Creating a Checklist and a Survey on Research That Used the Japanese Adverse Drug Event Report Database / 医薬品情報学

Objective: The purpose of this study was to create a checklist that summarizes checkpoints that should be noted when using the Japanese Adverse Drug Event Report database (JADER). After we created the checklist, we then used it to survey published academic papers that used JADER.Method: First, we created a draft checklist for research that uses JADER by citing the report of CIOMS working group VIII “Practical Aspects of Signal Detection in Pharmacovigilance”. Then, we conducted a pilot test and revised the draft checklist. Finally, the checklist was completed after the review by a pharmacoepidemiology expert. The checklist was applied to published academic papers that used JADER, and the fulfill rate of each checkpoints was calculated.Results: A “checklist of important points to be noted during research that uses the data mining method in JADER (mainly signal detection by disproportionality analysis)” was created. We also revealed problems with published academic papers that used JADER. For example, some researchers were thought to be inappropriately using JADER as a source of their research while others used an inappropriate version of MedDRA.Conclusion: The checklist created in this study summarizes key points that could be noted in research that uses JADER and is thought to contribute to an improvement in quality of research that uses JADER. Additionally, in our investigation of published academic papers that used JADER, we found the possibility that both the role of signal detection and the impact on analysis of JADER using the updated MedDRA version are not well understood.

A Study on the Effect of Changing the Dose on the Package Insert of Distigmine on Cholinergic Syndrome Onset Using the Japanese Adverse Drug Event Report (JADER) Database / 社会薬学

Distigmine has reversible and persistent cholinesterase (ChE) antagonism, and is used for the dysuria due to low activity bladders such as the neurogenic bladder dysfunction widely postoperatively, but fatal cases were reported by cholinergic syndrome. Therefore a dose was limited to 5mg only for adaptation of “the dysuria due to hypotonic bladder such as after surgery and the neurogenic bladder dysfunction” in March, 2010. In the current study, we examined a ministerial policy in the package insert revision using Japanese Adverse Drug Event Report database (JADER). Using a side effect report registered with JADER from January, 2004 to June, 2016, we calculated Reporting Odds Ratio (ROR) which was the index of the safe signal of the medical supplies adverse event and we compared number of reports and ROR of the cholinergic syndrome by the distigmine in approximately the measure in March, 2010 and evaluated it. The number of reports of the cholinergic syndrome by the distigmine was 138 cases before March 2010 and 65 cases after March 2010. After a measure, the number of reports decreased. The possibility that the package insert revision of the distigmine contributed to a decrease in cholinergic syndrome onset was suggested. Whereas monitoring careful sequentially needs the onset of the cholinergic syndrome in constant frequency to be found.

Comparison of the Side Effects of Lenvatinib between the Type of Cancer Using the Japanese Adverse Drug Event Report Database / 医薬品情報学

Lenvatinib hasapplicationsin thyroid and hepatocellular carcinomas. When lenvatinib wasapproved for hepatocellular carcinoma in Japan, the manufacturer noted an increase of 5% in the incidence of side effects than those observed in thyroid cancer, based on the clinical-trial data. The monitoring of side effectsisimportant during chemotherapy. It isdifficult to confirm all the side effects within a single practice, and it is important to consider the incidence and severity of side effects before prescribing a particular treatment regimen. An antineoplastic agent is often used for different diseases, and it may be difficult to confirm a specific side effect. Because clinical conditions vary among different diseases, it is likely that the onset of side effects also differs. We investigated the difference between the onset of side effects in thyroid and hepatocellular carcinomas using the Japanese Adverse Drug Event Report database. The main side effects reported for thyroid cancer included bleeding, hypertension, cardiac disorders, myelosuppression,acute cholecystitis, delayed wound healing, infection, gastrointestinal perforation, fistula formation, and pneumothorax. In addition,patients with hepatocellular carcinoma experienced liver damage and hepatic encephalopathy. A significant strong correlation was observed between the drug dose and number of reports of the varied side effects. We compared the side effects in patients with thyroid cancer to those with hepatocellular carcinoma; although the same drug was used, there was varied expression of the side effects. Thisneedsto be taken into account when determining which drugsare to be used for the treatment of a particular cancer type.

Comparison of Adverse Event Reports by Physicians and Pharmacists in Japanese Adverse Drug Event Report Database (JADER) / 医薬品情報学

Objective: In Japan, healthcare professionals are required to report the adverse drug events that occur with the use of medicines to the Minister of Health, Labor, and Welfare. The reported information is collected in the Japanese Adverse Drug Event Report database (JADER) and is freely available. There are no reports that evaluated the adverse events (AEs) in JADER based on the need for a physician’s diagnosis. This study classified AEs by pharmacists or physicians in JADER based on the need for a physician’s diagnosis and evaluated the differences in their contents.Methods: AEs reported by pharmacists, physicians, pharmacists and physicians in the economic years 2004 to 2017 in JADER were collected annually, and the trends were compared. The AEs of methotrexate in 2017 were classified into two groups based on the need for a physician’s diagnosis. The necessity of a physician’s diagnosis was judged by two senior pharmacists and compared using the chi-squared test.Results: The number of AEs reported by pharmacists and physicians from 2004 to 2017 increased from 689 to 7,127 and from 20,933 to 39,382, respectively. Among the AEs of methotrexate in 2017, AEs requiring physician’s diagnosis reported by pharmacists were 337 events and physicians were 2,413 events. Whereas, AEs that did not require a physician’s diagnosis reported by pharmacists were 172 events and physicians were 321 events. Physicians had significantly more AEs requiring diagnosis than pharmacists did (p＜ 0.0001).Conclusion: The reports of pharmacists with JADER have fewer AEs with the diagnosis than those of physicians.

Search for Oral Medicine That Might Exacerbate the Prognosis of Adverse Drug Events in Elderly Patients / 医薬品情報学

<b>Objective: </b>Elderly patients commonly experience adverse drug events (ADEs) owing to their poor drug metabolizing and excretion ability, and these often cause multiple organ dysfunction syndrome.  Therefore, it is important that we identify the adverse drug events early on during prognosis.  We searched for oral medicines that might exacerbate the prognosis of ADEs in elderly patients.<br><b>Methods: </b>The objects under analysis were oral medicines that were registered in the Japanese Adverse Drug Event Report database (JADER).  The associations between the elderly/non-elderly patients and exacerbation risk/non-exacerbation risk were analyzed by risk ratios (RR).  The signal detection of exacerbation risk was defined as 95% confidence interval of lower limit of risk ratio>1 and χ²≥4.<br><b>Results: </b>The oral medicines that might markedly exacerbate the prognosis of ADEs in the elderly patients in comparison with the ADEs of young patients included 84 items, of which 63 have not been described as potentially inappropriate medicines in all guidelines for medical treatment of the elderly patients.<br><b>Conclusion: </b>In this study, while we could not search for oral medicines having a high risk of ADEs, we were able to search for oral medicines that might exacerbate the prognosis of ADEs in elderly patients.  This result could contribute to the proper use of medicines in the elderly patients.

Pharmacoepidemiological Examination for the Safety of the Oral laxatives in the Elderly Patients / 医薬品情報学

<b>Objective: </b>Many of the elderly patients are suffering from constipation, are using the oral laxative.  However the risk assessment of the oral laxative is not performed.  Therefore, we used Japanese Adverse Drug Event Report database (JADER) and examined for the safety of the oral laxative in the elderly patients.<br><b>Methods: </b>Since the analysis target medicines; 12 oral laxatives and target ADEs; “digestive disorders” and “electrolyte abnormality,” the JADER database for April 2004 to January 2015 were analyzed in adults of age exceeds 60.  We used the reporting odds ratio for a safety index of drugs, using reporting odds ratio, when the Lower bound of the 95% two-sided confidence interval exceeds 1, it is the signal detection of ADE.<br><b>Results: </b>The oral laxatives detected the signal of “digestive disorders” were three medicines, and “electrolyte abnormality” were five medicines.  Especially, for electrolyte abnormalities not only increases the blood magnesium values as magnesium oxide, that there is also affect other electrolyte revealed.<br><b>Conclusion: </b>Some oral laxatives were also intended to signal detections of the adverse events that are not listed in the attached document, it is necessary to pay attention to the use of them for the elderly patients.

Examination for Safety of Antiplatelet Therapy in the Elderly Patients Using Data Mining of the Japanese Adverse Drug Event Report (JADER) Database / 医薬品情報学

<b>Objective: </b>Antiplatelet therapy is useful for infraction prevention.  But, in elderly patients, adverse events are easily observed, owing to the decrease in metabolism and excretion of drugs.  Furthermore, applying guidelines for medical care of each disease does not necessarily result in good conclusions.  Therefore, we used Japanese Adverse Drug Event Report database and assessed safety signals with signal detection about adverse events developed by the antiplatelet therapy in the elderly patients.<br><b>Methods: </b>We analyzed all adverse events reported on ticlopidine hydrochloride that should be carefully administered, and clopidogrel, bisulfate and aspirin that are recommended as the alternative drugs.  We used the proportional reporting ratio for a safety index of drugs.<br><b>Results: </b>While some adverse events were expressed in only ticlopidine hydrochloride, bleeding signal was detected in all the subject agents.  In addition, onset risk of ticlopidine hydrochloride was found to be the lowest value.  Moreover, adverse events expressed in clopidogrel bisulfate and aspirin were of a wide-variety compared with ticlopidine hydrochloride.<br><b>Conclusion: </b>It is necessary to carefully administer not only ticlopidine hydrochloride but also the alternative drugs to the elderly patients as indicated, and there is a need to pay careful attention to administration of the alternative drugs.

Analyses of oxycodone-induced adverse effects based on the Japanese Adverse Drug Event Report Database

　Recently, the amount of oxycodone used for palliative care in the medical setting has markedly increased in Japan. As the beneficial effects and pharmacokinetic profile of oxycodone are dependent on patient characteristics such as gender and age, it is important to understand the relationships between adverse effects and patient characteristics when administering oxycodone therapy to patients suffering from cancer-related pain. Therefore, we used the Japanese Adverse Drug Event Report Database administered by the Pharmaceuticals and Medical Devices Agency, Japan, to analyze the frequencies of adverse events associated with oxycodone therapy. Furthermore, the statistical significance of the associations between adverse effects and background parameters, such as age and gender, was determined using Fisher’s exact test and odds ratio. As a result, it was found that delirium, nausea, and vomiting are the most common adverse events seen after oxycodone administration. These symptoms are also caused by morphine and fentanyl. Nausea and diarrhea in female and interstitial lung disease in male reported more frequently. On the other hand, somnolence and delirium in elderly patients reported more often than in young patients. These findings might be helpful for managing the adverse effects of pain therapy on an individual basis.

Analyses of opioid-induced adverse effects based on Japanese Adverse Drug Event Report database：Distinctive tendencies of the adverse events induced by morphine, fentanyl and oxycodone

Potent opioid analgesics are applicable for the treatment of severe pain, especially in cancer patients. Management of opioid-induced adverse effects is important to continue treatment with opioids because these drugs are associated with a variety of kinds of adverse effect, such as deliria and respiratory depression. However, information regarding these adverse effects in Japanese patients is limited. Therefore, we searched and analyzed a database for drug-induced adverse effects in Japan, the Japanese Adverse Drug Event Report database（JADER）, to acquire information related to the adverse effects induced by potent opioids such as morphine, fentanyl, and oxycodone. Cases with adverse effects associated with medications for palliative care were extracted from JADER, and types and frequencies of the events for each analgesic were analyzed. As a result, a lot of common adverse effects were found among the three opioids. However, the orders of their frequency differed among the analgesics. In principal component analysis, the property of morphine was intermediate between those of fentanyl and oxycodone. These findings may contribute to safe and effective pain control for patients receiving medical treatment with potent opioid analgesics.