Mining and analysis of ADE signals of romiplostim and eltrombopag based on FAERS database / 中国药房

OBJECTIVE To provide a reference for the safe use of thrombopoietin receptor agonists romiplostim and eltrombopag in clinic. METHODS FDA adverse event reporting system （FAERS） in the United States was adopted to collect adverse drug event （ADE） reports of romiplostim and eltrombopag from their launch in the United States to September 30， 2022； the ADE signals of the two drugs were analyzed using the reporting odds ratio （ROR） method and the comprehensive standard method of the UK Medicines and Healthcare Products Regulatory Agency. RESULTS A total of 14 021 and 4 431 ADE reports were collected about romiplostim and eltrombopag， respectively， with a gender composition of more females than males. After signal screening， 563 ADE signals were obtained about romiplostim， involving 25 system organ classes （SOC）； eltrombopag had 433 ADE signals， involving 26 SOC. The most frequently reported ADE for both drugs was platelet count decreased （2 060， 1 585 cases）， which was mentioned in their drug instructions. In terms of signal intensity， romiplostim exhibited the highest signal for abnormal thrombopoietin levels （ROR of 2 268.85）， while eltrombopag had the highest signal for positive dengue virus test （ROR of 954.50）， with neither of these signals mentioned in their respective drug instructions. CONCLUSIONS The ADE of romiplostim and eltrombopag mainly affects the blood and lymphatic system， and there are many new suspicious high-risk signals.

Safety of interferon β-1a for treatment of COVID-19： a real-world study based on FAERS database / 上海预防医学

ObjectiveTo systematically evaluate the safety of interferon β-1a for treatment of corona virus disease 2019 （COVID-19）， and to provide references for interferon β-1a's clinical application. MethodsThis study was conducted with the database from US Food and Drug Administration adverse event reporting system （FAERS） from January 1， 2015 to March 31， 2021. Information component （IC） and reporting odds ratio （ROR） methods were applied for signal mining. ResultsA total of 463 700 records of COVID-19 were selected for analysis， and 45 positive drug adverse event signals were detected. Headache （IC025=1.09， ROR025=2.28）， pyrexia （IC025=0.51， ROR025=1.51） and multiple sclerosis relapse （IC025=3.67， ROR025=14.71） were positive adverse events with higher frequency. Autoimmune disorder （IC025=4.42， ROR025=24.03）， streptococcal infection （IC025=4.12， ROR025=19.82）， and multiple sclerosis relapse （IC025=3.67， ROR025=14.71） were positive adverse events. Acute lung injury， cardio-respiratory arrest and metabolic acidosis were associated with a higher proportion and frequency of death. ConclusionThere are certain safety issues with interferon β-1a in the treatment of COVID-19， and some adverse events with high frequency and high death rate deserve further attention by medical staffs.

Excavation and evaluation of adverse reaction signals of 4 kinds of imported PD- 1/PD-L1 inhibitors / 中国药房

OBJECTIVE To exc avate and evaluate the adverse reaction signals of 4 kinds of imported programmed cell death 1 （PD-1）and its ligand （PD-L1）inhibitors，and to guide rational drug use in clinic. METHODS OpenVigil 2.1 software was used to obtain the adverse event reports of four drugs as nivolumab ，pembrolizumab，atezolizumab and durvalumab from the first quarter of 2013 to the fourth quarter of 2020 in the US FDA adverse event reporting system. The reporting odds ratio and proportional reporting ratio were used for signal mining to evaluate new or potential adverse reaction signals. RESULTS A total of 46 840 reports of adverse events with PD- 1/PD-L1 inhibitors as the primary suspected drug were collected ，including 28 896 reports of nivolumab，13 298 reports of pembrolizumab ，3 398 reports of atezolizumab ，and 1 248 reports of durvalumab. From the general characteristics of these reports ，the gender distribution was more men than women ，and the age distribution was mainly in the range of 51-85 years old. The reporting year was mainly in the nearly 4-5 years，and the main reporting countries were the US and Japan，with“death”and“hospitalization or prolonged hospitalization ”as the main serious adverse events which were over 50％ of the whole of 4 kinds of adverse events. A total of 1 597 adverse reaction signals were obtained ，involving 26 systems，focusing on “benign，malignant and unspecified neoplasms （cystic and polypoid tumor ）”，“infections and infestations ”and“investigations”， etc. The analysis of the top 50 adverse reaction signals showed that the largest number of report was endocrine system disease ，the most frequency signal was “malignant neoplasm progression ”and the strongest adverse reaction signal was “radiation pneumonitis ”. And it was also found that 13 adverse reaction signals ，such as “radiation pneumonitis ”“cholangitis”“fulminant type 1 diabetes mellitus” “blood creatine phosphokinase increased ” “disseminated intravascular coagulation ”“cardiac failure ”and “cerebral infarction ”，etc.，were not reported in the drug instructions. CONCLUSIONS PD-1/PD-L1 inhibitors mediate a large number of adverse reaction signals，resulting in high safety risks in “benign，malignant and unspecified neoplasms （cystic and polypoid tumor ）”，“infections and infestations ”and “investigations”，etc. The newly discovered 13 adverse reaction signals ，such as “radiation pneumonitis ”“cholangitis”“blood creatine phosphokinase increased ”“cardiac failure ”and“cerebral infarction ”are of great significance for guiding rational drug use in clinic.

ADE Risk Signal Mining Related to Belimumab Based on the FARES Database / 中国药房

OBJECTIVE：To prov ide referen ce for clinical safe and rational use of belimumab by mining the risk signals of adverse drug event （ADE）. METHODS ：ADE reports related to belimumab were collected from FDA adverse event reporting system（FAERS）from the first quarter of 2015 to the first quarter of 2021. The reporting odds ratio （ROR）method and the Medicines and Healthcare Products Regulatory Agency （MHRA）method were adopted to mine the ADE risk signals related to belimumab，setting the threshold as the number of reports ＞3 and the lower limit of 95％ CI ＞1（ROR method ）and the proportional reporting ratio （PRR）＞2，and χ2 ＞4（MHRA method ）. ADEs were counted and classified by using the preferred system organ class （SOC）and preferred term （PT）of Medical Dictionary for Regulatory Activities （MedDRA）. RESULTS & CONCLUSIONS：A total of 3 529 ADE reports with belimumab as the primary suspicious drug were screened ，in which female patients（90.31％）were much more than male patients （6.15％）；age distribution was concentrated in 18-59 years old （41.80％）. There were 1 234 cases（34.97％）of severe ADE reports ，mainly involving hospital or prolonged hospital stay. Most of the reporters were consumers or other non-medical professionals （81.84％）. North America reported the most （70.39％）and the main reporting country was the United States （2 029 reports）. A total of 180 PTs were mined from 3 529 reports，in addition to PTs associated with primary disease （systemic lupus erythematosus ，pain，arthralgia，pyrexia，weight decreased ，swelling，oropharyngeal pain ， etc.），PTs related to medication error （product dose omission ，inappropriate schedule of product administration ，underdose， product availability issue ，etc.）and PTs related to infection （influenza，urinary tract infection ，infection，sinusitis，etc.）were reported in a large number of cases. Twenty-six SOCs were involved ，the top 10 SOC in ADE reports were all kinds of injuries ， poisoning and surgical complications （2 225 reports），infections and infectious diseases （1 247 reports），general disorders and administration site conditions （1 196 reports），musculoskeletal and connective tissue disorders （1 195 reports），surgical and medical procedures（515 reports），etc. PTs in SOC in the first place （all kinds of injuries ，poisoning and surgical complications ）of ADE reports were all related to medication error ；herpes zoster ，kidney infection and cellulitis in SOC in the second place （infections and infectious diseases ）of ADE reports were not included in the drug instruction of belimumab ；most PTs in SOCs such as various nervous system diseases ，immune system diseases ，mental diseases ，benign，malignant and unknown tumors （including cystic and polypoid）which were taken attention in clinic were not included in the drug instruction of belimumab. It is suggested to avoid medication errors as far as possible in clinical use of belimumab ，and to guard against adverse reactions such as herpes zoster ， kidney infection ，cellulitis and various nervous system diseases ，immune system diseases and mental diseases. In addition ，the patients with malignant tumor or related history should use belizumab carefully.

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.

Excavation and Analysis of ADR Signals of Fluconazole ，Ketoconazole，Itraconazole and Voriconazole after Marketing / 中国药房

OBJECTIVE：To excavate the safety warning signals induced by azole antifungal agents ，including fluconazole ， ketoconazole，itraconazole and voriconazole after marketing ，and to provide references for rational drug use in the clinic. METHODS：Reporting odds ratio （ROR）data mining algorithm was used to investigate signals of adverse drug event （ADE）for fluconazole，ketoconazole，itraconazole and voriconazole from FDA Adverse Event Reporting System （FAERS）during January 1st，2004 to March 30th，2019. ROR data mining method was used to excavate the ADR signals of the drugs ，and main ADR involved in the safety information of azole antifungal agents instructions were analyzed. RESULTS ：A total of 27 831，5 712， 5 381 and 11 333 reports were picked out for fluconazole ，ketoconazole，itraconazole and voriconazole ，respectively. All of these drugs had exhibited high-risk signals detection by ROR ，including medical examination ，blood and lymphatic system disorders ， renal and urinary disorders ，endocrine diseases ，hepatobiliary disorders. The hepatotoxic-related ADR signals were mainly concentrated in fluconazole and voriconazole （fluconazole ROR ＝6.51，voriconazole ROR ＝14.65）；ADR detection results of Cushing’s-like syndrome （ROR＝24.86） and adrenal suppression （ROR＝44.06） by itraconazole showed high-risk signals ； ketoconazole and itraconazole had showed a strong ADR signal in adrenocortical dysfunction （ketoconazole ROR ＝15.64， itraconazole ROR ＝23.26），and the signal intensity of ketoconazole （ROR＝2.81）in skin and subcutaneous tissue disorders was significantly higher than that of other drugs . In addition ，hemorrhagic cystitis caused by fluconazole，itraconazole and voriconazole were not included in the drug instructions （fluconazole ROR ＝17.73，itraconazole ROR ＝31.43，voriconazole ROR ＝17.06）； netted green spot caused by fluconazole （ROR＝10.50）were not included in the drug instructions . CONCLUSIONS：Clinical staff should pay more attention to the differences in serious ADR related to fluconazole ，ketoconazole，itraconazole and voriconazole ； particularly some ADRs not mentioned in the drug instructions but have high incidence such as hemorrhagic cystitis caused by fluconazole，itraconazole，voriconazole and netted green spot caused by fluconazole ，as well as ADRs mentioned in the drug instructions but have abnormally high signal ，such as Cushing ’s-like syndrome and adrenal suppression caused by itraconazole .

The Safety Profiles of Biological Drugs for Rheumatoid Arthritis / 薬剤疫学

To identify the most frequently reported preferred terms （PTs） in the cases of rheumatoid arthritis （RA） patients treated with immunosuppressive biological drugs as suspected drugs, we analyzed the cases in the Japanese Adverse Drug Event Report （JADER） database. We found that pneumonia, interstitial lung disease, Pneumocystis jiroveci pneumonia （PCP), cellulitis, sepsis, and herpes zoster were the most frequently reported PTs. We obtained the reporting odds ratio （ROR） and the time to onset of these six PTs and compared them in the cases reported for each immunosuppressant as a suspected drug. We focused on RA treatment, including five tumor necrosis factor （TNF） antagonists （infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol). For pneumonia, interstitial lung disease and sepsis, no specific correlation was observed for each immunosuppressant for RA. In the case of PCP, the highest ROR was observed in the patients treated with infliximab. The time to onset of PCP in the infliximab-treated patients （median, 0.19 yr） was significantly shorter than the onset time in the patients treated with tocilizumab, an interleukin-6 receptor blocker that is another type of drug for RA（0.32 yr, p<0.01, Mann-Whitney test). The onset time in the patients treated with golimumab （0.24 yr） was also significantly shorter than the onset time for tocilizumab（p<0.05), but the ROR was not as high. These results suggested a correlation between PCP and infliximab. In the cases of cellulitis and herpes zoster, a similar correlation was observed with tocilizumab and certolizumab pegol, respectively. We should consider these results when patients have a respiratory disorder or skin/subcutaneous tissue disorder.

<b>The Safety Profiles of Biological Drugs for Rheumatoid Arthritis </b> / 薬剤疫学

<p>To identify the most frequently reported preferred terms （PTs） in the cases of rheumatoid arthritis （RA） patients treated with immunosuppressive biological drugs as suspected drugs, we analyzed the cases in the Japanese Adverse Drug Event Report （JADER） database. We found that pneumonia, interstitial lung disease, <i>Pneumocystis jiroveci</i> pneumonia （PCP), cellulitis, sepsis, and herpes zoster were the most frequently reported PTs. We obtained the reporting odds ratio （ROR） and the time to onset of these six PTs and compared them in the cases reported for each immunosuppressant as a suspected drug. We focused on RA treatment, including five tumor necrosis factor （TNF） antagonists （infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol). For pneumonia, interstitial lung disease and sepsis, no specific correlation was observed for each immunosuppressant for RA. In the case of PCP, the highest ROR was observed in the patients treated with infliximab. The time to onset of PCP in the infliximab-treated patients （median, 0.19 yr） was significantly shorter than the onset time in the patients treated with tocilizumab, an interleukin-6 receptor blocker that is another type of drug for RA（0.32 yr, p<0.01, Mann-Whitney test). The onset time in the patients treated with golimumab （0.24 yr） was also significantly shorter than the onset time for tocilizumab（p<0.05), but the ROR was not as high. These results suggested a correlation between PCP and infliximab. In the cases of cellulitis and herpes zoster, a similar correlation was observed with tocilizumab and certolizumab pegol, respectively. We should consider these results when patients have a respiratory disorder or skin/subcutaneous tissue disorder.</p>

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.