Neurocognitive Disorders Associated with PCSK9 Inhibitors: a Pharmacovigilance Disproportionality Analysis.

PURPOSE: PCSK9 might affect central nervous system development, neuronal apoptosis, and differentiation. We investigate the neurocognitive adverse events associated with the use of PCSK9 inhibitors (alirocumab and evolocumab) using pharmacovigilance reports. METHODS: We used the World Health Organization pharmacovigilance database (VigiBase) to perform a disproportionality analysis comparing the proportion of neurocognitive adverse events reported with PCSK9 inhibitors versus the proportion of these effects reported since August 14, 2015 (date of first post-marketing report suspecting a PCSK9 inhibitor), for all drugs in the database. Associations between PCSK9 inhibitor use and neurocognitive adverse events were assessed using both proportional reporting ratio (PRR) and information component (IC). Complementary analyses were performed on other neurologic events, and different sensitivity analyses were conducted to evaluate the robustness of results. RESULTS: Among the 81,108 reports involving at least one PCSK9 inhibitor, 1,941 concerned the occurrence of neurocognitive disorders. Most of patients (52.3%) were aged 45-74 years, and 58.0% were women. Signals of disproportionate reporting were found for PCSK9 inhibitors (PRR 1.22, 95% CI 1.17; 1.28; IC 0.28, IC025 0.21) and for each drug individually. No signal of disproportionality was found for any of the other neurologic events investigated. Signals of disproportionate reporting were found for the positive control (benzodiazepines), but not for the negative control (aspirin). The results of the main analysis were confirmed by sensitivity analyses. CONCLUSIONS: This study identified a signal of neurocognitive disorders associated with PCSK9 inhibitors and encourages paying attention to at-risk populations.

Drug reaction with eosinophilia and systemic symptoms may occur within 2 weeks of drug exposure: A retrospective study.

BACKGROUND: Diagnosing drug reaction with eosinophilia and systemic symptoms (DRESS) is challenging. Some clinicians reject this diagnosis when the delay of onset is less than 15 days after drug intake. OBJECTIVES: To assess the delay of DRESS occurrence and culprit drugs. METHODS: All patients hospitalized in 3 dermatology departments with a first occurrence of DRESS for which a drug was highly suspected were included in this retrospective study. Based on the delay in DRESS occurrence, cases were classified into 2 groups: a rapid-onset group (≤15 days after exposure) and a delayed-onset group (>15 days). RESULTS: A total of 41 patients with DRESS were included: 14 in the rapid-onset and 27 in delayed-onset groups. In the rapid-onset group, antibiotics (n = 6/14) and iodinated contrast media (n = 5/5) were the predominant culprits. Carbamazepine (n = 4/4), lamotrigine (n = 6/6), allopurinol (n = 8/8), and sulfasalazine (n = 2/2) were exclusively found in the delayed-onset group. LIMITATIONS: The retrospective nature, limited number of participants, and lack of detailed information on previous exposure to sensitizing drugs in some instances. CONCLUSIONS: DRESS is frequently related to drugs introduced 15 or fewer days before the occurrence of cutaneous adverse reactions. The time of onset of DRESS may differ depending on the medications involved.

Immediate-Type Hypersensitivity Cross-Reactions to Proton Pump Inhibitors: A Descriptive Study of Data from the French National Pharmacovigilance Database.

BACKGROUND: Proton pump inhibitors (PPIs) can trigger immediate-type hypersensitivity reactions (HSRs). Three main patterns of cross-reactivity have been identified: reactions to a single PPI, selective cross-reactions, and cross-reactions with all PPIs. Several hypotheses have been advanced, but no consensus has been reached. OBJECTIVE: We sought to identify immediate-type hypersensitivity cross-reactions to PPIs using real-world data about hypersensitivity testing from French pharmacovigilance cases. METHODS: Potentially relevant immediate-type HSRs reported from January 1985 to February 2015 were extracted from the French pharmacovigilance database using a standardized MedDRA query (SMQ). Cases describing skin tests or oral provocation tests (OPTs) performed with several PPIs that yielded at least one positive result were included. RESULTS: The SMQ extracted 2,119 cases, 38 of which were included in our study. Data collected from skin tests and OPTs indicated cross-reactions with all PPIs (n = 1), reactions to a single PPI (n = 14), or selective cross-reactions (n = 23). Esomeprazole, omeprazole, and pantoprazole concerned 78% of all selective cross-reactions. In more than half of the cases (55.3%), only 2 PPIs were tested. CONCLUSION: To the best of our knowledge, this PPI cross-reactivity study is the largest to date in terms of population size, describing 38 immediate-type HSRs to PPIs explored by skin tests or OPTs. This paucity of data belies the lack of standardized procedures for PPI hypersensitivity testing. It is likely that PPI HSR workups in everyday clinical practice are often incomplete. Further research to gain insight into selective cross-reactions between PPIs is needed. In the meantime, thorough workups should be completed when a PPI is suspected to have triggered an HSR, instead of routine contraindication to all PPIs.

[MEOPA use practices in a university hospital: Which conformity?] / Pratiques d'utilisation du MEOPA dans un CHU : quelle conformité ?

INTRODUCTION: MEOPA (equimolar mixture of oxygen and nitrous oxide) is used for its analgesic and anxiolytic properties in order to obtain conscious sedation of the patient when performing painful care. It is subject to an enhanced pharmacovigilance and addictovigilance monitoring. In this context, it is important to dispose of hospital utilization data. This work aims to assess the compliance of the use of nitrous oxide regarding the recommendations of the summary of product characteristics, in a French university hospital (Nantes) and consider possible improvements. MATERIALS AND METHODS: Transversal descriptive study, conducted in 2014 with all health professionals using MEOPA. RESULTS: Two thousand thirty-four health professionals answered the questionnaire ; durations of administrations are in conformity and the premises are generally appropriate but almost 60% of professionals have the feeling of inhaling the drug. The systematization of the prescription (always or almost always prescribed for 67% of professionals) and traceability of use (always or almost always in the patient's file for 71% of professionals) are potential source of improvement, particularly since 18% of professional health reported "abuse demands" from patients. CONCLUSION: The formation and information of health professionals are major issues of good use of nitrous oxide.

Adverse Drug Reactions in Pediatric Emergency Medicine.

BACKGROUND: The pediatric population displays its own pharmacological characteristics, making children vulnerable to adverse drug reactions (ADRs). OBJECTIVE: To determine the incidence of ADRs among the pediatric emergency department (PED) population. METHODS: This is a descriptive, noncontrolled, prospective, and single-center study, during 4 consecutive months in the PED of Nantes University Hospital. RESULTS: Setting up active gathering of data on ADRs enabled 121 reports of 11 095 consultations at the emergency department, which corresponds to an ADR incidence of 1.09%. Digestive and cutaneous reactions made up the majority of reactions judged as being nonserious (53%) and were mainly found in children between 2 -11 years old. Of the serious ADRs, 25% were found in the 12-15-year-old age range because of the drug overdose. The main medications administered, which were responsible for the majority of the ADRs, were an equimolar mix of oxygen and nitrogen monoxide, amoxicillin, and acetaminophen. Three means of collecting data were possible: collecting files data, oral communication, or filling a form, the last being the most used method. CONCLUSIONS: This active data gathering shows the incidence and nature of the adverse effects as well as the age distribution in the PED population. It highlights the considerable misuse of medications among young teenagers and the high incidence of overmedication in the younger age group. This work also revealed the need for a better reporting system. Future joint studies should be carried out between clinical and pharmacological departments to optimize communication and the correct use of medications in children.

Adverse drug effect in the context of drug shortage: the CIRUPT prospective study from the French pharmacovigilance network.

OBJECTIVES: Drug shortages are of increasing concern to worldwide public health. The consequences of drug shortages for patient safety have been little studied, especially from a pharmacovigilance point of view. In this context, the network of French pharmacovigilance centres conducted the CIRUPT study (Conséquences Iatrogènes des RUPTures de stock/iatrogenic consequences of drug shortages) based on a prospective campaign of adverse effects occurring in the context of drug shortage notifications. METHODS: All notifications involving a shortage drug submitted to the French pharmacovigilance centres between 1 January 2020 and 30 June 2021 were collected and registered in the French national pharmacovigilance database with the standardised high level term 'product supply and availability issues' and with predefined keywords in the narrative section. RESULTS: 224 cases were included, involving mainly adverse drug reactions (ADRs) (n=131/224, 59%) and medication errors (n=51/224, 23%); 29% of the cases were serious. The most represented classes of shortage drugs were: vaccines (n=78/224, 35%); drugs for acid-related disorders (H2-receptor antagonists) (n=27/224, 12%); antineoplastic agents (n=17/224, 8%); and antiepileptics (n=15/224, 7%). In 82% of cases, the involved shortage drug was the subject of information delivered to health professionals by the National Agency for the Safety of Medicines and Health Products. Drug shortages were associated with an ADR related to replacement drugs in 59% (n=131/224) of the cases, drug inefficacy in 18% (n=41/224), and/or an aggravation of the underlying disease in 11% (n=25/224). CONCLUSIONS: From a pharmacovigilance point of view, a large diversity of anatomical therapeutic classes is involved and the risk related to drug shortages is not limited to drugs registered on 'major therapeutic interest or essential drug' lists. Information from health agencies is not sufficient to avoid the risks, and further strategies should be developed.

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.

Anti-tumour necrosis factor alpha therapy and increased risk of de novo psoriasis: is it really a paradoxical side effect?

OBJECTIVES: Tumour necrosis factor (TNF) alpha inhibitors (infliximab, etanercept, adalimumab) revolutionised the treatment of autoimmune diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD) and plaque psoriasis. During these treatments, cutaneous adverse effects may occur like eczema, lupus, alopecia areata or psoriasis, which represents a paradoxical adverse effect. The aim of this study was to collect and to analyse characteristics and outcomes of psoriasis induced by anti-TNF alpha treatments. METHODS: A search in the French Pharmacovigilance Database was performed between January 2002 and September 2009 using the following terms 'infliximab', 'etanercept', 'adalimumab' combined with the term 'psoriasis'. A literature review was performed utilising PubMed Database and Google scholar using permutations of the following terms 'infliximab', 'etanercept', 'adalimumab', 'tumour necrosis factor-α inhibitor' combined with 'psoriasis', 'palmoplantar pustular psoriasis', palmoplantar pustulosis'. Certolizumab pegol and golimumab were approved only recently and so were not included in the search. RESULTS: We found 57 cases in the French Pharmacovigilance Database and 184 cases in the literature. It appeared that the eruptions are most often pustular lesions and occur mainly on palms and/or soles (33.3% in the French Pharmacovigilance Database and 42.9% in the literature), while palmoplantar pustular psoriasis represents only 1.7% of the psoriatic patients. The three anti-TNF-alpha are involved in the psoriasis induction. Half the cases appeared with infliximab. The patients affected by this adverse effect are mostly women aged between 40-50 years old. The time of onset of psoriasis is highly variable. Those patients treated for their psoriasis with TNF-alpha inhibitor developed a psoriasis induced by the treatment with a different localisation and a different morphology from the initial psoriasis while other patients had a recurrence of this side effect with two different TNF-alpha antagonists, then the psoriasis developed with the 2nd anti-TNF alpha is of the same type as the psoriasis developed with the first molecule. CONCLUSIONS: This suggests that psoriasis occurring during anti-TNF alpha therapy are de novo psoriasis and not an aggravation of a pre-existing psoriasis. To this day several hypotheses have been proposed to explain the mechanism of action. The occurrence of this adverse effect may call into question the continuation of the treatment which is nevertheless effective.

Safety concerns on the abuse potential of esketamine: Multidimensional analysis of a new anti-depressive drug on the market.

Prominent features of esketamine (e.g., similar mechanism of action as ketamine and target population) require to be vigilant regarding its benefits/risks balance and its risks of abuse in real-life settings. The aim of this study was to review all available pharmacological and clinical data to assess the abuse potential of esketamine shortly after its marketing. This multidimensional study is a quantitative and qualitative analysis of complementary data sources, ranging from preauthorization data (i.e., fundamental pharmacology and clinical trials) to real-life settings data (i.e., pharmacovigilance databases and web forums). According to esketamine pharmacology, its psychoactive effects play a role both in its therapeutic effect and its abuse potential. Only one out of the three short-term efficacy trials found a significant difference between esketamine and placebo in treatment-resistant depression. Beside adverse events that may be sought for abuse purpose (e.g., dissociation, sedation, euphoric mood, hallucination, feeling drunk, and derealization), clinical signs related to substance use disorder (e.g., tolerance, withdrawal syndrome, and drug dependence) and misuse (e.g., off-label use) were also identified in pharmacovigilance databases. Analysis of pharmacovigilance narratives and web forums showed that esketamine psychoactive effects are appreciated by some patients, while they are badly experienced by others. Strict compliance with the market authorization, close monitoring of patients by psychiatrists, and surveillance of any signs of misuse, abuse, or dependence must be part of any treatment course.

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.

[Reactivity and communication of Health Authorities toward health professionals: a public health priority]. / Réactivité et communication des décisions de pharmacovigilance des autorités de santé vers les professionnels de santé: exemples du pergolide et du célécoxib.

OBJECTIVE: evaluate the impact of Health Authorities' communication on medical practices through 2 examples: celecoxib, taking into account the recent countra indication related to cardio vascular risks; pergolide, taking into account the risk of cardiac valvulopathy. MATERIAL AND METHOD: Use of the Pays de Loire Health Insurance Administration data base to monitor the number of cardio vascular patients at risk who receive celecoxib, and cardiac surveillance of pergolide exposed patients. RESULTS: Communication from Health Authorities resulted in a major decrease (71.9%) of the number of risking patients who take celecoxib, and a significant 14% decrease of pergolide treated patients needing cardiac monitoring CONCLUSION: Unlike the information related to pergolide, the information related to celecoxib was fully taken into account. The difference seems to come from the fact that one was widely relayed by medias, not the other.

Bacterial infections and NSAIDs exposure? Seek septic complications.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed. Some authors suggested a relationship between more severe infections and NSAIDs exposure, especially skin and soft tissue infections (SSTI). However, their impact during bacterial infections remains unclear. The aim of the study was to report the severity features of patients having bacterial infection who were exposed to NSAIDs prior to their hospitalisation. Cases of infected patients with these characteristics declared to the pharmacovigilance department of a French university hospital from 1 January 2011 to 31 December 2013 were retrospectively reviewed. Forty-one patients were included, mainly male (61%). Median age was 37years. No underlying disease was noted for 68% of cases. Ibuprofen was the most frequent drug (63%). Self-medication concerned 61% of cases. Respiratory tract, osteoarticular and SSTI were the most frequent infected sites. Patients suffered septic complications: dissemination of infection to more than one site (51%), suppuration (59%), and requirement for invasive procedures (32%). Eleven patients (27%) had severity criteria as usually defined (10 severe sepsis and 1 septic shock) and 30 did not. There was no significant difference regarding the rate of septic complications between the severe and non-severe group. Septic complications frequently occurred in patients with NSAIDs exposure, whether or not there was severe sepsis or shock. Further studies investigating the impact of NSAIDs in bacterial infections should consider the septic complications depicted here as clinically relevant endpoints. Moreover, clinicians should seek those complications in case of bacterial infections and NSAIDs use.

[A case of interstitial lung disease with atorvastatin (Tahor) and a review of the literature about these effects observed under statins]. / Un cas de pneumopathie interstitielle rapporté sous atorvastatine (Tahor) : synthèse des cas publiés sous statines.

The 3-Hydroxy-3-methyl-glutaryl coenzyme A (HGM-CoA) reductase inhibitors, or statins, are competitive inhibitors of the rate-limiting enzyme in cholesterol synthesis. Generally, statins have an excellent safety profile. Elevations of liver transaminases and creatine phosphokinase with myalgia have been associated with the use of HGM-Co A reductase inhibitors, case reports of rhabdomyolysis are rare, most occurring with concomitant use with other drugs such as cyclosporin, fusidic acid and gemfibrozil. We describe here the clinical case of a patient who developed interstitial lung disease as probably a result of the use of statins which particularly increased with long-term atorvastatin treatment. The present review details some case-reports of interstitial lung disease reported under statins in the literature. Few systemic adverse effects such as lupus-like-syndromes and polymyositis have been reported. Recent experimentations have demonstrated that cholesterol is not the only intracellular target of statins but that they also have a potential role in atherosclerosis and in organ transplantation as immunosuppressor agents.

Are adverse drug reaction patterns different between romiplostim and eltrombopag? 2009-2013 French PharmacoVigilance assessment.

BACKGROUND: Romiplostim and eltrombopag, the two marketed thrombopoietin receptor agonists (TPO-RAs), have distinct binding sites and might have distinct pharmacodynamic mechanisms. The aim of this study was to compare their adverse drug reaction (ADR) patterns. METHODS: We selected in the French PharmacoVigilance Database all ADRs associated with TPO-RAs from TPO-RA marketing until the 31st of December 2013. Medical charts were reviewed. We conducted disproportionality analyses comparing romiplostim exposure in the reports of a given ADR pattern (thrombosis, neurological, cutaneous, gastrointestinal or hematological) to romiplostim exposure in all other TPO-RA-related ADR reports. Reporting Odds Ratios (RORs) were adjusted for age and gender. We also compared the number of reports of a given ADR pattern per million daily defined doses (DDDs) dispensed in France during the study period. RESULTS: We described 45 reports (53 ADRs) with romiplostim and 26 reports (37 ADRs) with eltrombopag. There were 19 venous thromboses. At least one other risk factor was present in 83.3% of the cases. Ten (55.6%) patients had been splenectomized previously. There were eight arterial thromboses. Another risk factor was noticed in all cases. There was no signal for an excess risk of thrombosis with romiplostim versus eltrombopag (ROR: 1.45, 95% CI [0.48-4.45]). There was a signal for a higher risk of gastrointestinal ADRs with eltrombopag (ROR: 30.28, 95% CI [3.23-383.86]) and of hematological ADRs with romiplostim (ROR: 14.36, 95% CI [1.73-119.08]). Dispensing data-adjusted comparisons led to similar results. CONCLUSIONS: This study suggests different ADR patterns between romiplostim and eltrombopag.

First case of symmetric drug-related intertriginous and flexural exanthema (sdrife) due to rivastigmine?

The term 'baboon syndrome' was introduced in 1984 to describe a special form of systemic, contact-type dermatitis that occurs after ingestion or systemic absorption of a contact allergen in individuals previously sensitized by topical exposure to the same allergen in the same areas. Its clinical picture presents as an erythema of the buttocks and upper inner thighs resembling the red bottom of baboons. This reaction was originally observed with mercury, nickel, and ampicillin. In 2004, some authors proposed the acronym SDRIFE standing for 'symmetric drug-related intertriginous and flexural exanthema' specifically for cases elicited by systemically administered drugs. Since 1984, about 100 cases have been reported in the literature; for most of the concerned drugs, previous skin sensitization or possible cross-sensitization has not been shown. We report the first case of SDRIFE due to rivastigmine, with the exception of an erythematous maculopapular eruption due to rivastigmine that was previously reported. Rivastigmine is a reversible and noncompetitive acetylcholinesterase inhibitor used for the treatment of Alzheimer disease. SDRIFE is an important condition to keep in mind in order to avoid a misdiagnosis when dealing with other exanthematous disorders and to prevent re-exposure to the responsible allergen in the future.