French National Pharmacovigilance Database Research Articles

Cross-reactivity among and between macrolides, lincosamides, and streptogramins: Study on the French pharmacovigilance database.

Hypersensitivity reactions (HSR) are reported for the macrolides, lincosamides, and streptogramins (MLS) antibiotic family. Data about cross-reactivity among and between MLS remain scarce or controversial. The aim of this study was to provide an overview of hypersensitivity cross-reactions among MLSs based on data extracted from the French National Pharmacovigilance Database (FPVD). Cases of HSR to MLSs reported between January 1985 and December 2019 were extracted from the FPVD using standardized MedDRA queries (SMQ). Cases including an allergological test involving multiple MLSs and giving at least one positive result were included. Of the 8394 cases reviewed, 149 were included. HSR mainly involved pristinamycin (n= 83; 53.2%) and spiramycin (n= 31; 19.9%). HSR to MLS was immediate in 54 cases and delayed in 94 cases. Skin tests represented the majority of the allergological tests performed (n= 728; 84.7%), followed by reintroduction tests (n= 79; 9.2%). Eighty-six cross-reactivities among MLS were identified in 62 cases (41.6%). All the 25 explorations performed for streptogramins showed cross-reactivities, but only 30/253 among macrolides (11.9%). Cross-reactivities between the three MLS were observed in 31/322 (9.6%) of the allergological explorations. This study highlights the possibility of cross-reactivity among and between MLSs. Dermatologists and allergologists managing patients with HSR to MLSs should be aware of a risk of cross-reactivity among the macrolides and between the different classes of MLS and to perform MLSs allergological testing before recommending an alternative antibiotic, especially in severe drug hypersensitivity from the MLS family.

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

Due to its psychoactive effects, ketamine has become a drug used for non-medical purpose. 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. 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. 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. The trend observed over 10years 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.

Medication-overuse headache: A pharmacovigilance study in France

Overusing medication for primary headaches or other medical conditions can lead to dependency and medication-overuse headache (MOH) as an adverse drug reaction (ADR). To analyse reports of ADRs associated with MOH recorded in the French national pharmacovigilance database (FPVD). This retrospective study selected all MOH cases reported in the FPVD from January 2000 to June 2023. A search of the High-Level Group Term "headache" was performed for drugs classified under ATC codes for the musculoskeletal and nervous systems. Specific keywords were searched in report narratives to further reduce their number. Voluntary intoxication reports were excluded. Only MOH cases according to the International Classification of Headache Disorders or with a medical diagnosis of MOH were considered. Among the 2674 reports associated with the HLGT "headache", for 649 ATC drug codes, only 234 reports correspond to MOH, primarily notified by physicians. The median age was 45 years (IQR: 32-56), with 74.4% females and approximately 61.0% having pre-existing primary headaches. In all, 53.4% of the reports were classified as serious. Among patients, 84.2% had an isolated "headache" as the ADR. One drug was suspected in 47.4% of cases, two drugs in 29.1%, and three or more in 23.5%. In total, 473 suspected drugs, corresponding to 104 active ingredients, were involved, including analgesics (63.0%), in particular, acetaminophen-containing drugs, opioids, triptans and ergots, and non-steroidal anti-inflammatory drugs (12.7%). Antiepileptics and psycholeptics were found in 6.6% and 6.1% of cases, respectively. Drug withdrawal was successful in 84.6% of drug-discontinuation cases. Warnings about MOH are mentioned in the summary of product characteristics (SmPCs) for triptans, ergots, and certain acetaminophen-containing drugs, but not other drug classes. Certain drug classes show a high reporting rate of MOH and caution should be exercised when prescribing these drugs. Notably, warnings about MOH must be mentioned in the SmPC of all concerned drug classes.

Idiopathic intracranial hypertension secondary to fluoroquinolone therapy: French pharmacovigilance data review.

We investigate spontaneous reports of IIH related to fluoroquinolones recorded in the French national pharmacovigilance database in order to detect a possible pharmacovigilance signal. The association between IIH risk and fluoroquinolone exposure was assessed using a case/non-case study. Between 1985 and July 2023, 17 reports of IIH after fluoroquinolone exposure were recorded. No specific fluoroquinolone was predominant. IIH led to death in one case and blindness in one case. The Reporting Odds Ratio was 2.58 (95% confidence interval 1.59-4.19). We highlight statistically significant disproportionality, which constitutes a pharmacovigilance signal. IIH risk after fluoroquinolone exposure is a class effect.

Statins and immune-mediated necrotizing myopathy: Variability in the risk

Immune-mediated necrotizing myopathy (IMNM) is a form of statin myopathy characterized by the presence of antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti HMGCR). The aim of this study was to investigate the relationship between the different statins and the risk of IMNM. A two-time approach was used. First, we performed a descriptive analysis of the French national pharmacovigilance database (FNPV) for the period from 1985 to december2020. To identify relevant cases, we used Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) related to IMNM. We performed a quantitative and qualitative review of individual case safety reports (ICSRs) recorded in the french vigilance spontaneous reporting system. In a second time, we performed a comparative analysis with the World Health Organization global individual case safety reports database (Vigibase). The association between IMNM and statins exposure was assessed by calculating the reporting odds ratio (ROR) and its 95% confidence interval. After analysis, a total of 25 ICSRs were related to IMNM in the FNPV. The suspected statins were atorvastatin (n=21), simvastatin (n=2), pravastatin (n=1) and rosuvastatin (n=1). In Vigibase, 567 notifications were identified. A significant ROR value was found for atorvastatin, pitavastatin, simvastatin, pravastatin and rosuvastatin. Atorvastatin presents the highest risk of IMNM. Our data suggest that the occurrence of IMNM is a class effect.

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.

Nirmatrelvir/ritonavir (Paxlovid®): French pharmacovigilance survey 2022

Nirmatrelvir/ritonavir (Paxlovid®) is currently one of the few therapeutic options for coronavirus disease 2019 (COVID-19) curative treatment in non-oxygen-requiring adult patients at-high risk of progressing to severe disease. This recently approved boosted antiviral therapy presents a significant risk of drug-drug interactions (DDI). As part of the enhanced surveillance program in France for COVID-19 drugs and vaccines, the French national pharmacovigilance database (BNPV [base nationale de pharmacovigilance]) was queried in order to better characterize the drug safety profile, with a special focus on DDI. The aim of the study was to describe the adverse drug reactions reported through the BNPV. All nirmatrelvir/ritonavir reports validated in the BNPV from the first authorization in France (January, 20th 2022) to December, 3rd 2022 (date of the query) were considered. An analysis of the scientific literature (PubMed®) and from the WHO pharmacovigilance database (Vigibase) was also performed. Over this period (11 months), 228 reports (40% of serious reports) were registered with a sex ratio of 1.9 female/1 male and a mean age of 66 years old. DDI reports account for more than 13% of reports (n=30) and were mainly related to immunosuppressive drugs overexposure (n=16). A total of 10/228 reports with fatal outcomes were reported in complex clinical settings. The main reported unexpected adverse drug reaction (ADRs) were high blood pressure (n=7), confusion (n=5), acute kidney injuries (AKI, n=7) and various skin reactions (n=22). Apart from situations of disease recurrence (not found in this analysis), data from Pubmed® and Vigibase also reported the above-mentioned events of interest. Overall, this analysis shows that nirmatrelvir/ritonavir safety profile was conform to current summary of product characteristics (SmPC). The main concern was the risk of DDI. Therefore, SmPC and expert recommendations should be systematically consulted before initiation of this antiviral, which is particularly indicated in polypharmacy patients. A case-by-case multidisciplinary approach including a clinical pharmacologist is required in these complex situations. Blood pressure elevation, confusion, cutaneous reactions and AKIs were the main unexpected ADRs of interest to follow, but need to be confirmed with a qualitative approach over time and new reports.

Patient involvement in pharmacovigilance: determinants and evolution of reporting from 2011 to 2020 in France

IntroductionBecause patients and patient organizations want to strengthen their role in the care pathway and drug evaluation and in order to improve pharmacovigilance activities, European competent authorities implemented regulations to allow direct reporting of adverse drug reactions related to medicinal products by patients in 2012.ObjectivesTo describe evolution and analyze determinants of patient reporting activity in France in order to assess patient involvement in pharmacovigilance.MethodUsing the French national pharmacovigilance database, univariate and multivariate analyses were performed to compare the characteristics of adverse drug reaction (ADR) reports from patients and healthcare professionals (HCP) between 2011 and 2020. The relationship between regional patient ADR report activity and regional care provision and socio-professional characteristics was analyzed using the principal component analysis.ResultsA significant and higher increase in ADR reports over time from patients (r = 0.89, p < 0.001) compared to HCP (r = 0.27, p = 0.002) has been observed. Patient ADR report activities compared to HCP concerned more women (80% vs. 55%, p < 0.001), younger age classes (p < 0.001), reporting through web portal (83% vs. 17%, p < 0.001), and less serious events (26% vs. 63%, p < 0.001). In the principal component analysis, regional patient reporting activity was related to socio-professional categories, age classes, and densities of hospital beds and physicians.ConclusionOur results confirm an increasing involvement of patients in ADR report activities. The determinants of patient reporting activities are not only related to drug and medical factors but also to social factors. Digital tools may also play a role in health democracy in pharmacovigilance.

Adverse drug reaction related to drug shortage: A retrospective study on the French National Pharmacovigilance Database.

Drug shortages are a growing global health issue. The aim of the study was to evaluate the consequences of drug shortages on patient safety based on data recorded in the French National Pharmacovigilance Database. All cases involving drug shortages reported from 1985 to the end of 2019 were extracted from the database. Following the selection process, 462 cases were included. The number of cases increased significantly from 2004 to 2019. Cases mainly involved drugs from the nervous system (22.1%, 95% confidence interval [CI] 17.5-27.0%), the cardiovascular system (16.4%, 95% CI 11.9-21.4%) and anti-infectives for systemic use (14.3%, 95% CI 9.7-19.2%) ATC classes. Most of the cases reported an adverse drug reaction (ADR) belonging to the SOC nervous system (21%, 95% CI 18-24%), skin and subcutaneous (14%, 95% CI 11-17%), general (13%, 95% CI 10-17%) and gastrointestinal (8%, 95% CI 5-11%) disorders. Disease worsening was observed in 15.9% of the cases, mostly related to a lack of efficacy of the replacement drug. Half of the cases were considered as serious. Evolution was favourable in 79.4% of the cases. Death and/or life-threatening situations were reported in 5.8% of the cases. Medication errors (MEs) were identified in 51 cases (11%), mostly occurring at the administration step and involving a human factor. This study emphasizes the clinical impact of drug shortage in terms of ADRs, ME and inefficiency. These observations underline the importance of a global health policy programme to limit the occurrence of drug shortages and to reinforce the information provided to patients and health care professionals in this context to limit risk.

Intravenous and subcutaneous immunoglobulins-associated eczematous reactions occur with a broad range of immunoglobulin types: A French national multicenter study

Human immunoglobulins are used for treating diverse inflammatory and autoimmune disorders. Eczema is an adverse event reported but poorly described. To describe the clinical presentation, severity, outcome, and therapeutic management of immunoglobulin-associated eczema. This retrospective and descriptive study included a query of the French national pharmacovigilance database, together with a national call for cases among dermatologists. We included 322 patients. Eczema occurred preferentially in men (78.9%) and in patients treated for neurological pathologies (76%). The clinical presentation consisted mainly of dyshidrosis (32.7%) and dry palmoplantar eczema (32.6%); 5% of cases exhibited erythroderma. Sixty-two percent of the eczema flares occurred after the first immunoglobulin course. Eczema was observed with 13 intravenous or subcutaneous immunoglobulin types and recurred in 84% of patients who maintained the same treatment and in 68% who switched the immunoglobulin type. After immunoglobulin discontinuation, 30% of patients still had persistent eczema. Retrospective study, with possible missing data or memory bias. Immunoglobulin-associated eczema occurred with all immunoglobulin types, preferentially in patients with neurologic diseases who required prolonged immunoglobulin treatment. Recurrence was frequent, even after switching the immunoglobulin type, which can lead to a challenging therapeutic situation when immunoglobulin maintenance is required.

Use of the Capture-Recapture Method to Estimate the Frequency of Community- and Hospital-Acquired Drug-Induced Acute Kidney Injuries in French Databases.

Drug-induced acute kidney injury (AKI) can occur both in primary care (i.e., community-acquired AKI (CA-AKI)) and in hospital settings (i.e., hospital-acquired AKI (HA-AKI)). The reported prevalence of these events varies markedly from one study to another, mainly due to differences in the study design. To estimate the frequency of drug-induced AKIs (both CA-AKIs and HA-AKIs) observed in a French university hospital, we applied the capture-recapture method to 1) the French national pharmacovigilance database (FPVD) and 2) a cohort of hospitalized patients with drug-induced AKIs (documented by analyzing the French national hospital discharge database and the patients’ electronic medical records). Drug-induced AKIs were determined according to the Naranjo algorithm and then categorized as CA-AKIs or HA-AKIs. A total number of 1,557 episodes of AKI were record during the study period, of them, the estimated total number of drug-induced AKIs was 593 [95% confidence interval (CI): 485–702], and the estimated prevalence was 38.1% [95%CI: 35.67–40.50]. The prevalences of HA-AKIs and CA-AKIs were similar (39.4% [36.24–42.54] and 37.4% [33.67–41.21], respectively). Only 6.1% of the drug-induced AKIs were recorded in the FPVD, and the proportions of recorded HA-AKIs and CA-AKI differed markedly (3.0% vs. 10.5%, respectively). One of the most frequently involved drug classes were antibiotics in the HA-AKI subgroup (13.0%) and antineoplastics in the CA-AKI subgroup (8.3%). Application of the capture-recapture method to two incomplete data sources can improve the ability to identify and quantify adverse drug reactions like AKIs. The frequency of drug-induced AKI is relatively high and is probably underestimated. The clinical management of an AKI might depend on where it originated.

Bleeding risk of intramuscular injection of COVID‐19 vaccines in adult patients with therapeutic anticoagulation

Bleeding risk of intramuscular injection of COVID‐19 vaccines in adult patients with therapeutic anticoagulation

Utilisation de TRUVADA® en prophylaxie préexposition : analyse des bases de vigilance et revue de la littérature

Pre-exposure prophylaxis (PrEP) is a combination of antiretroviral regimen, tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) that has been shown to prevent HIV transmission. It had been regulated through a temporary recommendation use since December 2015 and had marketing authorization in France since March 2017. As, this product is proposed for adults and adolescents safe from HIV but at high risk of infection, the question is to know if there is a safety concern about this use. A request has been made in the French national pharmacovigilance database (ANPV) and VIGILYZE for an extraction of all cases containing TDF/FTC as suspect drugs in PrEP use. In the second part, we did a literature review in PubMED with MeSH terms and an analysis of the results of the American, English and French initial clinical trials was performed. In both database, 808 cases correspond to an indication of HIV prexposure prophylaxis who represent 2058 adverse effects (AEs) mainly distributed in gastro-intestinal disorders (38.5%), general disorders (16.8%) and 62 cases of seroconversion. We identify 24% of unexpected AEs including 12% of serious AEs in the French database. In literature review, there are no unexpected AEs published, the AEs are mainly gastro-intestinal disorders. There was no significant difference in the AE profile compared to the HIV-infected population treated with TDF/FTC. Data from the ANPV, combined with data from the worldwide pharmacovigilance database, show that the most commonly observed AEs are gastrointestinal, mainly nausea, vomiting and diarrhea. A significant number of asthenia and fatigue are also observed. These AEs are well described in the SMPc. However, we have little data, which can be explained by a probable under-reporting of AEs. We identify 24% of unexpected and potentially serious adverse effects in France mainly among chemsex users. Based on these results, our study confirms the safety of PrEP.

Psoriasis risk after beta-blocker exposure: Description of a pharmacovigilance signal.

We aimed to investigate French pharmacovigilance data. The objective was to characterize psoriatic conditions that occurred after beta-blocker (BB) exposure and bring to light a possible pharmacovigilance signal. Spontaneous reports of psoriatic conditions recorded in the French National Pharmacovigilance Database (FPVD) between 1985 and 2019 were extracted. We performed a retrospective, descriptive analysis of reports linked to BB exposure. Association between psoriasis risk and BB exposure was assessed using a case/noncase study. Two hundred and twenty-five reports of psoriatic conditions after BB exposure were recorded in the FPVD during the study period. Both cardioselective and noncardioselective, topical and systemic BBs are involved. Therapeutic indication of BB was mainly hypertension. Mean time to onset was 5months and outcome was favourable in 68% after BB discontinuation. These features were concordant with those of literature reports. The reporting odds ratio (ROR) was 8.95 (95% confidence interval 7.75-10.33). We highlighted a statistically significant disproportionality which constitutes a pharmacovigilance signal. Psoriasis risk with BBs is a class effect. Increasing surveillance during the first year of BB exposure is needed.

De novo and relapsing necrotizing vasculitis after COVID-19 vaccination.

ABSTRACTWe describe five cases of severe necrotizing vasculitis following the RNA-based vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including four relapsing anti neutrophil cytoplasmic antibodies (ANCA) vasculitis, 27 days (1–60) after vaccination and one patient with quiescent chronic hepatitis B and de novo polyarteritis nodosa (PAN) 21 days after vaccination. Ten other cases were reported to the French national pharmacovigilance database: six patients with ANCA-associated vasculitis and four patients with PAN (first symptoms 19 days on average after vaccination). Five of these 10 patients developed kidney dysfunction. In conclusion, coronavirus disease 2019 (COVID-19) vaccines can be associated with de novo or recurrent ANCA vasculitis or PAN. Attention should be paid to patients with known ANCA vasculitis or patients with a history of hepatitis B infection.

Safety of Cyproheptadine, an Orexigenic Drug. Analysis of the French National Pharmacovigilance Data-Base and Systematic Review.

Objectives: Cyproheptadine is a first-generation H1-antihistamine drug first that was distributed in the 1960s. While its orexigenic effect was observed early, cyproheptadine is not yet authorized for this indication in all countries today. There is an increasing medical interest and demand for the orexigenic effect of cyproheptadine, especially in children with poor appetite. As cyproheptadine might be evaluated in future clinical trials, we wanted to assess its safety profile.Methods: Using the French national pharmacovigilance database, we retrospectively analyzed all pediatric and adult reports of adverse effects of cyproheptadine recorded since its first distribution in France. Next, we performed a systematic review of the literature of cyproheptadine adverse effects.Results: Since 1985, 93 adverse effects were reported in the French pharmacovigilance database (adults 81.7%, children 18.3%); these were mainly neurological symptoms (n = 38, adults 71%, children 28.9%), and hepatic complications (n = 15, adults 86.7%, children 13.3%). In the literature, the most frequent adverse effect reported was drowsiness in adults or children, and five case reports noted liver complications in adults. We estimated the frequency of hepatic adverse effects at 0.27 to 1.4/1000, regardless of age.Conclusion: Cyproheptadine can be considered a safe drug. Mild neurological effects appear to be frequent, and hepatotoxicity is uncommon to rare. Randomized controlled trials are needed to evaluate the safety and efficacy of cyproheptadine before authorization for appetite stimulation, especially in young children as studies at this age are lacking. Possible hepatic complications should be monitored, as very rare cases of liver failure have been reported.

Delayed thrombocytopenia following administration of abciximab: Pharmacovigilance survey and literature review

Abciximab (ABX) is used for acute coronary syndrome and unstable angina. Thrombocytopenia is a frequent adverse effect described as occurring in the first 24hours. The aim of this study was to evaluate, in a context of pharmacovigilance survey, the occurrence of delayed thrombocytopenia following ABX infusion in pharmacovigilance database reports and in the literature. Individual case safety reports (ICSRs) of delayed thrombocytopenia-between 3 and 30 days - with ABX presented as a single suspect were selected in VigiBase®, the WHO global database of ICSRs. The French cases were then extracted from the French national pharmacovigilance database. In addition, a literature review of published cases was performed using PubMed. Among the 84 ICSRs selected from VigiBase®, 43 were also reported in the FPVD. Mean age was 60.1±12.3 years with a majority of male patients (77.4%). The average time to onset (TTO) was 8.9±5.2 days. Thrombocytopenia regressed in 5.1±2.7 days. Haemorrhagic complications were reported in 15% of ICSRs. In the French cases, the median nadir of platelet count was 28×109/L (range 1-110) with a majority of grade 4 thrombocytopenia (39.5%). The literature review identified 42 cases and provided additional information on administered therapies, which include platelet units, corticosteroids, and IV immunoglobulins. GPIIb/IIIa-ABX complex antibodies were described in 26 published cases. Delayed thrombocytopenia, probably due to immune reaction, is a possible life-threatening adverse effect of ABX with a mean TTO of 9 days, supporting the recommendation of a platelet count monitoring during at least two weeks. This recommendation was added to the abcximab SmPC in 2019.

Reply to Yan and Muller, "Captisol and GS-704277, but Not GS-441524, Are Credible Mediators of Remdesivir's Nephrotoxicity".

We thank Yan VC and Muller FL (1) for taking their valuable time to comment on our article.….

Calcium channel blocker exposure and psoriasis risk: Pharmacovigilance investigation and literature data

Evidence regarding a possible association between psoriatic manifestations and use of calcium channel blockers (CCBs) is sparse. Currently, psoriatic manifestations are not listed in the summary of product characteristics (SmPC) of CCBs. In this context, we aimed to investigate the association between psoriasis and CCB exposure. We reviewed spontaneous reports recorded in the French national pharmacovigilance database (FPVD) between 1985 and 2019. The association between CCB exposure and risk of psoriasis was assessed using the case/non-case method. We also analyzed literature data. Ninety-four reports of psoriatic manifestations after CCB exposure were recorded in the FPVD. Both induction and exacerbation cases were observed. Time to onset was less than 2 years in 64% of reports and outcome was favorable in 71% of reports after CCB discontinuation. These features were concordant with those of literature reports. The reporting odds ratio (ROR) was 2.45 (95% CI 1.99-3.02). Concomitant use of betablockers or angiotensin II receptor blockers did not interact with the association between CCB exposure and psoriasis risk. The ROR for the stratum "use of angiotensin converting enzyme inhibitors" (ACEI) was 2.14 (95% CI 1.29-3.55), while the ROR for the stratum ACEI non-use was 0.12 (95% CI 0.10-0.15). Large-scale epidemiologic studies were focused only on first diagnoses and did not include exacerbations; psoriasis risk was therefore probably underestimated. We found a statistically significant association between CCB exposure and psoriasis risk, which constitutes a safety signal. This risk is a class effect, time to onset is mostly less than 2 years and outcome is favorable after CCB discontinuation. Psoriasis should be mentioned in the SmPCs of all CCBs, and healthcare workers should be aware of this risk. Attention should be paid to patients taking CCB and ACEI concomitantly.

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

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. 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. 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. 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.