Early Post-marketing Phase Vigilance Research Articles

Overlapping risk factors for diabetic ketoacidosis in patients with type 1 diabetes on ipragliflozin: case analysis of spontaneous reports in Japan from a pharmacovigilance safety database

ABSTRACT Background In patients with type 1 diabetes mellitus (T1D), sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with an increased risk of diabetic ketoacidosis (DKA). Ipragliflozin is an SGLT2 inhibitor approved in Japan in combination with insulin for patients with T1D. Research design and methods Spontaneous safety reports of ipragliflozin adverse drug reactions (ADRs) in patients with T1D were collected during early post-marketing phase vigilance (EPPV; 21 December 2018–20 June 2019). For patients with T1D prescribed ipragliflozin who experienced DKA, we examined DKA event data registered in the manufacturer’s safety database (21 December 2018–31 December 2021), including patient background characteristics. Results During EPPV, there were 189 total events (45 serious) of ADRs, including 32 serious events of ketoacidosis. From 2018 to 2021, the major DKA risk factors were sick days, stopping or inappropriately decreasing insulin, insulin pump trouble, and low carbohydrate diet, with substantial overlap among these factors. Conclusions In Japanese patients with T1D using ipragliflozin, DKA events were linked to several overlapping factors, including sick days and reduced dose/interruption of insulin, whether intentional or unexpected. These results highlight the need for improved patient education regarding ipragliflozin use and appropriate self-management of ketosis from an early stage.

PS-C19-5: SAFETY PROFILES OF SACUBITRIL/VALSARTAN IN EARLY POST-MARKETING PHASE VIGILANCE FOR THE INDICATION OF CHRONIC HEART FAILURE AND HYPERTENSION

Background: The objective was to investigate and report the safety profile of Sacubitril Valsartan Sodium Hydrate (Sacubitril/Valsartan) (Entresto®) in Early Post-marketing Phase Vigilance (EPPV). Methods: In accordance with the regulation, the 6-month EPPV was conducted for the physicians or pharmacists at all medical institutions to which the drug was delivered. Safety information was collected and tabulated for the indication Chronic Heart Failure (CHF) (August 26, 2020 - February 25, 2021) and Hypertension (September 27, 2021 - March 26, 2022). The adverse drug reactions (ADRs) were classified using the basic terms of Medical Dictionary for Regulatory Activities (MedDRA). In addition, we focused on the five risks (hypotension, renal dysfunction/renal failure, hyperkalemia, angioedema, and dehydration) listed as Safety Specification in the Risk Management Plan (RMP). Results: The estimated number of patients treated with Sacubitril/Valsartan for the indication of CHF and hypertension was 24,898 and 165,000 during the data collection period. The number of ADRs were confirmed to be 850 (345 serious) for CHF and 455 (84 serious) for hypertension. No new safety findings were identified in both EPPVs. For both indications, the most common RMP-related ADRs were hypotension-related ADRs that occurred within 30 days after initiation were 87 (162 had, followed by renal dysfunction-related ADRs. Furthermore, hypotension-related ADRs were 268 (75 serious) for CHF and 93 (three serious) for hypertension. Hypotension-related ADRs that occurred within 30 days after initiation were 87 (162 had an unavailable date of onset) for CHF and 19 (71 had an unavailable date) for hypertension. Regarding renal dysfunction-related ADRs, the number of ADRs were 45 (45serious) for CHF and 19 (19serious) for hypertension. Renal dysfunction-related ADRs that occurred within 30 days after initiation were 17 (23 had an unavailable date of onset) for CHF and three (14 had an unavailable date) for hypertension. The number of hyperkalemia-related ADRs, angioedema, and dehydration were 35 (including 19 serious), five (five serious), and 25 (two serious) for CHF, and nine (five serious), four (four serious), and four (sero serious) for hypertension, respectively. Conclusion: No new safety findings were identified during the 6-month EPPV. Furthermore, there were no differences in safety profile by indication.

Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer: an early post-marketing phase vigilance study

BackgroundTriplet and doublet regimens of encorafenib plus cetuximab with and without binimetinib, respectively, were approved in Japan for unresectable, metastatic, BRAF V600E-mutated colorectal cancer (mCRC) that had progressed after 1–2 prior chemotherapies. This early post-marketing phase vigilance (EPPV) study collected adverse drug reactions (ADRs) from Japanese patients to ensure safety measures as appropriate.MethodsPatients with BRAF V600E mCRC who received the triplet or doublet regimens in Japan were selected for this study. ADRs were collected as spontaneous reports between November 27, 2020 and May 26, 2021. Serious ADRs were evaluated according to guidelines of the International Council for Harmonisation and the EudraVigilance list of Important Medical Event Terms.ResultsAn estimated 550 Japanese patients with mCRC received the triplet or doublet regimens during the 6-month EPPV period. Overall, 101 and 42 patients reported ADRs and serious ADRs, respectively. No ADRs leading to death were reported. The most frequently reported ADRs were nausea (17 patients), serous retinal detachment (16), decreased appetite (12), diarrhea (11), and vomiting (11). Among the important identified/potential risks that are defined in the risk management plans for encorafenib and binimetinib, eye disorder-related ADRs were observed in 32 patients, rhabdomyolysis-related ADRs in 12, hemorrhage-related ADRs in 7, and hepatic dysfunction-related ADRs in 7. Of 22 patients with serious eye disorders, 20 recovered or were recovering during the EPPV period.ConclusionThe safety profile in this EPPV study was similar to that from the phase III BEACON CRC study and no new safety concerns were identified.

4 ． Early Post-marketing Phase Vigilance and Post-marketing Survey of SARS‒CoV‒2 Vaccine Under COVID‒19 Situation

4 ． Early Post-marketing Phase Vigilance and Post-marketing Survey of SARS‒CoV‒2 Vaccine Under COVID‒19 Situation

Baseline risk characterization of early versus later adopters of long-acting paliperidone palmitate formulations.

Early Post‐Marketing Phase Vigilance (EPPV) is a unique system that encourages reporting of serious adverse reactions for medications newly introduced to Japan. When a once‐monthly paliperidone palmitate formulation (PP1M) was introduced in Japan in 2013, EPPV detected a signal of increased mortality, but this signal was not subsequently confirmed. To clarify whether that signal reflected increased adverse event reporting or an atypically high baseline mortality risk among early adopters of PP1M, we evaluated the baseline risk characteristics of early, mid, and later adopters of PP1M in a Japanese database and did a similar evaluation of PP1M and the three‐monthly formulation (PP3M) in two US databases. In Japan, early adopters compared with later adopters were older (mean 39.16 vs 33.70 years) but had a lower proportion of male patients (32.0% vs 44.44%), and a lower mean number of antipsychotic medications (distinct active medical substances) other than paliperidone (2.62 vs 2.85). In the United States, the baseline characteristics of early adopters of PP1M and PP3M did not suggest higher mortality risk than later adopters. These results offer no convincing evidence that the unconfirmed early signal of increased mortality with PP1M was due to increased baseline mortality risk among early adopters.

医薬品リスク管理計画のリスク最小化活動における「患者向医薬品ガイド」および「市販直後調査」の 記載に関する実態調査

医薬品リスク管理計画のリスク最小化活動における「患者向医薬品ガイド」および「市販直後調査」の 記載に関する実態調査

Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan

BackgroundPost-approval research or monitoring is important to determine real-world safety of new products; however, evidence is scant for vemurafenib in Japanese patients. In Japan, a unique system is officially obligated to investigate post-approval safety. Here we report the first adverse drug reaction (ADR) data from vemurafenib-treated Japanese patients with metastatic melanoma. Data were collected in an early post-marketing phase vigilance (EPPV) study.MethodsADRs were events for which a causal relationship with vemurafenib could not be ruled out or was unknown. ADR data were collected for patients treated with vemurafenib (960 mg bid) between 26 February and 25 August 2015.ResultsAmong 95 patients, 46 patients had 118 ADRs (24 serious ADRs in 13 patients). The most common serious ADRs were hypersensitivity (n = 1; 3 events), arthralgia (n = 2; 2 events), pyrexia (n = 2; 2 events) and drug eruption (n = 2; 2 events). Seven patients had serious skin disorders or hypersensitivity, six of whom had prior anti-programmed cell death-1 (PD-1) antibodies 5–35 days before starting vemurafenib. ADR reports of serious skin disorders appeared to be collected more rapidly than previously reported. Cutaneous squamous cell carcinoma developed in only one patient.ConclusionsEPPV in Japanese vemurafenib-treated patients identified no new safety signals. The most serious skin and hypersensitivity ADRs occurred in patients with prior anti-PD-1 exposure. Cutaneous squamous cell carcinoma appeared to be rare in Japanese patients. Further research is needed to clarify whether prior treatment with anti-PD-1 agents or racial differences affect the characteristic profile of cutaneous ADRs in Japanese patients.

Research on the Situation and Implications of the Early Postmarketing Phase Vigilance in Japan—Considerations Based on a Questionnaire Survey

Research on the Situation and Implications of the Early Postmarketing Phase Vigilance in Japan—Considerations Based on a Questionnaire Survey

Interstitial pneumonia in a patient treated with TAS-102 for metastatic colorectal cancer: a case report

BackgroundTAS-102, a new treatment option for patients with metastatic colorectal cancer that is refractory or intolerant to standard therapies, has been improving survival with acceptable tolerability and adverse events. Adverse hematological events associated with TAS-102 treatment were extensively profiled in the RECOURSE trial, but pulmonary toxicities associated with TAS-102 therapy are distinctly uncommon. In a recent early post-marketing phase vigilance on TAS-102 in Japan, seven cases of pulmonary disease were reported, but patient follow-up in this study was incomplete. Here, we present the first case of interstitial lung disease occurring in association with TAS-102 treatment.Case presentationA 57-year-old Japanese man who had previously received two standard treatments was admitted in 2014, at which time we administered TAS-102 (110 mg/day) as a third-line chemotherapy. He was safely treated with TAS-102 for the first planned cycle; however, approximately 4 days after receiving the second cycle of TAS-102, he complained of high fever and subsequent dyspnea with severe hypoxemia and went to the emergency room. A chest X-ray revealed diffuse coarse reticular shadows with ground-glass opacity on both lungs. Furthermore, a chest computed tomography scan showed thickening of the bronchovascular bundles with extensive ground-glass opacification and pleural effusions in both lung fields.In addition, a peripheral blood lymphocyte stimulation test with TAS-102 showed higher values compared with control samples. Consequently, we suspected drug-induced interstitial pneumonia, and discontinued treatment. Our patient was given an initial administration of high-dose methylprednisolone (1000 mg/day) for 3 days and oxygen. Our patient was discharged with oral prednisolone (20 mg/day) and improved symptomatically and radiologically.ConclusionsThese findings suggest that interstitial pneumonia is a rare complication of TAS-102 chemotherapy, but the possibility of interstitial pneumonia should always be considered when a patient presents with a respiratory disorder while undergoing TAS-102 systemic chemotherapy.Prompt discontinuation of TAS-102 and treatment with high-dosage corticosteroids is needed to avoid exacerbating respiratory symptoms.

Paliperidone palmitate: Japanese postmarketing mortality results in patients with schizophrenia

Objective: Paliperidone palmitate once-monthly injectable (PP1M) is approved in Japan and other countries for the treatment of schizophrenia. During the 6 month Japanese early postmarketing phase vigilance (EPPV) period, 32 deaths were reported. This report reviews potential contributing factors to the fatal outcomes in the PP1M-treated population.Research design and methods: All spontaneously reported adverse events following PP1M use received during EPPV from 19 November 2013 to 18 May 2014 were entered into the global safety database and these events were analyzed.Results: During the EPPV period, 10,962 patients were estimated to have been treated with PP1M in Japan. The mortality reporting rate during this EPPV period was higher than that observed in the US or globally after PP1M launch (5.84, 0.43, and 0.38 per 1000 patient-years, respectively), but was consistent with the mortality incidence rates (10.2 per 1000 person-years) observed during interventional clinical studies in Japan and in observational patient cohorts. Of the 32 deaths reported during the Japanese PP1M EPPV period, 19/32 (59.4%) were in patients over 50 years of age, 23/32 (71.9%) reported cardiovascular risk factors and 25/32 (78.1%) received antipsychotic polypharmacy.Conclusions: Based on this review of the 32 fatal cases in the PP1M EPPV period, the observed death rate does not necessarily result from a risk with PP1M treatment in Japanese patients. The higher mortality reporting rates in Japan may be attributed to a variety of factors: the effectiveness of mortality reporting in the unique Japanese EPPV program, the advanced age of the fatal cases, high cardiovascular risk factors, multiple underlying diseases and high antipsychotic polypharmacy among the cases with fatal outcomes.

Pharmacokinetic and Pharmacodynamic Analyses of Drug-Drug Interactions between Iguratimod and Warfarin.

Iguratimod (IGU), a disease-modifying antirheumatic drug launched in September 2012, has been reported to carry a risk of severe hemorrhages through a suspected interaction with warfarin (WF) in the all-case surveillance and early postmarketing-phase vigilance. To elucidate possible mechanisms of adverse interaction between IGU and WF, we analyzed the effects of IGU on the pharmacodynamics and pharmacokinetics of WF in rats. IGU was orally administered to male Wistar rats once daily for 5 d at 10 or 30 mg/kg in combination with WF at an oral dose of 0.25 mg/kg. Coadministration of IGU 30 mg/kg enhanced the anticoagulant activity of WF; prolonged blood coagulation time (prothrombin time and activated partial thromboplastin time) and decreased levels of vitamin K (VK)-dependent blood coagulation factors (II, VII, IX, and X) were observed. On the other hand, the pharmacokinetic parameters of WF including maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24 h) were not affected by the combination with IGU. IGU alone did not change blood coagulation time at doses up to 100 mg/kg, while VK-dependent blood coagulation factors decreased slightly at 30 and 100 mg/kg. These results suggest that the pharmacodynamic effect of IGU on VK-dependent blood coagulation factors is involved in the mechanism of drug-drug interaction of IGU with WF.

Mortality Risk Associated With Long-acting Injectable Antipsychotics: A Systematic Review and Meta-analyses of Randomized Controlled Trials.

Long-acting injectable (LAI) antipsychotics (LAI-APs) have several advantages over oral medications, but deaths reported in Japan during the early post-marketing phase vigilance period have raised safety concerns. We conducted a series of meta-analyses to assess whether LAI-APs affect the mortality of patients with schizophrenia. Three categorical meta-analyses of randomized controlled trials (RCTs) were performed to compare all-cause death (primary outcome) and death due to suicide: individual and pooled LAI-APs vs placebo, individual and pooled LAI-APs vs oral antipsychotics (OAPs), and head-to-head comparisons of LAI-APs. The risk ratios (RRs) and 95% CIs were calculated. We identified 52 RCTs (53 comparisons; total participants = 17 416, LAI-APs = 11 360, OAP = 3910, and placebo = 2146; mean study duration [wk]: LAI-APs vs placebo = 28.9, LAI-APs vs OAPs = 64.5). Neither pooled nor individual LAI-APs (aripiprazole, fluphenazine, olanzapine, paliperidone, and risperidone) differed from the placebo regarding the incidences of all-cause death (pooled LAI-APs: RR = 0.64, P = .37) and death due to suicide (pooled LAI-APs: RR = 0.98, P = .98). However, in a subgroup meta-analysis of only short-duration RCTs (≤13wk), pooled LAI-APs exhibited a trend toward lower incidence of all-cause death than placebo (RR = 0.29, P = .08). Pooled LAI-APs (aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, risperidone, and zuclopenthixol) did not differ from pooled OAPs regarding all-cause death (pooled LAI-APs: RR = 0.71, P = .30) and death due to suicide (pooled LAI-APs: RR = 0.94, P = .91). Individual LAI-APs and OAPs were associated with similar risks of death. Data for head-to-head comparisons of individual LAI-APs were insufficient. In conclusion, there was no significant difference between LAI-APs and placebo or OAPs regarding all-cause death and death due to suicide.

2113 Initial safety survey report from early post-marketing phase vigilance (EPPV) on TAS-102 for metastatic colorectal cancer (mCRC)

2113 Initial safety survey report from early post-marketing phase vigilance (EPPV) on TAS-102 for metastatic colorectal cancer (mCRC)

Bias in spontaneous reporting of adverse drug reactions in Japan.

BackgroundAttitudes of healthcare professionals regarding spontaneous reporting of adverse drug reactions (ADRs) in Japan are not well known, and Japan’s unique system of surveillance, called early post-marketing phase vigilance (EPPV), may affect these reporting attitudes. Our objectives were to describe potential effects of EPPV and to test whether ADR seriousness, prominence, and frequency are related to changes in reporting over time.MethodsA manufacturer’s database of spontaneous ADR reports was used to extract data from individual case safety reports for 5 drugs subject to EPPV. The trend of reporting and the time lag between ADR onset and reporting to the manufacturer were examined. The following indices for ADRs occurring with each drug were calculated and analyzed to assess reporting trends: Serious:Non-serious ratio, High prominence:Low prominence ratio, and High frequency:Low frequency ratio.ResultsFor all 5 drugs, the time lag between ADR onset and reporting to the manufacturer was shorter in the EPPV period than in the post-EPPV period. All drugs showed higher Serious:Non-serious ratios in the post-EPPV period. No specific patterns were observed for the High prominence:Low prominence ratio. The High frequency:Low frequency ratio for peginterferon alpha-2a and sevelamer hydrochloride decreased steadily throughout the study period.ConclusionsHealthcare professionals may be more likely to report serious ADRs than to report non-serious ADRs, but the effect of event prominence on reporting trends is still unclear. Factors associated with ADR reporting attitude in Japan might be different from those in other countries because of EPPV and the involvement of medical representatives in the spontaneous reporting process. Pharmacovigilance specialists should therefore be cautious when comparing data between different time periods or different countries. Further studies are needed to elucidate the underlying mechanism of spontaneous ADR reporting in Japan.

Safety evaluation of laninamivir octanoate hydrate through analysis of adverse events reported during early post-marketing phase vigilance

Abnormal behavior and delirium are common in children with influenza. While abnormal behavior and delirium are considered to be associated with influenza encephalopathy, an increased risk of such neuropsychiatric symptoms in patients receiving neuraminidase inhibitor treatment is suspected. Laninamivir octanoate hydrate, recently approved in Japan, is a long-acting neuraminidase inhibitor. It is important to establish a safety profile for laninamivir early, based on post-marketing experiences. Spontaneous safety reports collected in the early post-marketing phase vigilance were analyzed. Adverse events of interest such as abnormal behavior/delirium, dizziness/vertigo, respiratory disorders, shock/syncope, and any other serious events were intensively reviewed by the Safety Evaluation Committee. Abnormal behavior/delirium was a frequently reported event. Almost all the reported cases were considered to be due to influenza and not laninamivir. There were 32 cases of abnormal behavior/delirium that could lead to dangerous accidents, and these were observed more frequently in males and teenagers. Syncope probably related to the act of inhalation per se of laninamivir was reported during this survey. This safety review revealed that the safety profile of laninamivir for abnormal behavior/delirium and syncope was similar to that of other neuraminidase inhibitors. As stated in the labeling, teenage patients inhaling laninamivir should remain under constant parental supervision for at least 2 days and should be closely monitored for behavioral changes to prevent serious accidents associated with abnormal behavior/delirium. Furthermore, to avoid syncope because of inhalation, patients should be instructed to inhale in a relaxed sitting position.

Postmarketing safety experience with edoxaban in Japan for thromboprophylaxis following major orthopedic surgery.

PurposeEdoxaban is an oral, once-daily, selective, direct factor Xa inhibitor approved in Japan for the prevention of venous thromboembolism following major orthopedic surgery. Currently, edoxaban is in Phase III clinical development for the prevention of stroke and systemic embolic events in patients with atrial fibrillation, and for the treatment and prevention of recurrences of venous thromboembolism. This report describes the adverse drug reactions (ADRs) spontaneously reported during early postmarketing phase vigilance from the time of its commercial launch in Japan.Materials and methodsAll spontaneously reported ADRs following edoxaban use received by Daiichi Sankyo during early postmarketing phase vigilance from July 19, 2011, to January 18, 2012, were entered into the safety database and included in this review. Approximately 20,000 patients were estimated to have been treated with edoxaban.ResultsThe mean age of patients was 74.2 years, their mean weight was 59.4 kg, and approximately 70% were female. A total of 67 ADRs were reported in 56 patients, of which the majority included bleeding events (51 ADRs in 42 patients). Of these, 15 ADRs (in 14 patients) were serious, including cerebral hemorrhage (n = 1), gastric hemorrhage (n = 2; gastric hemorrhage [n = 1] and gastric ulcer hemorrhage [n = 1]), and surgical-site hemorrhage (n = 12; hemorrhage [n = 6], subcutaneous hemorrhage [n = 3], wound hemorrhage [n = 2], and wound hematoma [n = 1]). Most ADRs occurred within the first week of treatment and there were no fatalities. Nonserious ADRs associated with bleeding that occurred in >1 patient included subcutaneous hemorrhage (n = 9), wound hemorrhage (n = 5), postprocedural hematoma (n = 4), anemia (n = 4), and hemarthrosis (n = 3). Other nonserious ADRs not associated with bleeding and occurring in >1 patient included abnormal hepatic function (n = 4) and diarrhea (n = 2).ConclusionSafety data from the first 6 months of postmarketing experience with edoxaban did not identify any unforeseen safety signals, consistent with the known safety profile of edoxaban.

Factors associated with spontaneous reporting of adverse drug reactions in Japan

Spontaneous reported adverse drug reactions (ADRs) are currently the main source of pharmacovigilance activities in each country. The number of ADRs reported to the authority warns of safety risks to patients, but it also reflects the efficiency and limitations of the reporting system itself. This article explored how the accumulation of safety information, status in foreign countries (e.g., US approval), drug company attributes, and regulatory actions (e.g., early post-marketing phase vigilance; EPPV) were associated with the numbers of spontaneously reported ADRs in Japan. All serious ADRs for drugs for which the active ingredients or route of administration were approved in Japan from 2000 through 2005 were collected from the national database. The numbers of serious ADRs within the first 2 and 3 years after launch were analyzed using the negative binominal distribution model. The launch lag and the presence of drugs with a similar mode of action were negatively associated with the ADR numbers, but the number of study subjects for the new drug application (NDA) showed no clear association. The number of sales representatives and the implementation of EPPV were positively associated with the ADR numbers. The accumulation of foreign post-market evidence seemed to be more important for drug safety in Japan than was the amount of pre-approval safety data. The positive impacts of sales representatives and EPPV suggested a critical role for drug companies in drug safety and also the importance of considering how best to collect information in local situations with unique regulatory requirements.

Post-Marketing Safety Experience with Edoxaban in Japan for Thromboprophylaxis Following Major Orthopedic Surgery

AbstractAbstract 4697 BackgroundEdoxaban, an oral, selective, direct factor Xa inhibitor, is approved in Japan as a once-daily dose (15 mg or 30 mg tablets) for the prevention of venous thromboembolism (VTE) following major orthopedic surgery, including total knee arthroplasty, total hip arthroplasty, and hip fracture surgery. Currently, edoxaban is in phase 3 clinical development for the prevention of stroke and systemic embolic events in patients with atrial fibrillation as well as treatment and prevention of recurrence of VTE. This report describes the adverse drug reactions (ADRs) that were spontaneously reported during early post-marketing phase vigilance (EPPV) since the July 2011 commercial launch in Japan. MethodsEPPV was conducted for the initial 6 months from launch: July 19, 2011, to January 18, 2012. All ADRs that were spontaneously reported, were collected and analyzed. ResultsThe estimated exposure was approximately 20,000 patients. A total of 67 ADRs were reported in 56 patients, of which 15 (in 14 patients) were serious. The mean age of the patients was 74.1 years, mean weight was 59.4 kg, and approximately 70% of the patients were female. The majority of ADRs were bleeding events (51 ADRs in 42 patients), and serious ADRs included cerebral hemorrhage (n=1), gastric hemorrhage (n=1), gastric ulcer hemorrhage (n=1), and surgical site hemorrhage (n=12). Most of these ADRs occurred within the first week of treatment and there were no fatalities. The majority of non-serious adverse events associated with bleeding that occurred in more than one patient included subcutaneous hemorrhage (n=9), wound hemorrhage (n=5), post-procedural hematoma (n=4), anemia (n=4), and hemarthrosis (n=3). Other non-serious adverse events occurring in more than one patient included abnormal hepatic function (n=4) and diarrhea (n=2).SystemADRSeriousNon-seriousTotalBloodAnemia44NervousCerebral hemorrhage11VascularVenous embolism11Vascular hemorrhage617GastrointestinalDiarrhea22Feces discolored11Gastric hemorrhage11Gastric ulcer hemorrhage11Gastrointestinal hemorrhage11Gingival bleeding11Hematemesis11Hematochezia11HepatobiliaryAbnormal hepatic function44Hyperbilirubinemia11Jaundice11Liver disorder11SkinSubcutaneous hemorrhage3912Rash11MusculoskeletalHemarthrosis33Joint swelling11RenalHematuria11ReproductiveMetrorrhagia11GeneralEdema11Test resultsAlanine aminotransferase increased11Aspartate aminotransferase increased11Hemoglobin decreased11Liver function abnormal11Platelet count increased11InjurySubcutaneous hematoma11Wound hemorrhage257Post-procedural hematoma44Wound hematoma11Total155267 ConclusionsPreliminary data from EPPV for the first 6 months of commercial use of edoxaban did not identify any unforeseen safety signals. This evidence confirms the known safety profile of edoxaban—that edoxaban has been shown to be well tolerated. Disclosures:Kuroda:Daiichi Sankyo Pharma Development: Employment. Hotoda:Daiichi Sankyo Co., Ltd.: Employment. Nishikawa:Daiichi Sankyo Co., Ltd.: Employment. Nishiwaki:Daiichi Sankyo Co., Ltd.: Employment.

調剤薬局における「医療用医薬品の市販直後調査」への取り組み

Early Post-marketing Phase Vigilance for prescription drugs was enforced in October 2001. Under this system, hospitals and other medical institutions are considered as facilities for investigation, while dispensing pharmacies are not subject to investigation. However, considering the progress that has been made in the separation of dispensing from medical practice, we feel that the dispensing pharmacy can play an important role in the collection of safety information on prescription drugs.With this in mind, we began the collection of drug monitoring information in 1985 and more recently, we have been actively participating in Early Post-marketing Phase Vigilance as one of our activities in this regard. We have collected information on adverse drug reactions due to 20 prescription drugs in 12, 881 subjects. The number of subjects who reported adverse drug reactions was 213, and the number of adverse drug reactions reported was 220. Elderly patients of 60 years or more accounted for 36 % of the collected cases. Among adverse reactions involving body organs, the alimentary system (116 cases) came top with 52.7% of all cases and next came adverse reactions of the mental and nervous systems, accounting for 28.6% (63 cases) of the total.Since medical institutions issue over 50% of all of Japan's prescriptions, we must continue to actively participate in Early Post-marketing Phase Vigilance in the future through the collection of information on adverse drug reactions.

市販直後調査の臨床的評価 市販直後調査より報告された副作用シグナルの特徴

We examined differences in adverse drug reactions reported in trials for new drug applications and those reported in early post-marketing phase vigilance (EPPV) for drugs approved between October, 2001 and July, 2003. In EPPV reports, we found that the proportion of adverse drug reactions noted from blood tests (e.g. drug-induced hepatitis, hematology adverse reactions, electrolyte metabolism disorders, and renal dysfunction) was less than that of other adverse drug reactions. We consider that this was because blood tests were not conducted regularly enough and the reason that such reactions are severe when discovered.Since EPPV is considered as phase IV of drug testing, regular blood tests are still required and we feel that it is necessary to carry out pharmacovigilance more thoroughly to ensure the safety of drugs after they have been marketed.