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

Abstract

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.

Effects of denosumab treatment in chronic liver disease patients with osteoporosis

“…During the 12-mo study period, no patients experienced any fractures or moderate-to-severe adverse events. Hypocalcemia was observed in 11.7% (7 of the 60 patients) and mainly developed in the early phase after the first dosing, which was similar to results in a previous report[ 44 ]; however, it was asymptomatic, transient, and mild (grade 1). Thus, denosumab treatment was safe in CLD patients.…”

Postmarket safety communications on drugs approved in Japan: A 25‐year analysis

“…Fourth, we did not investigate the effect of DSCs on ADR prevention, although previous studies revealed that DSCs resulted in a change in prescriptions in Japan. DSC for denosumab‐induced hypocalcemia changed the physicians' attitudes toward the combination use of denosumab with vitamin D/calcium supplement 15 . Additionally, another study revealed that dabigatran use for patients with a specific background (i.e., elderly, renal dysfunction, receiving antiplatelet medication) was altered after the issuance of DSC for dabigatran‐induced bleeding 16 .…”

“…DSC for denosumab‐induced hypocalcemia changed the physicians' attitudes toward the combination use of denosumab with vitamin D/calcium supplement. 15 Additionally, another study revealed that dabigatran use for patients with a specific background (i.e., elderly, renal dysfunction, receiving antiplatelet medication) was altered after the issuance of DSC for dabigatran‐induced bleeding. 16 The effects of DSCs by the FDA 17 and the EMA 18 on drug use have been reported elsewhere.…”

Denosumab Versus Zoledronic Acid in the Prevention of Skeletal-related Events in Vulnerable Cancer Patients: A Meta-analysis of Randomized, Controlled Trials

“…It is recommended that, to minimize the risk for hypocalcemia, calcium (>500 mg) and vitamin D (400 IU) should be supplemented daily in patients receiving either of the BTAs. 7,45 The bone is a commonly involved site in malignant progression, either as a site of metastasis or as a feature of MM. Previous meta-analyses have shown the efficacy of denosumab mainly as intervention in bone metastases.…”