration of the patient’s quality of life (QOL). Thus, the aim of this study was to evaluate the incidence of DIGH using spontaneous reporting system (SRS) databases.MethodsWe analyzed reports of DIGH from SRS databases and calculated the reporting odds ratios (RORs) of suspected drugs (immunosuppressants, calcium channel blockers, and anticonvulsants). The SRS databases used were the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER) database. With the data, we evaluated the time-to-onset profile and the hazard type using the Weibull shape parameter (WSP). Furthermore, we used the association rule mining technique to discover undetected relationships such as possible risk factors.ResultsThe FAERS contained 5,821,716 reports. The RORs (95% confidence interval: CI) for cyclosporine, everolimus, sirolimus, mycophenolate mofetil, amlodipine, nifedipine, carbamazepine, clobazam, levetiracetam, phenobarbital, phenytoin, primidone, topiramate, and valproic acid, were 39.4 (95% CI: 30.3–51.2), 4.2 (1.7–10.0), 6.6 (2.5–17.7), 13.1 (7.2–23.2), 94.8 (80.0–112.9), 57.9 (35.7–94.0), 15.1 (10.3–22.3), 65.4 (33.8–126.7), 6.5 (3.6–11.8), 19.7 (8.8–44.0), 65.4 (52.4–82.9), 56.5 (21.1–151.7), 2.9 (1.1–7.7), and 17.5 (12.6–24.4), respectively. The JADER database contained 430,587 reports. The median time-to-onset of gingival hyperplasia values for immunosuppressants, calcium channel blockers, and anticonvulsants use were 71, 262, and 37 days, respectively. Furthermore, the 95% CI of the WSP β for anticonvulsants was over and excluded 1, which meant that they were wear-out failure type.ConclusionsOur results suggest that DIGH monitoring of patients administered immunosuppressants, calcium channel blockers, or anticonvulsants is important. We demonstrated the potential risk of DIGH following the long-term use of calcium channel blocker over approximately 260 days. Based on the results of the association rule mining approach, patients with intellectual disability who are administered phenytoin should be monitored carefully. We recommend that patients who experience symptoms related to DIGH should be closely monitored.

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.

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.

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.