Adverse event profiles of solvent-based and nanoparticle albumin-bound paclitaxel formulations using the Food and Drug Administration Adverse Event Reporting System.

OBJECTIVES: Paclitaxel is a highly effective antitumor agent with notable adverse events, including hypersensitivity reactions, peripheral neuropathy, arthralgia, myalgias, and neutropenia. Solvent-based paclitaxel causes severe allergic, hypersensitivity, and anaphylactic reactions. Nanoparticle albumin-bound paclitaxel was recently developed and provides an advantage over solvent-based paclitaxel in avoiding solvent/surfactant-related adverse events. The aim of this study was to assess the adverse event profiles of solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel formulations using data from the spontaneous adverse event reporting system of the US Food and Drug Administration Adverse Event Reporting System database. METHODS: This study relied on Medical Dictionary for Regulatory Activities preferred terms and standardized queries, and calculated the reporting ratio and reporting odds ratios of paclitaxel formulations. RESULTS: Of 8,867,135 reports recorded in the US Food and Drug Administration Adverse Event Reporting System database from January 2004 to December 2016, 3469 and 4447 adverse events corresponded to solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel, respectively. Reporting odds ratios (95% confidence interval) for anaphylactic reaction (standardized MedDRA query code: 20000021) associated with the use of solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel were 1.69 (1.56-1.84) and 0.75 (0.68-0.83), respectively. Reporting odds ratio signal for anaphylactic reaction was not detected for nanoparticle albumin-bound paclitaxel. Reporting odds ratios (95% confidence interval) for acute renal failure (standardized MedDRA query code: 20000003) associated with the use of solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel were 0.75 (0.58-0.98) and 1.60 (1.37-1.89), respectively. CONCLUSION: This is the first study to evaluate the adverse event profile of nanoparticle albumin-bound paclitaxel using US Food and Drug Administration Adverse Event Reporting System data. Considering that the US Food and Drug Administration Adverse Event Reporting System database does not allow to infer causality or risk ranking, the different reporting frequencies of anaphylactic reaction and acute renal failure between solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel must be further investigated via analytical observational research.

Adverse events of smoking cessation treatments (nicotine replacement therapy and non-nicotine prescription medication) and electronic cigarettes in the Food and Drug Administration Adverse Event Reporting System, 2004-2016.

OBJECTIVES: Several smoking cessation treatments (nicotine replacement therapy and non-nicotine prescription medication) and electronic cigarettes are widely used. We evaluated the adverse events related to smoking cessation treatments and electronic cigarettes in the US Food and Drug Administration Adverse Event Reporting System database. METHODS: We analyzed reports of adverse events associated with smoking cessation treatment and electronic cigarettes terms dated between January 2004 and December 2016. We used the reporting odds ratio with 95% confidence intervals to detect a signal for each adverse event. RESULTS: In total, 8,867,135 reports in the Food and Drug Administration Adverse Event Reporting System database were analyzed. The numbers of adverse events for nicotine replacement therapy (transdermal, buccal, oral, and respiratory administration) were 1673, 1016, 425, and 56, respectively. Nicotine replacement therapy (transdermal, buccal, and oral) demonstrated adverse events of nausea, nicotine dependence, and dizziness. For nicotine (transdermal) exposure, the top 5 adverse events reported were nausea (149 cases, reporting odds ratio: 2.28 (95% confidence interval: 1.92-2.69)), dizziness (132 cases, reporting odds ratio: 3.04 (95% confidence interval: 2.54-3.63)), application site erythema (108 cases, reporting odds ratio: 32.52 (95% confidence interval: 26.74-39.55)), headache (98 cases, reporting odds ratio: 1.84 (95% confidence interval: 1.50-2.25)), and dyspnea (94 cases, reporting odds ratio: 1.93 (95% confidence interval: 1.57-2.38)). Many cases of improper use of nicotine replacement therapies were reported. Nausea, depression, abnormal dreams, insomnia, and other adverse events were reported for varenicline. Insomnia, rash, anxiety, and dizziness were reported for bupropion. We observed electronic cigarettes-related adverse events such as dizziness, dyspnea, nausea, heart rate increased, and tremor. CONCLUSION: Our findings suggest that an association exists between nicotine-related adverse events and nicotine replacement therapy. Healthcare professionals should closely monitor smokers trying to quit nicotine use for the misuse of nicotine replacement therapy. These findings may be informative to healthcare professionals in order to improve the management of smoking cessation treatment.

Analysis of adverse events of renal impairment related to platinum-based compounds using the Japanese Adverse Drug Event Report database.

OBJECTIVES: Platinum compounds cause several adverse events, such as nephrotoxicity, gastrointestinal toxicity, myelosuppression, ototoxicity, and neurotoxicity. We evaluated the incidence of renal impairment as adverse events are related to the administration of platinum compounds using the Japanese Adverse Drug Event Report database. METHODS: We analyzed adverse events associated with the use of platinum compounds reported from April 2004 to November 2016. The reporting odds ratio at 95% confidence interval was used to detect the signal for each renal impairment incidence. We evaluated the time-to-onset profile of renal impairment and assessed the hazard type using Weibull shape parameter and used the applied association rule mining technique to discover undetected relationships such as possible risk factor. RESULTS: In total, 430,587 reports in the Japanese Adverse Drug Event Report database were analyzed. The reporting odds ratios (95% confidence interval) for renal impairment resulting from the use of cisplatin, oxaliplatin, carboplatin, and nedaplatin were 2.7 (2.5-3.0), 0.6 (0.5-0.7), 0.8 (0.7-1.0), and 1.3 (0.8-2.1), respectively. The lower limit of the reporting odds ratio (95% confidence interval) for cisplatin was >1. The median (lower-upper quartile) onset time of renal impairment following the use of platinum-based compounds was 6.0-8.0 days. The Weibull shape parameter ß and 95% confidence interval upper limit of oxaliplatin were <1. In the association rule mining, the score of lift for patients who were treated with cisplatin and co-administered furosemide, loxoprofen, or pemetrexed was high. Similarly, the scores for patients with hypertension or diabetes mellitus were high. CONCLUSION: Our findings suggest a potential risk of renal impairment during cisplatin use in real-world setting. The present findings demonstrate that the incidence of renal impairment following cisplatin use should be closely monitored when patients are hypertensive or diabetic, or when they are co-administered furosemide, loxoprofen, or pemetrexed. In addition, healthcare professionals should closely assess a patient's background prior to treatment.

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.

[Body Surface Area Formulas for the Calculation of the Chemotherapy Dosage].

Body surface area(BSA)is a parameter frequently used to calculate the chemotherapy dosage. Several different equations for predicting BSA have been developed. We examined the formula suggested for BSA calculation for 62 chemotherapy drugs where the recommended dosage was based on patient BSA. We found that the description of the formula to be used for BSA calculation was not provided in the package inserts or in the drug interview forms in the majority of cases; the BSA formula was mentioned in the guide for appropriate use of medication in only 8 of 62 chemotherapy drugs. Furthermore, we observed that the choice of formula used to calculate patient BSA caused differences in the dosage of drugs administered to patients undergoing certain oral anti-cancer drug therapies. The results ofour study indicate that clinical oncologists should pay careful attention to the formula used to calculate BSA.

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-ß 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.

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.

[Evaluation of the Association of Hand-Foot Syndrome with Anticancer Drugs Using the US Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) Databases].

The Japanese Ministry of Health, Labor, and Welfare lists hand-foot syndrome as a serious adverse drug event. Therefore, we evaluated its association with anticancer drug therapy using case reports in the Japanese Adverse Drug Event Report (JADER) and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). In addition, we calculated the reporting odds ratio (ROR) of anticancer drugs potentially associated with hand-foot syndrome, and applied the Weibull shape parameter to time-to-event data from JADER. We found that JADER contained 338224 reports from April 2004 to November 2014, while FAERS contained 5821354 reports from January 2004 to June 2014. In JADER, the RORs [95% confidence interval (CI)] of hand-foot syndrome for capecitabine, tegafur-gimeracil-oteracil, fluorouracil, sorafenib, and regorafenib were 63.60 (95%CI, 56.19-71.99), 1.30 (95%CI, 0.89-1.89), 0.48 (95%CI, 0.30-0.77), 26.10 (95%CI, 22.86-29.80), and 133.27 (95%CI, 112.85-157.39), respectively. Adverse event symptoms of hand-foot syndrome were observed with most anticancer drugs, which carry warnings of the propensity to cause these effects in their drug information literature. The time-to-event analysis using the Weibull shape parameter revealed differences in the time-dependency of the adverse events of each drug. Therefore, anticancer drugs should be used carefully in clinical practice, and patients may require careful monitoring for symptoms of hand-foot syndrome.