Drug-related hypophosphatemia: Descriptive study and case/non-case analysis of the French national pharmacovigilance database.

Phosphorus is an essential element for all living organisms and is involved in various biological pathways. A severe hypophosphatemia can lead to serious complications (acute heart or respiratory failure, rhabdomyolysis, hemolysis…) and increases mortality in patients at risk. Various drugs are known to induce hypophosphatemia through various mechanisms. The aim of this study was to highlight the main drugs associated with hypophosphatemia and to deduce the underlying mechanisms based on a descriptive analysis and a case/non-case analysis using the cases of drug-induced hypophosphatemia reported to the French Pharmacovigilance Network. A total of 368 cases of hypophosphatemia were included in the study. Patients' mean age was 52±18 years. One hundred and ninety-one cases (52%) were serious including 131 (36%) hospitalizations. The median value of serum phosphorus level was 0.54mmol/L [0.40-0.66] (n=309). Those 368 cases corresponded to 185 different suspected substances among which the most frequent drugs were tenofovir disoproxil (n=175; 48%), ferric carboxymaltose (n=29; 8%), denosumab (n=16; 4%), zoledronic acid (n=14; 4%) and hydrochlorothiazide (n=10; 3%). For these five drugs, a significant disproportionality was found. Tenofovir-disoproxil related hypophosphatemia occurred more than one year after its introduction, and a renal tubulopathy (Fanconi's syndrome) was reported in 44 cases (25%). Hypophosphatemia related to iron carboxymaltose occurred within a median of 20 days after injection and was mostly severe. Mechanism included the fibroblast growth factor 23 which can be measured to confirm drug origin. Concerning anti-osteoporosis treatments, hypophosphatemia could be explained by their mechanism of action (abrupt increase of parathormone induced by hypocalcemia) but the patient history (malignancy condition) was a major bias. For hydrochlorothiazide, hyphosphatemia was often moderate, associated with other electrolytic disturbances and occurred during a long-term treatment. Awareness of healthcare professionals is essential to detect as soon as possible hypophosphatemia and its complications related to these drugs.

Adverse effect of Pneumocystis Jirovecii infection associated with rituximab therapy for autoimmune disease are more frequently reported in older vs. younger patient.

INTRODUCTION: Rituximab is a chimeric anti-CD20 antibody commonly used to treat patients with autoimmune diseases. Such diseases mainly affect young people, but older patients may also be concerned. So far, very little data exist concerning the safety of rituximab in older patients with autoimmune diseases. METHODS: This study was intended to describe the adverse reaction profile of rituximab in patients over 75 years of age treated for autoimmune diseases and to compare such profile to those observed in patients below 75 years of age. Adverse reactions related to rituximab were reported to the French Pharmacovigilance Network. From such reports, a descriptive analysis as well as a disproportionality analysis were performed to identify safety signals. RESULTS: 1096 reports of rituximab-related adverse reactions reported in France between 2006 and 2019, were included in the study, such as 127 in the older group (>75 years) and 969 in the younger group (<75 years). Infusion reactions were less frequently reported than other adverse drug reaction in older patients (11 vs. 27%, P<0.001). By contrast, a higher rate of opportunistic infection due to Pneumocystis jirovecii was reported in the older subject group (3.9 vs. 0.6%, P<0.001), along with neutropenia (22.8 vs. 9.3%, P<0.0001). These results were confirmed by the disproportionality analysis. CONCLUSION: Pneumocystis jirovecii infection was significatively more reported in older patients treated by Rituximab which probably reflects a higher incidence in this population. The use of anti-pneumocystis prophylaxis should be considered in this population.

Safety profile of the lopinavir/ritonavir combination before and during the SARS-CoV-2 pandemic.

INTRODUCTION: When the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic began, there were no effective treatments assessed by clinical trials. In this context, in France, the French Public Health Council issued, from 5 March, 2020, several proposed recommendations for the therapeutic management of this new disease. This included the use of combination lopinavir/ritonavir, which is usually indicated as HIV treatment. Thanks to the reporting of adverse drug reactions (ADRs) to the French Regional Pharmacovigilance Centers, several safety signals including hepatobiliary and cardiovascular were quickly identified. OBJECTIVE: This study aimed to compare the ADRs reported with lopinavir/ritonavir used in its usual indication prior to the pandemic with the ADRs reported with the coronavirus disease 2019 (COVID-19) indication. METHODS: Cases of ADRs were extracted from the French Pharmacovigilance Database. ADRs were compared between the two periods: pre-COVID (1985 to 31 December 2019) and COVID (1 January 2020 to 21 July 2020). RESULTS: Patients with COVID-19 were found to have a different safety profile, with significantly more damage to the liver (43% of ADRs), heart (10.6%) and kidneys (7.1%). The ADRs reported before the pandemic were mainly gastrointestinal and cutaneous. CONCLUSIONS: This different safety profile may be related to the effect of the virus on the organs, the patient profile (age, medical history…) and the drugs associated with lopinavir/ritonavir. Our study should serve as a reminder that the safety profile of a drug can depend on its use. Spontaneous reporting and pharmacovigilance have a critical role in alerting health professionals to "new" ADRs reported with well-known drugs.

Drug-Induced Hearing Loss in Children: An Analysis of Spontaneous Reports in the French PharmacoVigilance Database.

INTRODUCTION: Hearing loss can have a negative impact on communication, with significant vocational, educational, and social consequences. Drugs are one of the causes of hearing loss in children. OBJECTIVES: The objective of our study was to describe drug-induced hearing loss in the pediatric population. METHODS: Reports of hearing loss from 1985 to December 2019 in the pediatric population (< 18 years) were extracted from the French PharmacoVigilance Database (FPVD). We performed a retrospective and descriptive analysis of adverse drug reaction (ADR) reports. RESULTS: A total of 70 ADR reports were identified among the 51,216 reports registered in the FPVD, 37 involving adolescents (12-17 years, 52.9%), 28 children (2-11 years, 40.0%), and 5 infants (28 days-23 months, 7.1%). Overall, 40 reports (57.1%) involved girls. A total of 56 reports (80.0%) were "serious." The most frequent hearing disorders were deafness (n = 31, 44.3%) and hypoacusis (n = 22, 31.4%). Suspected drugs (ATC 5th level) were amikacin (n = 11, 15.7%), cisplatin (n = 11, 15.7%), doxorubicin (n = 4, 5.7%), vincristine (n = 4, 5.7%), clarithromycin (n = 4, 5.7%), ceftriaxone (n = 3, 4.3%), isotretinoin (n = 3, 4.3%), and vancomycin (n = 3, 4.3%). CONCLUSIONS: This study shows that about three out of four cases of drug-induced hearing loss in the pediatric population were "serious". It also underlines the under-reporting of these ADRs and the importance of strengthening hearing monitoring in children during and long after drug exposure.

Antiretroviral Prophylaxis: A Digestive Complication to Know.

ABSTRACT: An 8-year-old child experienced abdominal pain and melena due to duodenal and ileal ulcerations throughout antiretroviral prophylactic treatment after a needlestick injury. Mild to moderate adverse effects often occur with lamivudine and zidovudine, but more severe adverse effects such as intestinal ulcers resulting in melena after a prophylactic antiretroviral treatment may question the safety of the current guidelines.

Amoxicillin-induced crystal nephropathy: A nationwide French pharmacovigilance databases study.

AIMS: Amoxicillin (AMX)-induced crystal nephropathy (AICN) is a rarely reported adverse drug reaction (ADR) but its increase has been recently reported in the Paris area. Our aim was to investigate the incidence, characteristics and outcome of AICN in France. METHODS: Retrospective analysis of all AICN cases reported to the French National Pharmacovigilance Database and the Marketing Authorization Holders Pharmacovigilance Database. AICN notification rate was compared to intravenous AMX and AMX-clavulanate sales. RESULTS: In total, 101 AICN cases were included. Intravenous AMX/AMX-clavulanate was prescribed as surgical prophylaxis (32 surgical patients) or to treat infection (69 medical patients). AKI KDIGO stage 3 was observed in 70 patients and 24/70 patients required renal replacement therapy and/or intensive care unit admission. The annual notification rate of AICN was increased by a factor of 13 since 2010 (6 [0;7] and 77 [24;111] cases per 100 000 patient-years of exposure, before and after 2010 respectively; P < .001). In surgical patients, the increase in AICN has been reported since 2010 and was mainly related to inadequate AMX administration. In medical patients, the increase in AICN was observed since 2014. After 2014, medical patients were older (67 [42;77] vs 74 years [64;84] respectively; P < .05) and were treated more frequently for endocarditis (0/20 vs 15/49 respectively; P < .01). A contributing factor was observed or suspected in 62 patients. CONCLUSION: AICN is a severe ADR that dramatically increased in France since 2010. Assessment of AICN contributing factors and AMX drug monitoring in patients receiving high dose of AMX could reduce the risk of AICN.