Influence of Japanese Regulatory Action on Denosumab-Related Hypocalcemia Using Japanese Adverse Drug Event Report Database

Takeyama, Mayu; Sai, Kimie; Imatoh, Takuya; Segawa, Katsunori; Hirasawa, Noriyasu; Saito, Yoshiro

doi:10.1248/bpb.b17-00266

Cited by 13 publications

(14 citation statements)

References 18 publications

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“…There are few studies investigating the effectiveness of regulatory action for denosumab‐induced hypocalcaemia. In a previous study using the Japanese spontaneous adverse reaction reporting database, we suggested that regulatory action decreased denosumab‐induced hypocalcaemia signals, especially in post 2 . However, a spontaneous reporting database includes reporting biases, which need to be considered.…”

Section: Discussionmentioning

confidence: 98%

Evaluating the impact of regulatory action on denosumab‐induced hypocalcaemia in Japan

et al. 2019

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What is known and Objective Since its introduction in April 2012, denosumab has been administered to approximately 7,300 patients as of August 2012, and 32 cases of serious hypocalcaemia after denosumab administration, including two deaths, have been reported in Japan. A Dear Healthcare Professional Letter of Rapid Safety Communication (‘Blue letter’) was released to warn about the risks of hypocalcaemia associated with denosumab. The goal of this study therefore was to measure the impact of regulatory action on denosumab‐induced hypocalcaemia in Japan by using an electronic medical information database (MID). Methods We used two different aggregated data sets based on MIDs (data sets one and two). The patients studied were those who were newly prescribed denosumab or zoledronic acid between April 2012 and September 2014. We assessed four indicators: (a) the proportion of patients with calcium supplementation at the initial denosumab treatment, (b) the proportion of patients who underwent a serum calcium test, (c) the average number of serum calcium tests performed and (d) the prevalence of hypocalcaemia. All indices were aggregated by every 3 months. To evaluate the impact of regulatory action, we used difference in difference (DID) analysis. Results and Discussion The proportion of patients with calcium supplementation at the initial denosumab treatment increased year by year in both data sets. The average number of serum calcium tests increased year by year in data set two. There was a significant difference in the prevalence of hypocalcaemia in data set two. This suggests that the estimate of impact of the regulatory action may vary according to the database. In DID analysis, however, significant influences of the regulatory action on combination use with a calcium supplement were detected in both data sets. What is New and Conclusion There was a significant influence on combination use of denosumab with vitamin D and/or calcium supplement in both data sets. That there was no apparent increase in the prevalence of denosumab‐induced hypocalcaemia, suggests that the regulatory action had an impact in the clinical setting studied. Such regulatory actions may play an important role in the promotion of drug safety.

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Section: Discussionmentioning

confidence: 98%

Evaluating the impact of regulatory action on denosumab‐induced hypocalcaemia in Japan

et al. 2019

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“…On the contrary, ROR and PRR have high sensitivity. Especially, ROR is usually used in signal detection algorithms due to its simplicity . However, ROR‐based algorithms have the disadvantage of decreased detection power when the number of adverse event reports is small.…”

Section: Discussionmentioning

confidence: 99%

“…Especially, ROR is usually used in signal detection algorithms due to its simplicity. 17,21,24 However, ROR-based algorithms have the disadvantage of decreased detection power when the number of adverse event reports is small. The number of reports of impaired glucose metabolism related to BCR-ABL inhibitors was not small, and it was reasonable to use ROR in signal detection in our study.…”

Section: Discussionmentioning

confidence: 99%

“…The US Food and Drug Administration (FDA) manages the FDA Adverse Event Reporting System (FAERS), which has registered more than three million spontaneous reports of adverse events and is the largest SRS database in the world . In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) manages the Japanese Adverse Drug Event Report (JADER) database, which has registered approximately 300 000 spontaneous reports of adverse events . These databases are publically available and reflect full adverse event profiles in real clinical settings.…”

Section: Introductionmentioning

confidence: 99%

“…16 In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) manages the Japanese Adverse Drug Event Report (JADER) database, which has registered approximately 300 000 spontaneous reports of adverse events. 17 These databases are publically available and reflect full adverse event profiles in real clinical settings. Therefore, these databases are used in pharmacovigilance analyses and are useful for evaluating the risk of adverse events reflected in real clinical settings.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacovigilance evaluation of the relationship between impaired glucose metabolism and BCR‐ABL inhibitor use by using an adverse drug event reporting database

et al. 2018

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Breakpoint cluster region‐Abelson murine leukemia (BCR‐ABL) inhibitors markedly improve the prognosis of chronic myeloid leukemia. However, high treatment adherence is necessary for successful treatment with BCR‐ABL inhibitors. Therefore, an adequate understanding of the adverse event profiles of BCR‐ABL inhibitors is essential. Although many adverse events are observed in trials, an accurate identification of adverse events based only on clinical trial results is difficult because of strict entry criteria or limited follow‐up durations. In particular, BCR‐ABL inhibitor‐induced impaired glucose metabolism remains controversial. Pharmacovigilance evaluations using spontaneous reporting systems are useful for analyzing drug‐related adverse events in clinical settings. Therefore, we conducted signal detection analyses for BCR‐ABL inhibitor‐induced impaired glucose metabolism by using the FDA Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) database. Signals for an increased reporting rate of impaired glucose metabolism were detected only for nilotinib use, whereas these signals were not detected for other BCR‐ABL inhibitors. Subgroup analyses showed a clearly increased nilotinib‐associated reporting rate of impaired glucose metabolism in male and younger patients. Although FAERS‐ and JADER‐based signal detection analyses cannot determine causality perfectly, our study suggests the effects on glucose metabolism are different between BCR‐ABL inhibitors and provides useful information for the selection of appropriate BCR‐ABL inhibitors.

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Denosumab-induced hypocalcemia in patients with osteoporosis: can you know who will get low?

et al. 2019

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Influence of Japanese Regulatory Action on Denosumab-Related Hypocalcemia Using Japanese Adverse Drug Event Report Database

Cited by 13 publications

References 18 publications

Evaluating the impact of regulatory action on denosumab‐induced hypocalcaemia in Japan

Evaluating the impact of regulatory action on denosumab‐induced hypocalcaemia in Japan

Pharmacovigilance evaluation of the relationship between impaired glucose metabolism and BCR‐ABL inhibitor use by using an adverse drug event reporting database

Denosumab-induced hypocalcemia in patients with osteoporosis: can you know who will get low?

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