Reality of drug-induced erythema multiforme: A French pharmacovigilance study.

BACKGROUND: Since the 2002 SCAR study, erythema multiforme (EM), a post-infectious disease, has been distinguished from Stevens-Johnson syndrome (SJS), drug-induced. Nevertheless, EM cases are still reported in the French pharmacovigilance database (FPDB). OBJECTIVES: To describe EM reported in the FPDB and to compare the quality and the characteristics of the reports. METHODS: This retrospective observational study selected all EM cases reported in the FPDB over two periods: period 1 (P1, 2008-2009) and period 2 (P2, 2018-2019). Inclusion criteria were 1) a diagnosis of clinically typical EM and/or validated by a dermatologist; 2) a reported date of onset of the reaction; and 3) a precise chronology of drug exposure. Cases were classified confirmed EM (typical acral target lesions and/or validation by a dermatologist) and possible EM (not-otherwise-specified target lesions, isolated mucosal involvement, doubtful with SJS). We concluded possible drug-induced EM when EM was confirmed, with onset ranging from 5 to 28 days without an alternative cause. RESULTS: Among 182 selected reports, 140 (77%) were analyzed. Of these, 67 (48%) presented a more likely alternative diagnosis than EM. Of the 73 reports of EM cases finally included (P1, n=41; P2, n=32), 36 (49%) had a probable non-drug cause and 28 (38%) were associated with only drugs with an onset time ≤4 days and/or ≥29 days. Possible drug-induced EM was retained in 9 cases (6% of evaluable reports). Etiological work-up was more often performed in period 2 than 1 (53.1% vs 29.3%, P=0.04), and the time to onset from 5 to 28 days was more frequent in period 2 (59.2% vs 40%, P=0.04). CONCLUSIONS: This study suggests that possible drug-induced EM is rare. Many reports describe "polymorphic" rashes inappropriately concluded as EM or post-infectious EM with unsuitable drug accountability subject to protopathic bias.

Real-world safety profiles of pirfenidone and nintedanib in idiopathic pulmonary fibrosis patients.

INTRODUCTION: While pirfenidone and nintedanib have greatly influenced the treatment of idiopathic pulmonary fibrosis (IPF), both drugs have significant early adverse drug reactions (ADRs) and almost nothing is known of their rare and delayed ADRs. We collected and analyzed pirfenidone- or nintedanib-related ADRs identified in a French rare lung disease center, recorded their profiles and identified potential safety signals. METHODS: We analyzed the medical records of IPF patients treated with pirfenidone or nintedanib between January 2011 and January 2020 at the Rennes University Hospital to estimate the incidence of serious and non-serious ADRs cases due to each drug and the incidence of ADRs involving the cardiovascular, hepatobiliary, gastro-intestinal, dermatological, and metabolic/nutritional systems. RESULTS: The 176 patients included 115 (65%) initially treated with pirfenidone and 61 (35%) given nintedanib. ADRs occurred in 78.3% of those given pirfenidone and in 70.5% of those given nintedanib. The incidence of first serious ADRs cases was about 33 per 100 person-years (100 PY) for both drugs; first non-serious pirfenidone ADRs cases were 102 per 100 PY and 130 per 100 PY for nintedanib. The incidence involving each organ system were quite similar, except for the gastro-intestinal and skin disorders. Cardiovascular disorders occurred in about 10 cases per 100 PY in both pirfenidone and nintedanib patients. DISCUSSION: Most ADRs were consistent with the expected antifibrotic drug safety profiles. As arterial and venous thromboembolic events are rare, it is important to assess the risk associated with using antifibrotics by a dedicated pharmacoepidemiological study.

The Trigger Tool Method for Routine Pharmacovigilance: A Retrospective Cohort Study of the Medical Records of Hospitalized Geriatric Patients.

OBJECTIVE: The main objective was to assess the feasibility of the trigger tool method for the retrospective detection of adverse drug reactions (ADRs) in the Rennes University Hospital. The secondary objective was to describe the performance of the method in terms of positive predictive values (PPVs) and severity or preventability of ADRs. METHODS: Using the Rennes University Hospital clinical data warehouse, pharmacovigilance experts performed a retrospective review of a random sample of 30 inpatient hospital medical records per month using the triggers "fall" and "delirium" to identify related ADRs among patients 65 years and older in 2018 in the geriatrics department. Using the Z test, we compared the proportion of medical records with a positive (identified) trigger related to an ADR, which were reviewed within 20 minutes using the reference of 50% reviewed within 20 minutes. RESULTS: Among the 355 medical records reviewed, 222 had at least 1 trigger and 98 at least 1 related ADR. Among the 222 positive trigger medical records, 99.6% were reviewed in under 20 minutes (P < 0.001). The pharmacovigilance assessment took 3 months. The PPVs reached 53.9% (46.0%-61.7%) for falls and 21.0% (14.3%-27.5%) for delirium. Among the ADRs, 80% were serious and 53% were preventable. CONCLUSIONS: Given the low PPV of the triggers used and the considerable need for technical and human resources, the trigger tool method cannot be used as a routine tool at the pharmacovigilance center. However, it could be implemented occasionally for specific purposes such as monitoring the impact of risk minimization measures to prevent ADRs.

Hospital databases for the identification of adverse drug reactions: A 2-year multicentre study in 9 French general hospitals.

AIMS: To estimate the actual number of adverse drug reactions (ADRs), we used the French medical administrative database (PMSI) in addition to ADRs spontaneously reported in the French Pharmacovigilance Database (FPVDB). METHODS: Capture-recapture method was applied to these 2 sources (PMSI and FPVDB), checking their independence via a third data source. The study ran from 1 July 2014 to 30 June 2016 in 9 French general hospitals. From PMSI, all discharge summaries including a selection of 10th International Classification of Diseases codes related to ADRs were analysed. This selection was based on the results of a previous study. All ADRs corresponding to these codes, spontaneously reported in the FPVDB, were included. RESULTS: In PMSI, 56.9% of hospital stays were related to an ADR (628 out of 1104). In the FPVDB, we retained 115 cases. A total of 43 ADRs were common to the 2 databases. In both sources, the most frequently reported ADRs were cutaneous (33.1 and 19.1%) and renal (25.2% and 11.6%). The most frequently suspected drugs were anti-infectives in PMSI (31.1%) and antineoplastic drugs in the FPVDB (30.4%). Using the capture-recapture method, the estimated number of ADRs was 1657 [95% CI: 1273 to 2040]. CONCLUSION: The use of the PMSI could constitute an additional tool for the estimation of the actual number of ADRs in French hospitals. A model involving a third data source enabled the independence of the 2 sources (PMSI and FPVDB) to be checked before applying the capture-recapture method.

Reversible anti-TNFα treatment induced dementia: A case report.

We report the first case of a reversible rapidly progressive dementia occurring in a patient with ankylosing spondylitis, a few months after the beginning of a TNFα inhibitor treatment (TNFi). The exhaustive neurologic explorations were negative. No etiology was found to explain dementia. The dementia slowly improved after TNFi withdrawal. The chronology of this observation suggests a responsibility of the TNFi in the dementia manifestations.

[Pitch perception modification due to antiepileptics: A literature and pharmacovigilance databases review]. / Modification de la perception des sons sous antiépileptiques : une revue de la littérature et des bases de pharmacovigilance.

Pitch perception modifications are among the little-known adverse effects observed with antiepileptics, mainly affecting patients treated with carbamazepine (CBZ). Here, we describe an original French case of pitch perception modification due to CBZ resulting in perfect pitch loss. We also reviewed the literature as well as French and world health organisation global pharmacovigilance database. The case report concerns a 22-year-old patient with perfect pitch with untreated left temporal partial epilepsy. Following a generalized seizure, the introduction of CBZ prolonged release (200mg twice a day) is decided. As soon as CBZ is introduced, the patient notices a change in pitch perception, about a semitone lower. This adverse effect persisted despite a gradual decrease in doses. The patient reported a total recovery of his perfect pitch when CBZ stopped completely 11 years later. In the French pharmacovigilance database, only one other case of pitch perception modification under CBZ was recorded (no cases were found with oxcarbazepine, lacosamide, sodium valproate, lamotrigine, levetiracetam, phenobarbital, phenytoin, primidone, ethosuximide, vigabatrine, felbamate, gabapentin, tiagabine and topiramate). In the literature, 27 cases of pitch perception modification have been published with CBZ, 1 case with oxcarbazepine and 1 case with lacosamide. Pitch perception modification is a very rare adverse effect of CBZ, oxcarbazepine and lacosamide, identified in the literature mainly in the Japanese population, in experienced musicians. A rapid onset after the introduction of treatment, a complete resolution of symptoms, in most cases upon discontinuation of treatment, is observed, with no sequelae reported. Due to the impact on quality of life, especially in patients whose profession is related to music, knowledge of this adverse event seems important to evoke this diagnosis.

Photodermatitis from topical phenothiazines: A case series.

BACKGROUND: In Europe, contact photosensitivity to phenothiazines is well-known, particularly in southern countries. Topical phenothiazines are widely used and sold over-the-counter (OTC) for the treatment of mosquito bites and pruritus in France. OBJECTIVE: To report a series of cases with photodermatitis following use of topical phenothiazines. METHOD: A retrospective study of cases of contact dermatitis from phenothiazines seen in French photodermatology centers was performed. RESULTS: In all, 14 patients with a diagnosis of contact dermatitis from phenothiazines were included. These patients developed eczema on the application sites, and in 13 the eruption spread to photodistributed sites. Topical products containing isothipendyl were the most common cause of photodermatitis. One patient had photoaggravated eczema due to promethazine cream. All patients stopped using topical phenothiazines and were treated successfully with topical corticosteroids. One patient relapsed and developed persistent light eruption. In all of the nine cases tested, photopatch testing to the topical phenothiazine used "as is" was positive. Isothipendyl, chlorproethazine, and the excipients were not tested. Photopatch tests to chlorpromazine and promethazine were positive in 8 of 12 and 7 of 13 tested, respectively. CONCLUSION: Use of isothipendyl and promethazine as OTC (or even prescribed) drugs needs to be limited due to severe reactions and sensitization to other phenothiazines that consequently will have to be avoided.

Drug safety and big clinical data: Detection of drug-induced anaphylactic shock events.

RATIONALE, AIMS, AND OBJECTIVES: The spontaneous reporting system currently used in pharmacovigilance is not sufficiently exhaustive to detect all adverse drug reactions (ADRs). With the widespread use of electronic health records, biomedical data collected during the clinical care process can be reused and analysed to better detect ADRs. The aim of this study was to assess whether querying a Clinical Data Warehouse (CDW) could increase the detection of drug-induced anaphylaxis. METHODS: All known cases of drug-induced anaphylaxis that occurred or required hospitalization at Rennes Academic Hospital in 2011 (n = 19) were retrieved from the French pharmacovigilance database, which contains all reported ADR events. Then, from the Rennes Academic Hospital CDW, a training set (all patients hospitalized in 2011) and a test set (all patients hospitalized in 2012) were extracted. The training set was used to define an optimized query, by building a set of keywords (based on the known cases) and exclusion criteria to search structured and unstructured data within the CDW in order to identify at least all known cases of drug-induced anaphylaxis for 2011. Then, the real performance of the optimized query was tested in the test set. RESULTS: Using the optimized query, 59 cases of drug-induced anaphylaxis were identified among the 253 patient records extracted from the test set as possible anaphylaxis cases. Specifically, the optimal query identified 41 drug-induced anaphylaxis cases that were not detected by searching the French pharmacovigilance database but missed 7 cases detected only by spontaneous reporting. DISCUSSION: We proposed an information retrieval-based method for detecting drug-induced anaphylaxis, by querying structured and unstructured data in a CDW. CDW queries are less specific than spontaneous reporting and Diagnosis-related Groups queries, although their sensitivity is much higher. CDW queries can facilitate monitoring by pharmacovigilance experts. Our method could be easily incorporated in the routine practice.

[Peranesthesic Anaphylactic Shocks: Contribution of a Clinical Data Warehouse]. / Chocs anaphylactiques peranesthésiques : contribution d'un entrepôt de données cliniques.

AIM: To evaluate the performance of the collection of cases of anaphylactic shock during anesthesia in the Regional Pharmacovigilance Center of Rennes and the contribution of a query in the biomedical data warehouse of the French University Hospital of Rennes in 2009. METHODS: Different sources were evaluated: the French pharmacovigilance database (including spontaneous reports and reports from a query in the database of the programme de médicalisation des systèmes d'information [PMSI]), records of patients seen in allergo-anesthesia (source considered as comprehensive as possible) and a query in the data warehouse. RESULTS: Analysis of allergo-anesthesia records detected all cases identified by other methods, as well as two other cases (nine cases in total). The query in the data warehouse enabled detection of seven cases out of the nine. CONCLUSION: Querying full-text reports and structured data extracted from the hospital information system improves the detection of anaphylaxis during anesthesia and facilitates access to data.

[Use of the PMSI for the detection of adverse drug reactions]. / Utilisation du PMSI pour la détection d'effets indésirables médicamenteux.

AIM: To evaluate the performance of a query on international classification of diseases 10(th) version (ICD10) codes in the database of the programme for the medicalisation of information systems (programme de médicalisation des systèmes d'information, PMSI) to identify serious adverse drug reactions (ADR). METHODS: The query concerned hospital stays of patients discharged from the French University Hospital of Rennes in 2009. All the hospitalization summaries including a selected ICD10 code were analysed to validate ADR. RESULTS: Out of 383 cases, 142 cases were validated (37.1%). Performance of some ICD10 codes was particularly interesting, above 40% (T88.6, L27.0, J70.4, G62.0 and N14.1) and 79.5% of the ADR were detected by these five codes. During the study period, 98 ADR of the same type were spontaneously reported by physicians, 22 of which were common with the ICD10 query. CONCLUSIONS: The use of PMSI can be a tool for signal detection of serious ADR, in addition to spontaneous reporting.