Patterns of ketamine use among people with substance use disorder in France: Multisource analysis of the data from the French Addictovigilance Network.

BACKGROUND: Due to its psychoactive effects, ketamine has become a drug used for non-medical purpose. OBJECTIVES: To assess the latest trends in ketamine use among people with substance use disorder and to characterize its clinical complications using complementary health data sources of the French Addictovigilance Network. METHODS: First, we extracted all reports involving ketamine from 2012 to 2021 from the database of the OPPIDUM program (i.e., a multicentric program conducted in collaboration with hundreds of substance abuse treatment facilities that collects data on drugs used by subjects with substance use disorders). We described the reports globally and the changes from 2012 to 2021. Second, we extracted all cases involving ketamine from July 2020 to December 2022 from the French National Pharmacovigilance Database (BNPV). We identified the cases related to ketamine use among people with substance use disorder and described them. RESULTS: There was a 2.5-fold increase in the number of ketamine users with substance use disorder in the OPPIDUM program, from 35 (0.7%) subjects in 2012 to 89 (1.7%) subjects in 2021. There was an increase in the proportion of subjects who were daily users, had distress upon discontinuation, and presented addiction. There were 238 cases related to ketamine use among people with substance use disorder in the French National Pharmacovigilance Database from July 2020 to December 2022. Among them, 94 (39.5%) cases involved ketamine use disorder, 20 (8.4%) cases involved urinary tract and kidney symptoms, and 13 (5.5%) cases involved hepatobiliary symptoms. CONCLUSION: The trend observed over 10 years reflects the growth in ketamine use among people with substance use disorder, although it does not allow to estimate the rates of non-medical use of ketamine in the general population. Ketamine-induced uropathy and cholangiopathy are reported in ketamine users with substance use disorder, especially in case of repeated and/or prolonged use of high doses.

Invasive fungal infection incidence and risk factors in patients receiving ibrutinib in real-life settings: A nationwide population-based cohort study.

BACKGROUND: Data on the risk of invasive fungal infections (IFI) with ibrutinib treatment are scarce. OBJECTIVES: This study aimed to determine IFI incidence and risk factors in ibrutinib-treated patients in real-life settings. METHODS: We constituted a cohort of ibrutinib incident users in the French National Healthcare Database. All patients ≥18 years with a first dispensing of ibrutinib between 21 November 2014 and 31 December 2019 were included. Patients were followed from the cohort entry date until IFI, ibrutinib discontinuation, death, or 31 December 2020, whichever came first. The cumulative incidence function method was used to estimate the probability of IFI accounting for competing risk of death. A multivariate cause-specific Cox proportional hazards model was used to assess independent IFI risk factors. RESULTS: Among 6937 ibrutinib-treated patients, 1-year IFI cumulative incidence was 1.3%, with invasive aspergillosis being the most frequent. Allogenic or autologous stem cell transplantation (ASCT) (hazard ratio [HR] 3.59, 95% confidence interval [1.74; 7.41]), previous anticancer treatment (HR 2.12, CI 95% [1.34; 3.35]) and chronic respiratory disease (HR 1.66, [1.03; 2.67]) were associated with higher risk of IFI. Besides neutropenia and corticosteroids, use of anti-CD20 agents was significantly more frequent in patients having experienced IFI (HR 3.68, [1.82; 7.45]). CONCLUSIONS: In addition to patients with ASCT history, severe neutropenia or treated with corticosteroids, our findings support active surveillance of IFIs in those with chronic respiratory disease, previously treated, or treated with anti-CD20 agents in combination with ibrutinib. Further studies are needed to optimise IFI prophylaxis in these patient subgroups.

Maternal, Fetal and Neonatal Outcomes Related to Recreational Cannabis Use during Pregnancy: Analysis of a Real-World Clinical Data Warehouse between 2010 and 2019.

BACKGROUND: Cannabis is the main illicit psychoactive substance used in French childbearing women and very few data are available about adverse events (AEs) related to its use during pregnancy. The aim of this study was to evaluate the association between recreational cannabis use during pregnancy and adverse outcomes from a real-world clinical data warehouse. METHODS: Data from the Poitiers University Hospital warehouse were analyzed between 1 January 2010 and 31 December 2019. Logistic regression models were used to evaluate associations between outcomes in three prenatal user groups: cannabis alone ± tobacco (C ± T) (n = 123), tobacco alone (T) (n = 191) and controls (CTRL) (n = 355). RESULTS: Pregnant women in the C ± T group were younger (mean age: 25.5 ± 5.7 years), had lower pre-pregnancy body mass index (22.8 ± 5.5 kg/m2), more psychiatric history (17.5%) and were more likely to benefit from universal free health-care coverage (18.2%) than those in the T and CTRL groups. Cannabis use increases the occurrence of voluntary interruption of pregnancy, at least one AE during pregnancy, at least one neonatal AE, the composite adverse pregnancy outcome over 28, prematurity and small for gestational age. CONCLUSION: Given the trivialization of recreational cannabis use during pregnancy, there is an urgent need to communicate on AEs of cannabis use during pregnancy.

Bleeding risk with concurrent use of anticoagulants and ibrutinib: A population-based nested case-control study.

Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants.

Immune Checkpoint Inhibitor-Related Cytopenias: About 68 Cases from the French Pharmacovigilance Database.

Immune checkpoint inhibitor (ICI)-related cytopenias have been poorly described. This study aimed to further characterize ICI-related cytopenias, using the French pharmacovigilance database. All grade ≥ 2 hematological adverse drug reactions involving at least one ICI coded as suspected or interacting drug according to the World Health Organization criteria and reported up to 31 March 2022, were extracted from the French pharmacovigilance database. Patients were included if they experienced ICI-related grade ≥ 2 cytopenia. We included 68 patients (75 ICI-related cytopenias). Sixty-three percent were male, and the median age was 63.0 years. Seven patients (10.3%) had a previous history of autoimmune disease. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) were the most frequently reported (50.7% and 25.3%, respectively). The median time to onset of ICI-related cytopenias was 2 months. Nearly half were grade ≥ 4, and three patients died from bleeding complications of refractory ITP and from thromboembolic disease with active AIHA. Out of 61 evaluable responses, complete or partial remission was observed after conventional treatment in 72.1% of ICI-related cytopenias. Among the 10 patients with ICI resumption after grade ≥ 2 ICI-related cytopenia, three relapsed. ICI-related cytopenias are rare but potentially life-threatening. Further studies are needed to identify risk factors of ICI-related cytopenias.

Adverse events of recreational cannabis use during pregnancy reported to the French Addictovigilance Network between 2011 and 2020.

Cannabis is the main illicit psychoactive substance used by pregnant women in France. The aim of the present national survey was to describe adverse events (AEs) of recreational cannabis use during pregnancy reported to the French Addictovigilance Network (FAN). Spontaneous reports (SRs) of AEs related to recreational cannabis use during pregnancy were collected by the FAN between 01/01/2011 and 31/01/2021 (excluding cannabidiol and synthetic cannabinoids). Over the study period, 160 SRs involved cannabis use alone or in association with tobacco (59% of all SRs) which increased. Among the 175 maternal AEs, the most commons were psychiatric AEs experienced by 96 (64.9%) women, in particular cannabis use disorders (n = 89, 60.1%), dependence (n = 54, 36.5%) and abuse (n = 21, 14.2%). Among the 57 fetal AEs, the most common were heart rhythm disorders that affected 25 (16.9%) fetuses and intrauterine growth restriction (IUGR) (n = 20, 13.5%). Among the 140 neonatal AEs, the most common were IUGR experienced by 39 (26.3%) newborns and prematurity (n = 32, 21.6%). Twelve cases of congenital malformations were observed and 4 intrauterine/neonatal deaths. Furthermore, some of these AEs (n = 13) were unexpected. Cannabis use during pregnancy has problematic consequences for both mothers and infants who need close monitoring.

Immune Checkpoint Inhibitors and Venous Thromboembolism: An Analysis of the WHO Pharmacovigilance Database.

Data on venous thromboembolic events (VTEs) in patients receiving immune checkpoint inhibitors (ICIs) are scarce and conflicting. This study investigated the risk of reporting VTEs associated with ICIs in comparison with all other anticancer drugs. The World Health Organization pharmacovigilance database (VigiBase), comprising >30 million individual case safety reports, was queried. All reports on patients with cancer, involving at least one anticancer drug as a suspect or interacting drug and registered from January 1, 2008, to May 31, 2021, were included. The association between ICIs and the risk of reporting VTEs was estimated using the reporting odds ratio (ROR) as a measure of disproportionality with all other anticancer drugs as comparators. RORs were estimated as crude and adjusted RORs for age, sex, and other medications (excluding anticancer drugs) associated with risk of VTEs. Among 1,196 patients experiencing VTEs after ICI treatment, the median age was 65 years and 57.6% were men. Anti-PD-1 agents (62.5%) were the most frequently reported. ICIs were not associated with higher reporting of VTEs when compared with other anticancer drugs (crude ROR 0.63, 95% confidence interval (CI) 0.60 to 0.67 and adjusted ROR 0.70, 95% CI 0.65-0.74). No signal of disproportionate reporting was found when considering each class of ICIs. In conclusion, ICIs were not associated with higher reporting of VTEs, in comparison with all other anticancer drugs in a large-scale pharmacovigilance database. Owing to the limitations inherent to pharmacovigilance studies, prospective studies, including an adequate comparison group, are needed to assess the risk of VTEs in ICI-treated patients.

Exposure to High Precariousness Prevalence Negatively Impacts Drug Prescriptions of General Practitioners to Precarious and Non-Precarious Populations: A Retrospective Pharmaco-Epidemiological Study.

(1) Background: Precarious patients are more difficult to care for due to low literacy rates and poor adherence to treatment and hospitalization. These difficulties have detrimental effects on general practitioners (GPs), deteriorating medical communication, advice, diagnoses, and drug prescriptions. To better understand how precariousness affects primary care, we tested whether, among GPs, exposure to high precariousness prevalence more severely impacts drug prescriptions to precarious and non-precarious populations compared to low precariousness prevalence. Materials and methods: This pharmaco-epidemiological study, using linear regression analyses, compared the defined daily dose of 20 drugs prescribed by GPs to precarious and non-precarious patients in four French regions with low and high precariousness prevalence in 2015. (2) Findings: Exposure to high precariousness prevalence significantly impacted the prescriptions of nine medications to precarious patients and two medications to non-precarious patients, and distributed into three interaction patterns. (3) Interpretation: The selective over-prescription of drugs with easy intake modalities to precarious patients probably reflects GPs' attempts to compensate for poor patient compliance. In contrast, the under-prescription of drugs targeting fungal infections in precarious populations and diabetes and cardiovascular diseases in non-precarious populations was seemingly due to a breakdown of empathy and professional exhaustion, causing medical neglect.

Safety of Immune Checkpoint Inhibitor Resumption after Interruption for Immune-Related Adverse Events, a Narrative Review.

Immune checkpoint inhibitors (ICIs) have become the standard of care for several types of cancer due to their superiority in terms of survival benefits in first- and second-line treatments compared to conventional therapies, and they present a better safety profile (lower absolute number of grade 1-5 adverse events), especially if used in monotherapy. However, the pattern of ICI-related adverse events is totally different, as they are characterized by the development of specific immune-related adverse events (irAEs) that are unique in terms of the organs involved, onset patterns, and severity. The decision to resume ICI treatment after its interruption due to irAEs is challenged by the need for tumor control versus the risk of occurrence of the same or different irAEs. Studies that specifically assess this point remain scarce, heterogenous and mostly based on small samples of patients or focused only on the recurrence rate of the same irAE after ICI resumption. Moreover, patients with grade ≥3 irAEs were excluded from many of these studies. Herein, we provide a narrative review on the field of safety of ICI resumption after interruption due to irAE(s).

Impact of brain-derived neurotrophic factor Val66Met polymorphism and response to escitalopram or paroxetine in obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a severe psychiatric disorder characterized by its heterogeneous nature and by different dimensions of obsessive-compulsive (OC) symptoms. Serotonin reuptake inhibitors (SRIs) are used to treat OCD, but up to 40% to 60% of patients do not show a significant improvement with these medications. In this study, we aimed to test the impact of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on the efficacy of antidepressants in OCD overall, and in relation to the different OC dimensions. METHODS: In a 6-month prospective treatment study, 69 Caucasian OCD patients were treated with escitalopram for 24 weeks or with escitalopram for 12 weeks followed by paroxetine for an additional 12-week period. Patients were genotyped and assessed for treatment response. The main clinical outcomes were improvement of the Yale-Brown Obsessive-Compulsive Scale score and in different OC symptom dimension scores. RESULTS: The Val/Val group comprised 43 (62%) patients, the Val/Met and Met/Met group comprised 26 (38%) patients. Forty-two patients were classified as responders at 12 weeks and 38 at 24 weeks; no significant association was found between BDNF Val66Met and SRIs response at 12 and 24 weeks. In analyses of the different OC symptom dimensions, the Met allele was associated with a slightly reduced score in the aggressive/checking dimension at 6 months (P = .048). CONCLUSIONS: Our findings do not support the usefulness of BDNF Val66Met genotyping to predict overall response to treatment with SRIs in OCD; they did however suggest a better outcome at 6 months for the aggressive/checking symptom dimension for patients carrying the Met allele.

Safety Profile of Ibrutinib: An Analysis of the WHO Pharmacovigilance Database.

As ibrutinib has become a standard of care in B-cell malignancies in monotherapy or in combination with other agents, definition of its safety profile appears essential. The aim of this study was to further characterize the safety profile of ibrutinib through the identification of potential safety signals in a large-scale pharmacovigilance database. All serious individual case safety reports (ICSRs) in patients aged ≥18 years involving ibrutinib suspected in the occurrence of serious adverse drug reactions or drug interacting from November 13th, 2013 to December 31st, 2020 were extracted from VigiBase, the World Health Organization global safety database. Disproportionality reporting was assessed using the information component (IC) and the proportional reporting ratio (PRR), with all other anticancer drugs used as the reference group. To mitigate the confounding of age, two subgroups were considered: patients aged<75 years and ≥75 years. A signal of disproportionate reporting (SDR) was defined if both IC and PRR were significant. A total of 16,196 ICSRs were included. The median age of patients was 72.9 years, 42.6% of ICSRs concerned patients aged ≥75 years, and 64.2% male patients. More than half (56.2%) of ICSRs resulted in hospitalization or prolonged hospitalization. Among 713 SDRs, 36 potential safety signals emerged in ibrutinib-treated patients, mainly ischemic heart diseases, pericarditis, uveitis, retinal disorders and fractures. All potential safety signals having arisen in this analysis may support patient care and monitoring of ongoing clinical trials. However, owing to the mandatory limitations of this study, our results need further confirmation using population-based studies.

Adverse events of recreational cannabis use reported to the French addictovigilance network (2012-2017).

AIMS: To describe the adverse events (AEs) of recreational cannabis use in France between 2012 and 2017. METHODS: AEs related to recreational cannabis use, alone or in combination with alcohol and/or tobacco reported to the French Addictovigilance Network were analysed (excluding cannabidiol and synthetic cannabinoids). RESULTS: Reporting of AEs tripled between 2012 (n = 179, 6.3%, 95% confidence interval [CI] = 5.4-7.2) and 2017 (n = 562, 10.1%, 95% CI = 9.3-10.9), reaching 2217 cases. They concerned mainly men (76.4%) and users aged between 18 and 34 years (18-25: 30.9%; 26-34: 26.3%, range: 12-84 years). Cannabis was mainly inhaled (71.6%) and exposure was most often chronic (64.2%). Many types of AEs were reported: psychiatric (51.2%), neurological (15.6%), cardiac (7.8%) and gastrointestinal (7.7%), including unexpected AEs (n = 34, 1.1%). The most common effect was dependence, ranging from 10.1% (95% CI = 7.9-12.3) to 20.3% (95% CI = 17.3-23.2) over the study period. Cannabinoid hyperemesis syndrome (n = 87, 2.8%) emerged from 2015. Deaths accounted for 0.2% of all AEs (4 men and 3 women aged on average 35 years). A chronic pattern of cannabis use was reported in 4 of them (intracranial hypertension in the context of lung cancer, suicide, cerebral haematoma, neonatal death with concomitant chronic alcohol use), while in the other cases the toxicological analysis identified cannabis use (ruptured aneurysm and unknown aetiology). CONCLUSION: This study showed a multitude of AEs related to recreational cannabis use, including unexpected AEs and deaths. It highlights the problem of dependence and the emergence of cannabinoid hyperemesis syndrome.

The French pharmacovigilance surveys: A French distinctiveness, a real input.

INTRODUCTION: According to French guidelines on good pharmacovigilance practices, a pharmacovigilance survey is an assessment of the available drug safety data. It is requested by the French national agency for medicines and health products safety (ANSM). The objective is to validate a signal, to characterize it, or to provide strengthened monitoring of a drug. MATERIAL AND METHODS: All the available data were retrieved by ANSM/Regional Pharmacovigilance Centers (RPC) and assessed by a nominate RPC which provides a report for discussion during the monthly Committee between ANSM and the Regional Pharmacovigilance Network (RPN). A descriptive analysis of the minutes available on the ANSM website between 2016 and 2018 has been done: objective, data sources, duration of the survey, number of suspected adverse drug reactions, nature of the drugs and of the signals and recommendations for actions. RESULTS: Between 2016 and 2018, a total of 115 surveys were discussed concerning 135 drugs, mainly from the nervous system according to the anatomic therapeutic chemical classification (n=31, 27%). They involved a whole pharmacological class for 18 ones. The main objective of the 115 surveys was to provide a strenghtened monitoring for some drugs (72%) or to validate one or more than one signal (28%). Result from surveys allowed to detect one or several new potential safety signals in 63 ones (55%), an off-label-use in 12 (10%) or to characterize some others signals in all the studies. The Committee recommended one or several actions by survey: 67 prolongations (58%) of the survey and regulatory or investigatory actions which included 43 European actions (37%), 37 label changes (32%), 30 national communications (26%) and 29 additional monitoring (25%). DISCUSSION/CONCLUSION: The current process allows a collegiate, clinical and pharmacological discussion with integration of the regulatory framework. A significant number of new signals are detected and/or validated. This efficient tool which is unique in Europe and is allowed by the decentralized pharmacovigilance which leads to a great reactivity of decision-making. It has to be reassessed and to be adapted continuously to the new challenges of the growing multiplication of signals.

Patterns of use and safety of ibrutinib in real-life practice.

AIMS: To provide real-life data on patterns of use and safety of ibrutinib. METHODS: A cohort study including all patients initiating ibrutinib between 21 November 2014 and 21 November 2018, and followed for 1 year was conducted. Patient characteristics, ibrutinib use and adverse drug reactions (ADRs) were collected from medical records. Kaplan-Meier analysis estimated the probability of developing ibrutinib-associated serious ADRs (SADRs) with a 95% confidence interval (CI). A Cox proportional hazards model was used to investigate factors associated with SADR occurrence. RESULTS: In total, 102 patients were included in the study. The median age was 70.3 years (interquartile range 64.7-75.6), the male/female gender ratio was 2.9. Almost half the patients (47.1%) were prescribed ibrutinib for chronic lymphocytic leukaemia (CLL). Forty-three patients (42.1%) permanently discontinued ibrutinib in the first year, mostly for progression (51.2%) or ADRs (32.6%). Forty-eight patients (47.1%) experienced at least one ibrutinib-associated SADR. Haematological, infectious and vascular disorders were the most frequent SADRs. The probability of developing ibrutinib-associated SADR was 35.1% (95% CI 26.3-45.7%) at 3 months, 44.8% (35.2%; 55.8%) at 6 months and 54.3% (44.0%; 65.2%) at 12 months. Age ≥80 years (hazard ratio [HR] 2.03; 95% CI 1.02-4.05) and CLL (HR 1.81; 95% CI 1.01-3.25) were significantly associated with a higher risk of SADR occurrence. CONCLUSION: This study found a high cumulative incidence of ibrutinib-associated SADRs within the first year of treatment. In view of the risk of SADR, patients aged ≥80 years or treated for CLL deserve special attention.

The Characteristics of Care Provided to Population(s) in Precarious Situations in 2015. A Preliminary Study on the Universal Health Cover in France.

Background: The French Universal Health Cover (CMU) aims to compensate for inequalities between precarious and non-precarious populations, enabling the former to access to free healthcare. These measures rely on the principle that precarious populations' health improves if healthcare is free. We designed a study to examine whether CMU fails to compensate for inequalities in reimbursed drugs prescriptions in precarious populations. Material and method: This retrospective pharmaco-epidemiological study compared the Defined Daily Dose relative to different reimbursed drugs prescribed by general practitioners (GPs) to precarious and non-precarious patients in France in 2015. Data were analysed using Mann-Whitney tests. Findings: 6 out of 20 molecules were significantly under-reimbursed in precarious populations. 2 were over-reimbursed. The 12 remaining molecules did not differ between groups. Interpretation: The under-reimbursement of atorvastatin, rosuvastatin, tamsulosine and timolol reflects well-documented epidemiological differences between these populations. In contrast, the equal reimbursement of amoxicillin, pyostacine, ivermectin, salbutamol and tiopropium is likely an effect of lack of compensation for inequalities. Precarious patients are more affected by diseases that these molecules target (e.g., chronic bronchitis, bacterial pneumonia, cutaneous infections). This could also be the case for the equal and under-reimbursement of insulin glargine and metformin (targeting diabetes), respectively, although this has to be considered with caution. In conclusion, the French free healthcare cover does not fail to compensate for all but only for some selective inequalities in access to reimbursed drugs prescriptions. These results are discussed with respect to the interaction of the doctor-patient relationship and the holistic nature of primary care, potentially triggering burnout and empathy decrease and negatively impacting the quality of care in precarious populations.

Drug-induced hearing loss: a case/non-case study in the French pharmacovigilance database.

Hearing loss is defined as a decrease in the ability to perceive sounds which can occur suddenly or gradually and affects one ear or both. It is related to various etiologies, in particular drugs. The identification of all drugs that could be associated with hearing loss is essential for the patients' life quality. The objective of our study was to identify signals of hearing loss involving drugs approved in the last 20 years. The occurrence in association with drugs known for their ototoxicity was also analyzed. We used a case/non-case method in the French Pharmacovigilance Database (FPVD). The cases were reports of hearing loss in the FPVD between January 2007 and August 2017. Non-cases were all reports over the same period. We calculated the reporting odds ratio (ROR) with 95% confidence intervals. Among the 555 reports of hearing loss, significant RORs were found for 68 drugs. The main therapeutic classes implicated were antineoplastic agents (n = 240), systemic anti-infective agents (n = 182), immunosuppressants (n = 42) loop diuretics (n = 26), and salicylate analgesics (n = 26). We found signals of hearing loss with azacitidine, vaccines and nevirapine, immunosuppressants such as leflunomide, and biotherapies such as panitumumab and vandetanib. Prescribers should be informed about the potential associations with all these drugs. The role of the pathology itself and the known ototoxic drugs that can be associated do not allow to conclude definitively. Audiograms for the early detection of hearing loss induced by drugs known to be ototoxic are rarely carried out. Preventive treatments exist and must be considered.