Osteonecrosis of the jaw under palbociclib: A case series description.

INTRODUCTION: Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses. MATERIALS AND METHODS: A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors. RESULTS: We identified eight cases, most of them at stages 0-1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug's half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific. CONCLUSION: We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ.

Budd-Chiari syndrome after BNT162b2 mRNA vaccination: two case reports.

Budd-Chiari syndrome (BCS) is a rare disease characterised by an obstruction in the hepatic venous outflow. We describe two cases of patients hospitalised a few days after tozinameran vaccination. Liver tests and medical imaging were carried out, and BCS was diagnosed. After treatment including anticoagulant therapy, the first patient improved clinically, unlike the second patient with persistent hepatic thrombosis. According to the WHO-UMC causality assessment system, the vaccine's share was assessed as 'probable' for the first patient as BCS occurred during anticoagulant therapy, and 'possible' for the second patient as no other aetiology was found. Further epidemiological studies are needed to confirm or refute the causal relationship between BCS and tozinameran vaccination.

[Adverse effects of the tezacaftor/ivacaftor/elexacaftor combination that may lead to discontinuation: About a series of 10 cases]. / Effets indésirables de l'association tezacaftor/ivacaftor/elexacaftor pouvant mener à un arrêt de traitement : à propos d'une série de 10 cas.

INTRODUCTION: Cystic fibrosis transmembrane regulator (CFTR) channel modulators (ivacaftor, lumacaftor, tezacaftor and elexacaftor) represent a major advance in the management of cystic fibrosis. However, few data are available on the real-life safety profile of these medications, in particular on adverse events that may lead to their discontinuation. The aim of this study is to describe the characteristics and evolution of adverse reactions to the tezacaftor/ivacaftor/elexacaftor combination that led to discontinuation and were reported to the Centre régional de pharmacovigilance (CRPV) in Rennes (France). MATERIALS AND METHODS: A retrospective study was conducted from December 2021 to May 2023, focusing on cases of discontinuation of the tezacaftor/ivacaftor/elexacaftor combination due to the occurrence of one or more adverse effects, and reported to the CRPV of Rennes, France. RESULTS: Ten cases of drug discontinuation were reported to the Rennes CRPV (6 women/4 men). Adverse effects mainly involved neuropsychiatric disorders (n=6), followed by liver disorders (n=2), ear, nose and throat disorders (n=1), and digestive disorders (n=1). The average duration of treatment at discontinuation was 339.8 [39-668] days. The drug was reintroduced in 7 patients on average 48.7 [7-123] days after discontinuation, with a dosage adjustments (n=4) consisting of changes in dosing times or a reduction in daily doses, with varying success in alleviating adverse symptoms depending on the case. CONCLUSION: This small case series suggests that neuropsychiatric adverse effects may occur more frequently than initially described after initiation of tezacaftor/ivacaftor/elexacaftor, and should be carefully screened and monitored. Dosage or administration schedule modifications may be considered for patients experiencing these adverse effects. Further pharmacovigilance studies are needed to better understand the adverse effect profiles of "caftors", their possible risk factors, and the impact of adjusting dosing modalities.

[Adverse drug reactions profiles for abiraterone and enzalutamide: A pharmacovigilance descriptive analysis]. / Profils d'effets indésirables sous abiratérone et enzalutamide : analyse descriptive des données de la base nationale de pharmacovigilance.

OBJECTIVE: The aim of this study was to describe the profile of adverse drug reactions (ADRs) observed with abiraterone and enzalutamide, based on cases registered in the French regional pharmacovigilance centres to identify potential pharmacovigilance signals. METHODS: We extracted from the French pharmacovigilance database all cases of ADRs or drug interactions involving abiraterone or enzalutamide from the time they market authorization date until December 31st, 2017. Signal detection results have been transmitted by the French Agency for Health Products (ANSM). The data were compared with those of the risk management plans for each drug and the literature. RESULTS: Among the 233 observations analyzed, nearly 62% involved abiraterone as a suspect drug and 38% involved enzalutamide; only 1 case involved both drugs. The ADRs profile is different between the drugs. Abiraterone is mostly associated with expected cardiac diseases (heart failure, and QT prolongation), expected with the drug. Also described, several cases of hepatotoxicity have been reported, however some cases with fatal outcome suggest that despite a follow-up of the liver function tests, it is difficult to anticipate this risk. Signals concerning acute renal failure and ischemic stroke have arisen. Enzalutamide is more particularly associated with various neurological disorders (convulsions, hallucinations, fatigue, and memory impairment) expected with the drug. While ischemic heart disease is also expected, signals of heart failure and atrial fibrillation have arisen. A potential hepatotoxicity of the molecule is discussed because of cases of cholestatic hepatitis. CONCLUSION: The analysis of the French pharmacovigilance database cases allows to confirm an expected and monitored risk profile in the risk management plan for both drugs. Several signals have arisen, some of which will be investigated through a pharmacoepidemiology study.

[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.

Liquid formulation of ifosfamide increased risk of encephalopathy: A case-control study in a pediatric population.

BACKGROUND: Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal. METHODS: We performed a case-control study in pediatric oncology Departments of 25 university hospitals between July 1st, 2016 and July 1st, 2018. All children (<18 y.o.) receiving liquid formulation or lyophilized powder formulation during the study period were included. Patients with at least one occurrence of encephalopathy were considered as cases. Logistic regression model was used to estimate the odds ratio of encephalopathy between exposure groups. RESULTS: During the study period, 52 cases and 495 controls were included. A residual over-risk of encephalopathy was associated with ifosfamide 7-month shelf-life liquid formulation compared to lyophilized powder (adjusted OR 1.91, 95% CI: 1.03-3.53). CONCLUSIONS: Observed difference does not seem to be related to the pathology treated, the doses used, the co-medications, a meningeal localization and/or an irradiation of the central nervous system. This study confirms data from spontaneous reports that led to the precautionary measure for the liquid formulation. Even if the risk of encephalopathy seems reduced, our study suggests the persistence of a residual risk of encephalopathy associated with liquid formulation compared to the lyophilized powder.

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.

Acute kidney injury during treatment with high-dose cloxacillin: a report of 23 cases and literature review.

BACKGROUND: International guidelines recommend high-dose cloxacillin for endocarditis or osteoarticular infections due to methicillin-susceptible staphylococci. However, data on the tolerability of these regimens are scarce. METHODS: We used the computerized registry of suspected drug-related adverse events in our institution. Cases of acute kidney injury (AKI), as defined by KDIGO, in patients receiving high-dose cloxacillin were retrospectively reviewed. Data were collected from medical charts on a standardized questionnaire. RESULTS: From 2009 to 2015, 23 consecutive patients (16 men, 7 women) with a median age of 75 years (interquartile range [IQR], 66-80) fulfilled inclusion criteria. By the time of AKI diagnosis, patients were treated with a median cloxacillin dose of 12 g/day (IQR, 10-12) after a median duration of 7 days (IQR, 4-10). Most patients (n=20) fulfilled RIFLE criteria for failure, with a median peak serum creatinine concentration of 339 µmol/L (IQR, 249-503). Urinalysis was indicative of tubular disease in 7 patients, 3 had hypereosinophilia and 8 had abnormal liver function tests. All patients presented at least one risk factor for AKI, including concomitant nephrotoxic drugs: gentamicin (n=19), diuretics (n=15), angiotensin-converting enzyme inhibitors (n=8) and angiotensin II receptor-blockers (n=6). Thirteen patients (57%) had cloxacillin plasma concentrations >50 µg/mL. Thirteen patients (57%) had complete recovery of renal function. CONCLUSIONS: AKI during high-dose cloxacillin treatment mostly occurs in elderly patients taking concomitant nephrotoxic drugs. The outcome is usually favourable after cloxacillin discontinuation. Therapeutic drug monitoring may decrease the risk of AKI in patients treated with high-dose cloxacillin.

Macrophage activation syndrome with acute hepatitis E during tocilizumab treatment for rheumatoid arthritis.

Tocilizumab is a humanized antibody against the membrane and soluble receptors for interleukin-6. Tocilizumab is among the disease-modifying antirheumatic drugs (DMARDs) used to treat moderate-to-severe active rheumatoid arthritis (RA) refractory to conventional DMARDs. We report a case of macrophage activation syndrome that complicated acute hepatitis E and started within 24hours after the fourth tocilizumab infusion in a patient with RA.