Post-marketing Safety Research Articles

Post-Market Safety of Laparoscopic Ultrasound-Guided Radiofrequency Ablation.

Background and Objectives:Postoperative safety outcomes with laparoscopic intra-abdominal ultrasound-guided radiofrequency ablation, as performed by gynecologic surgeons new to the procedure, were evaluated and compared to the premarket, pivotal study. Post-procedure feedback from surgeons was reported.Methods:This was a post-market, prospective, single-arm analysis with 4 to 8 weeks follow-up among surgeons (n = 29) with varying levels of laparoscopic surgery experience participating in the ongoing, multinational Treatment Results of Uterine Sparing Technologies randomized clinical trial. Patients were premenopausal adult women (n = 110) desiring uterine-conserving treatment for symptomatic fibroids. During run-in, surgeons received proctored training. Following training, and after performing ≥ 2 procedures, surgeons provided self-assessment and feedback using a standardized form.Results:Surgeons performed 105 procedures with 100 per-protocol patients. The average number of proctored cases per surgeon was 2.48. No acute (≤ 48 hours) serious adverse events occurred (0/101, 0.0%) compared with 2 acute serious adverse events in the premarket study (2/137, 1.46%). Both studies reported 1 near-term (∼30 days) serious adverse event (< 1% for both). In this study, the near-term complication was fever of unknown origin requiring hospitalization related to uterine entry/manipulation. This was categorized as probably device-related; the patient was treated with antibiotics and discharged. Twenty-six surgeons completed the evaluation form; none reported experiencing problems with the procedure.Conclusion:Minimally invasive gynecologic surgeons can learn laparoscopic intraabdominal ultrasound-guided radiofrequency ablation and perform it safely (in terms of acute and near-term serious adverse events) after ≥ 2 proctored cases. There were no significant differences in safety outcomes compared to the premarket, pivotal study.

Post-Market Clinical Follow-up Performance and Safety Study of Etermis 3 and 4 in the Face (POMET)

Post-Market Clinical Follow-up Performance and Safety Study of Etermis 3 and 4 in the Face (POMET)

The impact of post-market regulatory safety advisories on patients, prescribers, and the healthcare system

The impact of post-market regulatory safety advisories on patients, prescribers, and the healthcare system

Post-marketing safety-related regulatory actions on first-in-class drugs: A double-cohort study.

New first-in-class (FIC) drugs with novel mechanisms of action may be highly effective, but lack adequate safety information, and therefore may be associated with crucial post-marketing safety issues. The objective of this study was to evaluate the post-marketing risk of FIC drug with comparison occurrence of Post-marketing safety-related regulatory actions (PSRAs) due to FIC drugs to that due to other new drugs. A full list of all new molecular entities and therapeutic biologics, except diagnostic agents and vaccines, which were approved in the United States between 1 January 2003, and 31 December 2013, were included in this study. Drugs with novel mechanisms of action at the time of approval were classified as the FIC cohort and other new drugs as the control cohort. PSRAs were defined as safety-related post-marketing withdrawal, new issuance or the addition of black box warnings. Specifically, we identified PSRAs associated with adverse drug reactions (ADR-PSRAs). Subsequently, we identified drug allergyADR-PSRAs and class-effect ADR-PSRAs, and also extracted drug-specific ADR-PSRAs. To evaluate the post-marketing safety risk of FIC drugs, we estimated the odds ratio of the occurrence of ADR-PSRAs between the FIC cohort and the control cohort. The odds ratio of the occurrence of all ADR-PSRA in the FIC cohort was 0.96 (95% CI: 0.57-1.61, P=.8758), showing no difference compared to that of the control cohort. However, the odds ratio of the occurrence of drug-specific ADR-PSRAs in the FIC cohort was 2.06 (95% CI: 1.20-3.55, P=.0091). This study demonstrated that a strong relationship existed between FIC drugs and the occurrence of drug-specific ADR-PSRAs, suggesting that post-marketing safety risk for FIC drugs is higher than that for other new drugs given the same class at approval.

Evaluation of Serious Postmarket Safety Signals Within 2 Years of FDA Approval for New Cancer Drugs.

We examined how often new serious safety signals were identified by the U.S. Food and Drug Administration within the first 2 years after approval for new molecular entities (NMEs) for treatment of cancer that required specific regulatory actions described here. We identified, for all NMEs approved for treatment of cancer or malignant hematology indications between 2010 and 2016, substantial safety-related changes within the first 2 years after approval, which included a new Boxed Warning or Warning and Precaution; requirement for (or modification of existing) Risk Evaluation and Mitigation Strategies (REMS); and withdrawal from the market because of safety concerns. Fifty-five NMEs were approved between 2010 and 2016: 32 (58%) under regular approval (RA) and 23 (42%) under accelerated approval (AA). Of these 55 NMEs, 9 (16%) had substantial safety-related changes after approval. Across all 55 NMEs, one was temporarily withdrawn from the market for safety reasons (1.8%); one (1.8%) required a new REMS; nine required labeling revisions-new Boxed Warnings were required for two NMEs (3.6%), and new Warnings and Precautions subsections were required for eight (14.6%). One drug (ponatinib) was responsible for several of the substantial safety-related changes (withdrawal, REMS, Boxed Warnings). One of 32 NMEs approved under RA required a new Warning and Precaution, whereas 7 of 23 NMEs approved under AA had substantial safety-related changes in the first 2 years after approval. Based on our analysis we conclude that although there was a greater incidence of substantial safety-related changes to AA drugs versus RA drugs, the majority of these were changes to the Warnings and Precautions and did not substantially alter the benefit-risk profile of the drug. The majority of new cancer drugs (84%) approved in the U.S. do not have new substantial safety information being added to the label within the first 2 years of approval. Unprecedented efficacy seen in contemporary cancer drug development has led to early availability of effective cancer therapies based on large effects in smaller populations. More limited premarket safety data require diligent postmarketing safety surveillance as we continue to learn and update drug labeling throughout the product lifecycle.

Review of the initial post-marketing safety surveillance for the recombinant zoster vaccine

BackgroundThe adjuvanted recombinant zoster vaccine (RZV) received its first marketing authorization in October 2017, for prevention of herpes zoster in individuals aged ≥50 years. MethodsWe summarized safety information, following RZV administration, received by GSK via spontaneous adverse event (AE) reports submitted by healthcare providers, vaccine recipients and other reporters. Observed-to-expected (O/E) analyses were performed for selected outcomes: reports of death, Guillain–Barré syndrome and Bell’s palsy. Standard case definitions were used to assess individual case reports. Data mining, using proportional reporting ratio and time-to-onset signal detection methods, was employed to identify RZV-AE pairs with disproportionate reporting or unexpected time-to-onset distribution. ResultsBetween October 13, 2017 and February 10, 2019, an estimated 9.3 million doses were distributed and GSK received 15,638 spontaneous AE reports involving RZV. Most reports were classified as non-serious (95.3%) and originated from the United States (81.7%), where the majority of doses were distributed. Among reports with age or sex reported, individuals were mainly 50–69-year-olds (62.1%) and female (66.7%). Of all reports, 3,579 (22.9%) described vaccination errors, of which 82.7% were without associated symptoms. Of all vaccination error reports, most described errors of vaccine preparation and reconstitution (29.7%), inappropriate schedule or incomplete course of administration (26.7%), incorrect route of administration (16.4%), and storage errors (12.9%). The most commonly reported symptoms were consistent with the known RZV reactogenicity profile observed in clinical trials, including injection site reactions, pyrexia, chills, fatigue, headache. O/E analyses for selected outcomes and data mining analyses for all reported AEs did not identify any unexpected patterns. ConclusionsReview of the initial data from the post-marketing safety surveillance showed that the safety profile of RZV is consistent with that previously observed in pre-licensure clinical trials. Other studies are ongoing and planned, to continue generating real-world safety data and further characterize RZV.

Completeness of pharmacovigilance reporting in general medicine in France.

Spontaneous reporting remains one of the cornerstones of post-marketing drug safety surveillance. One of its main limitations is a lack of completeness.The main aim of this study was to assess the completeness of pharmacovigilance reports sent by general practitioners (GPs) to regional pharmacovigilance centers (RPC) reported in the French pharmacovigilance database (FPVD). Secondary aim was to identify factors associated with complete reports. All adverse drugs reactions (ADRs) sent by GPs in France in 2015 were analyzed. According to information provided in ADR reports (ADR, date of occurrence, clinical description, drugs suspected, etc.), completeness was analyzed from &#8220;mandatory&#8221; criteria (age, gender, ADR&#160;and suspected drug(s)) and &#8220;non-mandatory&#8221; criteria (medical history, concomitant drugs, symptoms evolution and complementary exams) and classified&#160;as&#160;&#8220;well-documented&#8221;, &#8220;slightly-documented&#8221; or &#8220;poorly-documented&#8221;. In 2015, the FPVD contained 3,020 ADR reports realized by GPs. Only 16.4% of these reports were classified as &#8220;well-documented&#8221;, in accordance with study criteria. The most poorly documented items were concomitant drugs (41.4%) and complementary exams (37.4%). An association between a &#8220;well-documented&#8221; ADR report and its &#8220;seriousness&#8221; (OR = 3,02 [95%&#160;CI&#160;2,44; 3,23], P&#160;&lt;&#160;10&#8211;3) and elderly compared to adults (OR&#160;=&#160;1,76 [95% CI 1,42; 2,18], P&#160;&lt;&#160;10&#8211;3) or children (OR = 4,59 [95% CI 2,51; 8,39], P&#160;&lt;&#160;10&#8211;3). Our study shows that only one out of six ADR reports was &#8220;well-documented&#8221;. It appears to be important to promote pharmacovigilance to improve completeness of ADR reports.

Robot-assisted bronchoscopy for pulmonary lesion diagnosis: results from the initial multicenter experience

BackgroundThe Robotic Endoscopic System (Auris Health, Inc., Redwood City, CA) has the potential to overcome several limitations of contemporary guided-bronchoscopic technologies for the diagnosis of lung lesions. Our objective is to report on the initial post-marketing feasibility, safety and diagnostic yield of this technology.MethodsWe retrospectively reviewed data on consecutive cases in which robot-assisted bronchoscopy was used to sample lung lesions at four centers in the US (academic and community) from June 15th, 2018 to December 15th, 2018.ResultsOne hundred and sixty-seven lesions in 165 patients were included in the analysis, with an average follow-up of 185 ± 55 days. The average size of target lesions was 25.0 ± 15.0 mm. Seventy-one percent were located in the peripheral third of the lung. Pneumothorax and airway bleeding occurred in 3.6 and 2.4% cases, respectively. Navigation was successful in 88.6% of cases. Tissue samples were successfully obtained in 98.8%. The diagnostic yield estimates ranged from 69.1 to 77% assuming the cases of biopsy-proven inflammation without any follow-up information (N = 13) were non-diagnostic and diagnostic, respectively. The yield was 81.5, 71.7 and 26.9% for concentric, eccentric and absent r-EBUS views, respectively. Diagnostic yield was not affected by lesion size, density, lobar location or centrality.ConclusionsRAB implementation in community and academic centers is safe and feasible, with an initial diagnostic yield of 69.1–77% in patients with lung lesions that require diagnostic bronchoscopy. Comparative trials with the existing bronchoscopic technologies are needed to determine cost-effectiveness of this technology.

Towards early detection of adverse drug reactions: combining pre-clinical drug structures and post-market safety reports

BackgroundAdverse drug reaction (ADR) is a major burden for patients and healthcare industry. Early and accurate detection of potential ADRs can help to improve drug safety and reduce financial costs. Post-market spontaneous reports of ADRs remain a cornerstone of pharmacovigilance and a series of drug safety signal detection methods play an important role in providing drug safety insights. However, existing methods require sufficient case reports to generate signals, limiting their usages for newly approved drugs with few (or even no) reports.MethodsIn this study, we propose a label propagation framework to enhance drug safety signals by combining drug chemical structures with FDA Adverse Event Reporting System (FAERS). First, we compute original drug safety signals via common signal detection algorithms. Then, we construct a drug similarity network based on chemical structures. Finally, we generate enhanced drug safety signals by propagating original signals on the drug similarity network. Our proposed framework enriches post-market safety reports with pre-clinical drug similarity network, effectively alleviating issues of insufficient cases for newly approved drugs.ResultsWe apply the label propagation framework to four popular signal detection algorithms (PRR, ROR, MGPS, BCPNN) and find that our proposed framework generates more accurate drug safety signals than the corresponding baselines. In addition, our framework identifies potential ADRs for newly approved drugs, thus paving the way for early detection of ADRs.ConclusionsThe proposed label propagation framework combines pre-clinical drug structures with post-market safety reports, generates enhanced drug safety signals, and can potentially help to accurately detect ADRs ahead of time.AvailabilityThe source code for this paper is available at: https://github.com/ruoqi-liu/LP-SDA.

Exact sequential analysis for multiple weighted binomial end points.

Sequential analysis is used in clinical trials and postmarket drug safety surveillance to prospectively monitor efficacy and safety to quickly detect benefits and problems, while taking the multiple testing of repeated analyses into account. When there are multiple outcomes, each one may be given a weight corresponding to its severity. This paper introduces an exact sequential analysis procedure for multiple weighted binomial end points; the analysis incorporates a drug's combined benefit and safety profile. It works with a variety of alpha spending functions for continuous, group, or mixed group-continuous sequential analysis. The binomial probabilities may vary over time and do not need to be known a priori. The new method was implemented in the free R Sequential package for both one- and two-tailed sequential analysis. An example is given examining myocardial infarction and major bleeding events in patients who initiated non-steroidal antiinflammatory drugs.

Comparing rates of atrioesophageal fistula with contact force-sensing and non-contact force-sensing catheters: analysis of post-market safety surveillance data

PurposeThere is limited data on the specific incidence of serious adverse events, such as atrioesophageal fistula (AEF), associated with either contact force (CF) or non-CF ablation catheters. Since the actual number of procedures performed with each type of catheter is unknown, making direct comparisons is difficult. The purpose of this study was to assess the incidence of AEF associated with the use of CF and non-CF catheters. Additionally, we aimed to understand the workflow present in confirmed AEF cases voluntarily provided by physicians.MethodsThe number of AEFs for 2014–2017 associated with each type of catheter was extracted from an ablation device manufacturer’s complaint database. Proprietary device sales data, a proxy for the total number of procedures, were used as the denominator to calculate the incidence rates. Additional survey and workflow data were systematically reviewed.ResultsBoth CF and non-CF ablation catheters have comparably low incidence of AEF (0.006 ± 0.003% and 0.005 ± 0.003%, respectively, p = 0.69). CF catheters are the catheter of choice for left atrium (LA) procedures which pose the greatest risk for AEF injury. Retrospective analysis of seven AEF cases demonstrated that high power and force and long RF duration were delivered on the posterior wall of the left atrium in all cases.ConclusionsCF and non-CF ablation catheters were found to have similar AEF incidence, despite CF catheters being the catheter of choice for LA procedures. More investigation is needed to understand the range of parameters which may create risk for AEF.

Risk of Malignancies in Patients with Rheumatoid Arthritis Treated with Rituximab: Analyses of Global Postmarketing Safety Data and Long-Term Clinical Trial Data.

IntroductionPatients with rheumatoid arthritis (RA) are at an increased risk of developing malignancies, but it is unclear whether this increased risk is the result of disease pathobiology or immunosuppressant treatments for RA. This analysis evaluated the potential risk of malignancy in patients with RA treated with rituximab (MabThera®/Rituxan®) a CD20+ B-cell depleting agent manufactured by F. Hoffmann-La Roche Ltd.MethodsMalignancy rates were obtained from the rituximab global company safety database for adverse event reporting and from the rituximab global clinical trial program for RA consisting of eight randomized clinical trials, two long-term open-label extensions, and one open-label prospective study. Global company safety database searches were performed using the standard Medical Dictionary for Regulatory Activities (MedDRA) queries “Malignant tumors wide” and “Skin malignant tumors wide” up to April 30, 2017. Age- and sex-specific comparator values from the general population were obtained from the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database.ResultsFor the 409,706 patients with RA in the rituximab global company safety database since first market approval in 2006, 1739 cumulative malignant events were reported, with an overall malignancy reporting rate of approximately 4.2 events per 1000 patients. No evidence of increased risk of malignancy, of any organ-specific type, was found following rituximab treatment. The rate of malignancies from rituximab-treated patients in RA clinical trials was 7.4 per 1000 patient-years. This is within the expected range, with no evidence for increased risk over time or with additional rituximab courses.ConclusionsAnalyses of the global postmarketing safety database and long-term clinical trial data showed no evidence of an increased risk of malignancy of any type following rituximab treatment in patients with RA.FundingF. Hoffmann-La Roche Ltd.

Vedolizumab use is not associated with increased malignancy incidence: GEMINI LTS study results and post-marketing data.

Vedolizumab is a gut-selective antibody to α4 β7 integrin approved to treat moderate-to-severe Crohn's disease and ulcerative colitis in adults. Inflammatory bowel disease (IBD) and immunosuppressant use are associated with increased risk of malignancy. To analyse the incidence of malignancy with vedolizumab treatment in the GEMINI long-term safety (LTS) study and post-marketing (PM) setting. Malignancy data from the LTS study (May 2009 to May 2018), and data from the vedolizumab Global Safety Database (20 May 2014 to 19 May 2018), were identified using Medical Dictionary for Regulatory Activities coding. The number of patients experiencing malignancies in the LTS study (excluding malignancies within 1year following vedolizumab initiation) was indirectly standardised against the number expected, using age- and sex-specific rates in patients with IBD from Optum's Clinformatics™ Data Mart (CDM) database. Among 1785 patients with ≥1year of follow-up post-vedolizumab initiation in the LTS study (total 5670 patient-years), observed numbers of malignancies were similar to those expected compared with CDM data (31 vs 29; ratio of observedto expected events=1.08; P=0.71; 95% confidence intervals [CI] 0.73, 1.53). The most common malignancies were renal and bladder (6). PM, 293 patients reported 299 malignancies (including malignancies within 1year following vedolizumab initiation), in approximately 208050 patient-years of vedolizumab exposure. Lower gastrointestinal malignancies were most common (59). The number of malignancies in the LTS study was similar to that expected from an IBD population with no statistically significant differences, although few confounders could be corrected for. Limitations of PM safety reporting require consideration; however, the number of malignancies with vedolizumab appeared low.

Post-marketing safety and efficacy surveillance of cell and gene therapies in the EU: A critical review

Post-marketing safety and efficacy surveillance of cell and gene therapies in the EU: A critical review

Sodium Glucose Cotransporter 2 Inhibition Heralds a Call-to-Action for Diabetic Kidney Disease.

Diabetes is a global health emergency with 425 million people affected in the year 2017 and a projection for 629 million by 2045. Half develop diabetic kidney disease, and its prevalence is rising progressively in concert with the overall diabetes epidemic, largely driven by type 2 diabetes ([1][1

Real-World Analysis of Adverse Events Associated with CAR T-Cell Therapy Among Adults Age ≥65 Years

Introduction: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel) are chimeric antigen receptor (CAR) T-cell therapies that target CD19-expressing B cells. Both therapies have been approved by the United States (US) Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after at least 2 lines of systemic therapy. The median age at diagnosis of diffuse LBCL is 66 years, with over half the cases occurring in patients over age 65. Patients &gt;65 years have worse survival than younger patients. Despite this predilection for older age, only one quarter of the patients in the pivotal trials supporting approval of the 2 therapies were age 65 or older. An analysis of the safety of axi-cel in the pivotal ZUMA-1 trial showed no significant differences between the age &lt;65 and ≥65 subgroups; however, the small number of older patients included on the original clinical trials due to the constraints of the stringent eligibility criteria limits the generalizability of these findings (Sano et al, Blood 2018 132:96). In this analysis, we reviewed post-approval adverse events (AEs) involving axi-cel or tis-cel for LBCL and compared reactions and outcomes by age utilizing the FDA Adverse Events Reporting System (FAERS) Database, which was created to support FDA's post-marketing safety surveillance program for drug and therapeutic biologic products. Methods: The FAERS database contains anonymized reports of product-related AEs, classified using the Medical Dictionary for Regulatory Activities (MedDRA) and categorized as serious or non-serious. The database was queried for cases involving axi-cel or tis-cel (and their respective trade names) from the FDA approval date for the LBCL indication (October 18, 2017 for axi-cel; May 1, 2018 for tis-cel) through March 31, 2019. Cases were excluded if the age of the patient was unknown. Cases reported outside the US were excluded. Patient characteristics and adverse events were summarized using descriptive statistics. Comparisons of rates of AEs by age group were made using Fisher's exact test; statistical significance was determined at a two-sided α=0.05. Results: A total of 397 cases were retrieved (360 involving axi-cel, 37 involving tis-cel). The median age of the patients involved was 62 years (range 18-81), with 153 (39%) of the patients age 65 or older. The vast majority of reactions (376, 95%) reported to FAERS were classified as serious. Overall, 141 (36%) cases resulted in hospitalization; 33 (8%) cases had an outcome categorized as life-threatening; 46 (12%) cases resulted in death; 6 (2%) resulted in disability. The most common reaction in each age group was cytokine release syndrome (CRS), reported in 64% and 56% of patients &lt;65 and ≥65 groups, respectively (Table). When a composite definition for CRS was utilized by including individual clinical features that comprise CRS, a higher proportion of patients &lt;65 were noted to have CRS (80% vs. 67%, p&lt;0.01). Pyrexia (41% vs. 24%, p&lt;0.01), tachycardia (17% vs. 8%, p=0.01), hospitalization (42% vs. 25%, p&lt;0.01) and elevated ferritin levels (3% vs. 0%, p=0.03) were significantly more common among the younger age group. Patients ≥65 had a significantly higher proportion of cases of neurotoxicity (50% vs. 39%, p=0.04); atrial fibrillation was also reported more frequently in the older age group compared to younger patients (8% vs. 3%, p=0.02). Conclusions: This large-scale post-marketing report of CAR T-cell therapy associated AEs in the real world suggests differences based on age: patients ≥65 had a higher incidence of neurotoxicity and atrial fibrillation while younger patients had increased incidence of some CRS components, especially pyrexia and tachycardia. There was no demonstrable difference in deaths between the 2 groups, but younger patients had higher rates of hospitalization. This report provides real-world evidence for use of CAR T-cell therapy in patients ≥65 and can inform clinical care based on patterns of AEs observed. Potential under-reporting of cases to the FAERS database, the retrospective design of this study and limited data available in the case reports preclude interpretation of causality. Despite these limitations, our findings identified real-world trends in reported signals that complement clinical trial safety data and support further pharmacoepidemiologic study. Disclosures Zettler: Cardinal Health: Employment. Feinberg:Cardinal Health: Employment. Phillips Jr.:Cardinal Health: Employment. Klink:Cardinal Health: Employment. Mehta:Cardinal Health: Employment. Gajra:Cardinal Health: Employment.

FDA's Unimproved Enforcement of Postmarketing Requirements and Commitments: Implications for Providers and Patients

The 2007 reauthorization of the Prescription Drug User Fee Act empowered the Food and Drug Administration (FDA) to require and enforce postmarketing studies to monitor the safety of prescription drugs, an increasing number of which are approved under expedited development or review programs. However, compliance rates for postmarketing requirements are low, and the FDA has not exercised its enforcement authority, allowing the very safety concerns that prompted the expansion of its power to continue. Prior evaluations have found that the FDA lacks reliable, timely, and readily accessible data for tracking postmarket safety issues, and that it has failed to enforce the postmarket surveillance measures it requires of the pharmaceutical industry. This study provides an updated evaluation of FDA oversight of postmarketing requirements and commitments and assesses whether there have been improvements since 2010. This study utilized data from the FDA's annual Report on the Performance of Drug and Biologics Firms in Conducting Postmarketing Requirements and Commitments. It evaluated studies opened in FY 2011-2014 and tracked their status through the FDA's FY 2018 report (data as of September 30, 2018), thereby allowing the pharmaceutical industry 4-7 years to complete a given PMR/PMC. Descriptive statistics were calculated, and differences in the status of postmarketing requirements and postmarketing commitments between FYs 2011-2014 and FY 2009-2010 were evaluated. During fiscal years 2011-2014, there was little difference in the FDA's oversight of postmarketing studies compared to fiscal years 2009-2010. While there were some year-to-year significant differences, the overall trend indicated no change. The FDA's oversight of postmarketing studies has not improved since 2010. This paper discusses implications for providers and patients who unduly assume the responsibility of postmarketing surveillance due to the lack of FDA oversight.

US FDA enhancing postmarketing drug safety surveillance

US FDA enhancing postmarketing drug safety surveillance

Carbamazepine promotes specific stimuli-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury in mice.

The occurrence of idiosyncratic drug-induced liver injury (IDILI) is a leading cause of post-marketing safety warnings and withdrawals of drugs. Carbamazepine (CBZ), widely used as an antiepileptic agent, could cause rare but severe idiosyncratic liver injury in humans. Although recent studies have shown that inflammasome is implicated in CBZ-induced hepatocellular injury in vitro, the precise pathogenesis of hepatotoxicity remains largely unexplored. Here we report that CBZ causes idiosyncratic liver injury through promoting specific stimuli-induced NLRP3 inflammasome activation. CBZ (40μM) enhances NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) or nigericin, rather than SiO2, monosodium urate crystal or intracellular lipopolysaccharide (LPS). In addition, CBZ has no effect on NLRC4 or AIM2 inflammasome activation. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial event in the enhancement effect of CBZ on ATP- or nigericin-induced NLRP3 inflammasome activation. Moreover, the "C=C" on the seven-membered ring and "C=O" on the nitrogen of CBZ may be contribute to NLRP3 inflammasome hyperactivation and hepatotoxicity. Notably, in vivo data indicate that CBZ (50mg/kg) causes liver injury in an LPS (2mg/kg)-mediated susceptibility mouse model of IDILI, accompanied by an increase in caspase-1 activity and IL-1β production, whereas the combination of CBZ and LPS does not exhibit the effect in NLRP3-knockout mice. In conclusion, CBZ specifically promotes ATP- or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury. Our findings also suggest that CBZ may be avoided in patients with NLRP3 inflammasome activation-related diseases that are triggered by ATP or nigericin, which may be risk factors for IDILI.

Safety and effectiveness of bevacizumab in Japanese patients with malignant glioma: a post-marketing surveillance study

ObjectiveThis surveillance study was conducted to verify the post-market safety and effectiveness of bevacizumab, which was approved in Japan in 2013 for the treatment of patients with newly diagnosed and or recurrent malignant glioma.MethodsThis was a prospective, observational, multicenter post-marketing surveillance study. Patients with newly diagnosed or recurrent malignant glioma scheduled for bevacizumab treatment were enrolled. The incidence and severity of adverse drug reactions were calculated. The effectiveness of bevacizumab was assessed by the 1-year survival rate and the overall survival rate.ResultsThe safety analysis set and the effectiveness analysis set each comprised 258 of the 268 enrolled patients: tumours were newly diagnosed in 80 patients (31%) and recurrent in 178 patients (68.9%). The incidence of grade ≥ 3 adverse drug reactions was 15.1%. Adverse drug reactions of special interest included 14 cerebral bleeding events and 11 infections. Of the 80 patients with newly diagnosed malignant glioma, 44 (55%) were alive throughout the 18-month observation period. The 1-year survival rate for patients with newly diagnosed glioblastoma was 78%. Median overall survival was not calculated, but 51.2% of patients were alive at the last date of observation of the last observed patient. In patients with recurrent glioblastoma, the 1-year survival rate was 38.9%, and the median overall survival was 10.2 months.ConclusionsThe results suggest no new safety concerns, and the effectiveness might be similar to previously reported data in clinical trials. Therefore, bevacizumab is considered as one of the treatment options for patients with malignant glioma in real-world clinical practice.