Practical Epoxidation of Olefins Using Air and Ubiquitous Iron-Based Fluorous Salen Complex.

The epoxidation of olefins by substituting "air" for potentially harmful oxidants was achieved using an oxidation method that integrated a fluorous iron(III) salen catalyst derived from common metals and pivalaldehyde. Several aromatic disubstituted olefins were converted into their corresponding epoxides with high efficiency and quantitative yields. This reaction represents an environmentally friendly oxidation process that utilizes an abundant source of air and employs a readily available metal, iron, in the form of salen complexes, making it an environmentally conscious oxidation reaction.

Asymmetric Henry Reaction Using Cobalt Complexes with Bisoxazoline Ligands Bearing Two Fluorous Tags.

The effect of the presence of fluorous tags in bisoxazoline ligands on the stereoselectivity of the cobalt-catalyzed asymmetric Henry reaction was investigated. In contrast to the stereoselectivity obtained with conventional nonfluorous ligands, using bisoxazoline bidentate ligands featuring two fluorous tags in adjacent positions on the aromatic ring yielded a reversed stereoselectivity. The stereoselectivity also reversed when the fluorous tags were replaced with alkyl chains of equivalent length, albeit to a considerably lesser degree, highlighting the effect of the fluorous tags.

Development of Liquid-Chromatography Tandem-Mass-Spectrometry Method for Determining Environmental Contamination by Powdered Medicinal Drugs in Pharmacies.

The environment and personnel are both exposed to powdered pharmaceuticals inside pharmacies. This makes developing new methods for rapidly determining such contaminants an important objective. In this study, we developed a liquid-chromatography tandem-mass-spectrometry (LC-MS/MS) method for the simultaneous qualitative and quantitative determination of powdered medicinal drugs, such as famotidine, risperidone, lansoprazole, olanzapine, haloperidol, clarithromycin, promethazine, levomepromazine, and chlorpromazine. The method involves the use of acetaminophen as the internal standard, an LC-MS/MS method with a core-shell column, and a 10 mM ammonium formate/acetonitrile gradient mobile phase. The analytes were separated within 14 min, and MS with an electrospray ionization source in positive-ion mode was used. The limits of detection for the 9 drugs were .1-8.4 ng/mL. Linear calibration curves in the 10-50 000 ng/mL range were constructed, and inter-day accuracies of 92.6-113.8% were determined for the 9 drugs. The coefficients of variation were less than 14.6%. These data suggest that the proposed method is applicable for the routine assaying of powdered-medicine contamination in pharmacies.

Neuropsychiatric Adverse Events of Montelukast: An Analysis of Real-World Datasets and drug-gene Interaction Network.

Montelukast is a selective leukotriene receptor antagonist that is widely used to treat bronchial asthma and nasal allergy. To clarify the association between montelukast and neuropsychiatric adverse events (AEs), we evaluated case reports recorded between January 2004 and December 2018 in the Food and Drug Administration Adverse Event Reporting System (FAERS). Furthermore, we elucidated the potential toxicological mechanisms of montelukast-associated neuropsychiatric AEs through functional enrichment analysis of human genes interacting with montelukast. The reporting odds ratios of suicidal ideation and depression in the system organ class of psychiatric disorders were 21.5 (95% confidence interval (CI): 20.3-22.9) and 8.2 (95% CI: 7.8-8.7), respectively. We explored 1,144 human genes that directly or indirectly interact with montelukast. The molecular complex detection (MCODE) plug-in of Cytoscape detected 14 clusters. Functional analysis indicated that several genes were significantly enriched in the biological processes of "neuroactive ligand-receptor interaction." "Mood disorders" and "major depressive disorder" were significant disease terms related to montelukast. Our retrospective analysis based on the FAERS demonstrated a significant association between montelukast and neuropsychiatric AEs. Functional enrichment analysis of montelukast-associated genes related to neuropsychiatric symptoms warrant further research on the underlying pharmacological mechanisms.

Adverse reaction profiles of hemorrhagic adverse reactions caused by direct oral anticoagulants analyzed using the Food and Drug Administration Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database.

Direct oral anticoagulants (DOACs) are used in anticoagulant therapy. The purpose of this study was to evaluate the association of DOAC-induced gastrointestinal (GI) and nervous system hemorrhage using the FDA's Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database. We identified and analyzed the reports of hemorrhagic reactions between 2004 and 2016 from the FAERS and JADER databases, and calculated the adjusted reported odds ratio (ROR) using the multiple logistic regression method. Additionally, we used the time-to-onset analysis. In the FAERS database, the adjusted ROR of apixaban, rivaroxaban, and dabigatran for GI hemorrhage was 6.79 (5.84-7.91), 19.58 (18.85-20.34), and 14.51 (13.58-15.51), respectively. In the JADER database, the adjusted ROR of apixaban, rivaroxaban, edoxaban, and dabigatran for GI hemorrhage was 11.80 (9.50-14.64), 11.03 (9.18-13.26), 10.17 (6.95-14.88), and 9.85 (7.23-13.42), respectively. We found that the association of GI hemorrhage with DOACs was affected by sex (female). Additionally, 30% of GI hemorrhage was observed after 30 days. Hemorrhagic reactions of both GI and nervous systems were observed in both the spontaneous reporting system databases. We recommend that female patients who experience symptoms related to GI hemorrhage should be closely monitored and advised to adhere to an appropriate care plan. Additionally, our results show that patients should be closely monitored for hemorrhage even after a month.

Analysis of fall-related adverse events among older adults using the Japanese Adverse Drug Event Report (JADER) database.

BACKGROUND: Falls are a common but serious problem in older adults, and may lead to fractures and bleeding. As many factors, such as medication, aging, and comorbid diseases may simultaneously affect fall-related adverse events (AEs) in older adults, we evaluated the association between fall-related AEs and the use of medication, aging, and comorbid diseases using the Japanese Adverse Drug Event Report (JADER) database. METHODS: We analyzed reports of fall-related AEs associated with α-blockers, diuretics, calcium channel blockers, central nervous system (CNS)-active drugs (opioids, benzodiazepines, hypnotics and sedatives, non-selective monoamine reuptake inhibitors, and selective serotonin reuptake inhibitors (SSRI)) in the JADER database using the reporting odds ratio (ROR). For the definition of falls, we used the Preferred Terms of The Medical Dictionary for Regulatory Activities (MedDRA). We used the association rule mining technique to discover undetected associations, such as potential risk factors. RESULTS: The JADER database comprised 430,587 reports between April 2004 and November 2016. The RORs (95% CI) of α-blockers, diuretics, calcium channel blockers, opioids, benzodiazepines, hypnotics and sedatives, non-selective monoamine reuptake inhibitors, and SSRIs were 1.63 (1.27-2.09), 0.74 (0.63-0.86), 1.26 (1.15-1.38), 0.93 (0.80-1.07), 1.83 (1.68-2.01), 1.55 (1.12-2.14), 2.31 (1.82-2.95), and 2.86 (2.49-3.29), respectively. From the lift value in the association rule mining, the number of administered CNS-active drugs and patient age were associated with fall-related AEs. Furthermore, the scores of lift for patients with herpes zoster administered calcium channel blockers or benzodiazepines and patients with dementia administered benzodiazepines were high. CONCLUSION: Our results suggest that the number of administered CNS-active drugs and patient age are both associated with fall-related AEs. We recommend that patients with herpes zoster treated with calcium channel blockers and benzodiazepines be closely monitored for fall-related AEs.

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

Aim: 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. Design: Retrospective study. Method: Reports of postpartum depression events between 2004-2015 were analysed with a reporting odds ratio (ROR) algorithm. The Medical Dictionary for Regulatory Activities was used to identify postpartum depression. Results: The reporting odds ratios (95% confidence intervals, CI) of levonorgestrel (an intrauterine device with progestogen), etonogestrel (a hormonal contraceptive implant), sertraline and drospirenone (an oral contraceptive) were 12.5 (8.7-18.0), 14.0 (8.5-22.8), 12.2 (6.5-23.1) and 5.4 (2.7-10.9) respectively. Among the drugs in the US Food and Drug Administration Adverse Event Reporting System database, the use of contraceptives or an intrauterine device with progestogen might convey risk for postpartum depression.

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.

Adverse Event Trends Associated with OTC Analgesic and Antipyretic Drug: Data Mining of the Japanese Adverse Drug Event Report Database.

OTC drugs play an important role in self-medication. OTC analgesic and antipyretic drugs are widely used in Japan. The present study aimed to survey the components of OTC drug package inserts for analgesic and antipyretic drugs and to evaluate the adverse event profiles using the Japanese Adverse Drug Event Report database (JADER). The JADER contains 430587 reports from between April 2004 and November 2016; a total of 750 reports of adverse events resulted from the use of OTC analgesic and antipyretic drugs. The safety signals were detected by the reporting odds ratio (ROR). The ROR values for "Skin & subcutaneous tissue disorders", "Immune system disorders", and "Hepatobiliary disorders" stratified by system organ class of the Medical Dictionary for Regulatory Activities (MedDRA) were 7.58 (6.56-8.76), 4.25 (3.51-5.14), and 2.35 (1.93-2.85), respectively. OTC analgesic and antipyretic drugs containing allylisopropylacetylurea (AIAU) exhibited a significantly high reporting ratio of "Skin & subcutaneous tissue disorders" compared with the drugs without AIAU. No difference in the reported incidence of "Hepatobiliary disorders" was found between the drugs with or without acetaminophen. Our results suggested that it was important to monitor patients who use OTC analgesic and antipyretic drug containing AIAU; in particular, careful attention should be paid to skin and subcutaneous tissue disorders.

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 Stevens-Johnson syndrome and toxic epidermal necrolysis using the Japanese Adverse Drug Event Report database.

BACKGROUND: Stevens-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. METHODS: We 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. RESULTS: The 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 ß values for the drugs were all less than 1, with the exceptions of those for carbamazepine, ACE inhibitors, and corticosteroids. CONCLUSIONS: Our 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.

[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.

Association between Selective Serotonin Reuptake Inhibitor Therapy and Suicidality: Analysis of U.S. Food and Drug Administration Adverse Event Reporting System Data.

Selective serotonin reuptake inhibitors (SSRIs) are prescribed for the treatment of depression worldwide. SSRIs are suspected to increase the risk of suicidal ideation and behavior (suicidality) in children, adolescents, and young adults. We examined the association between SSRI therapy and suicidality by applying a logistic regression model to age-stratified data from the Food and Drug Administration (FDA) Adverse Event Reporting System database. We attempted to mitigate the effect of patient-related factors by data subsetting. We selected case reports for SSRIs as referred to in the World Health Organization Anatomical Therapeutic Chemical classification code N06AB. The association between SSRIs and "suicidal events" or "self-harm events" was calculated as a reporting odds ratio (ROR) and adjusted for covariates by logistic regression. For subjects <18 years old (y.o.) the adjusted RORs (95% confidence interval) of SSRI therapy with suicidal events were 9.58 (8.97-10.23) in the whole data analysis and 4.64 (4.15-5.19) in the subset analysis; those with self-harm events were 31.40 (27.71-35.58) and 16.31 (13.12-20.29), respectively. Although the adjusted RORs were lower in the subset analyses than in the whole data analyses, both analyses indicated associations between SSRI treatment and suicidal and self-harm events. In both analyses these associations were stronger in the <18 y.o. group than other age groups. Children and adolescents should be closely monitored for the occurrence of suicidality when they are prescribed SSRIs. In addition, we found that data subsetting might mitigate the effect of an intrinsic risk among patients taking the suspected drug.

Analysis of Neuropsychiatric Adverse Events in Patients Treated with Oseltamivir in Spontaneous Adverse Event Reports.

There have been concerns that oseltamivir causes neuropsychiatric adverse events (NPAEs). We analyzed the association of age and gender with NPAEs in patients treated with oseltamivir using a logistic regression model. NPAE data were obtained from the U.S. Food and Drug Administration Adverse Event Reporting System (2004 to 2013). The lower limit of the reporting odds ratio (ROR) 95% confidence interval (CI) of "abnormal behavior" in Japan, Singapore, and Taiwan was ≥1. The effects of the interaction terms for oseltamivir in male patients aged 10-19 years were statistically significant. The adjusted ROR of "abnormal behavior" was 96.4 (95% CI, 77.5-119.9) in male patients aged 10-19 years treated with osletamivir. In female patients, the results of the likelihood ratio test for "abnormal behavior" were not statistically significant. The adjusted NPAE RORs were increased in male and female patients under the age of 20 years. Oseltamivir use could be associated with "abnormal behavior" in males aged 10-19 years. After considering the causality restraints of the current analysis, further epidemiological studies are recommended.

[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 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.

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

BACKGROUND: Antipsychotics 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. FINDINGS: We 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. CONCLUSION: Antipsychotic 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.

Analysis of the time-to-onset of osteonecrosis of jaw with bisphosphonate treatment using the data from a spontaneous reporting system of adverse drug events.

BACKGROUND: Bisphosphonates (BPs) are potent antiresorptive agents used to treat osteoporosis and the complications associated with malignant bone metastasis. The aim of this study was to evaluate the incidence of bisphosphonate-related osteonecrosis of the jaw (BRONJ) using the Japanese Adverse Drug Event Report (JADER) database. In particular, we focused on the time-to-onset profile of BRONJ. FINDINGS: We analyzed reports of BRONJ in the JADER database and calculated the reporting odds ratio (ROR) of BPs potentially associated with BRONJ. We applied the weibull shape parameter to time-to-event data in JADER. The drugs selected for this investigation were seven BPs approved in Japan (alendronate [intraveneous, I.V.], pamidronate, and zoledronate as I.V. BPs; and alendronate (oral), etidronate, minodronate, and risedronate as oral BPs). We analyzed reports of BRONJ events associated with BPs in the JADER database from April 2004 to November 2014. The median value of BRONJ cases caused by alendronate (I.V.), pamidronate, zoledronate, alendronate (oral), etidronate, minodronate, and risedronate were 1342, 812, 486, 863, 1461, 432, and 730 days, respectively. The lower 95 % confidence interval of the Weibull-shape parameter ß for I.V. BPs (pamidronate and zoledronate) exceeded 1. The risk of BRONJ with I.V. BPs increased over time. CONCLUSION: Thus, the incidence of BRONJ with BP treatment should be closely monitored for a 3-year period. Further studies are required to draw conclusions, and we believe that this information about BRONJ induced by BPs will prove beneficial to patients and pharmacists.