[Bariatric surgery and drugs: Review of the literature and Adverse Drug Reactions analysis in French National Pharmacovigilance Database]. / Chirurgie bariatrique et médicaments : revue de la littérature et analyse des effets indésirables dans la banque nationale de pharmacovigilance.

INTRODUCTION: Bariatric surgery is the only treatment for severe obesity (BMI>35kg/m2) currently recognized as effective both in achieving tangible and lasting weight loss, and in improving obesity-related comorbidities such as type 2 diabetes, hypertension, and cardiovascular complications. Bariatric surgery, like any other surgery of the digestive tract, can have an impact on nutrient absorption, as well as on drug absorption. The literature on drug management in bariatric surgery patients concerned mainly of case reports and retrospective studies involving a small number of patients. No official guidelines are available. METHODS: We conducted a literature search on the consequences of bariatric surgery in terms of drug bioavailability and/or effect. The Medline® (PubMed) database was searched using the following keywords: "bariatric surgery", "bioavailability", "gastric bypass", and "obesity". We completed this review with an analysis of reports of adverse drug reactions (ADRs) in post-bariatric surgery patients for obesity registered in the National pharmacovigilance database (PVDB). We selected all cases with the mention of "bariatric surgery and/or gastrectomy" as "medical history". After reading the cases, we excluded those in which the patient had undergone surgery for an indication other than obesity, where the route of administration was other than oral, and cases in which ADRs resulted from voluntary overdose, attempted suicide, allergy, switch to Levothyrox® new formulation, meningioma under progestative drugs, inefficacy related to generic substitution and medication error. RESULTS: The literature search identified mainly "case report" about the impact of bariatric surgery on so-called "narrow therapeutic window" drugs. We identified 66 informative cases out of a total of 565 cases selected (11%) in the PVDB. Nevertheless, the information does not allow a clear relationship between the occurrence of the ADR and the influence of bariatric surgery. CONCLUSION: There is a lack of official information and/or recommendations on medication use in subjects who have undergone bariatric surgery. Apart from under-reporting, ADRs reports remain largely uninformative. Health professional and patients would be awareness for improving, quantitatively and qualitatively the reporting of ADRs 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.

Trastuzumab-emtansine induced pleural and pericardial effusions.

INTRODUCTION: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combine trastuzumab (T), a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2), and a cytotoxic molecule derived from maytansine (DM1). CASE REPORT: We report the first case of T-DM1-associated pleural and pericardial effusions three weeks after the second course of T-DM1 in a patient with breast cancer. Drug-induced pleural and pericardial effusions was implicated in the absence of other etiologies. The Naranjo Scale indicated a probable drug-induced adverse reaction.Management & outcome: The patient fully recovered after thoracentesis and discontinuation of T-DM1. The patient has reported no side effect after the sixth course of trastuzumab. DISCUSSION: To our knowledge, this is the first case in the literature of bilateral pleural and pericardial effusions in a patient treated with T-DM1. The successful initiation of treatment with trastuzumab following withdrawal of T-DM1 suggests that emtansine played a role in the development of bilateral pleural and pericardial effusions. We hypothesize that the patient's condition was a result of a local inflammatory reaction to emtansine by direct toxicity.

Leukoencephalopathy with transient splenial lesions related to 5-fluorouracil or capecitabine.

BACKGROUND: 5-Fluorouracil (5-FU) and its oral prodrug capecitabine have been rarely but consistently associated with acute central nervous system toxicity, including transient leukoencephalopathies involving the splenium of the corpus callosum. METHODS: We performed a retrospective search in the French Pharmacovigilance database (FPDB) (January 1985-July 2020) for adult patients affected by solid cancers who developed acute toxic leukoencephalopathies with splenial lesions following treatment with 5-FU or capecitabine. A comprehensive review of the literature helped to circumstantiate our findings. RESULTS: Our research in the FPDB identified six patients who, within 3 days from their first cycle of 5-FU or capecitabine, developed acute neurological symptoms, including gait ataxia (n = 4), dysarthria (n = 3), dysmetria (n = 2), headache (n = 2), and confusion (n = 2). Brain magnetic resonance imaging (MRI) showed T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities in the corpus callosum, with diffusion restriction and no contrast enhancement, generally accompanied by additional alterations in the bilateral supratentorial white matter (n = 5). All patients discontinued the agent supposedly responsible for the toxicity and experienced full recovery after a median of 8.5 days from symptom onset. Control MRI showed a progressive normalization of acute MRI abnormalities. Literature review identified 26 cases with similar clinical and paraclinical characteristics. A single patient from the literature resumed 5-FU at a lower dose, with no recurrent toxicity. CONCLUSIONS: 5-FU and capecitabine might be responsible for acute leukoencephalopathies with transient splenial lesions that are generally reversible upon drug discontinuation. Resuming the agent responsible for toxicity might be feasible in selected cases, after having excluded dihydropyrimidine dehydrogenase deficiency, if expected benefits outweigh the risks.

Adalimumab and myositis: A case report and review of the French and international Pharmacovigilance Databases.

TNFα inhibitors, including adalimumab, are widely used in inflammatory rheumatologic and bowel diseases. Well-known adverse effects include: opportunistic infections, immunogenicity and new inflammatory manifestations. Myositis is an inflammatory disease, which manifests with muscle symptoms and can be life-threatening. Little is known about drug-induced myositis. We aimed to describe a case of myositis induced by adalimumab and reviewed national and international pharmacovigilance databases for other cases until 01/02/2019. This was a 63 years old woman with Crohn's disease, who developed muscle weakness, and rhabdomyolysis 3 months after starting adalimumab. Diagnosis of myositis was suspected and confirmed with electromyography and muscle biopsy. Improvement in muscle symptoms was observed after stopping adalimumab and starting corticosteroids. Muscular adverse effects are well-known and usually benign with adalimumab. However, five cases of myositis during treatment with adalimumab were registered in French PharmacoVigilance Database (FPVD) with muscle symptoms observed 3 months to 7 years after starting adalimumab. In VigiBaseⓇ, 90 cases of myositis associated with adalimumab with some similar characteristics were registered. When a patient treated with adalimumab complains of muscular symptoms, inflammatory myopathies should be considered. This adverse effect should be mentioned in a 'Summary of Product Characteristics' to alert healthcare professionals.

Hypertension induced by serotonin reuptake inhibitors: analysis of two pharmacovigilance databases.

Drug-induced hypertension was described with several pharmacological classes, especially with serotonin reuptake inhibitors (SRIs). However, this link has remained controversial: the French summary of product characteristics specify a risk of hypertension only with paroxetine and sertraline. To identify a possible class effect common to all SRIs, our study investigated the reports of hypertension associated with SRIs in two pharmacovigilance databases. Two different types of investigations were performed: (i) a comparative study in VigiBase® , which is the World Health Organization (WHO) pharmacovigilance database (PVDB), from where notifications of hypertension with six SRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) were extracted. The relationship between the suspected SRIs and the occurrence of hypertension was assessed by calculating reporting odds ratio (ROR) in a case/non-case design; (ii) a descriptive study of hypertension reports associated with SRIs in the French pharmacovigilance database (FPVDB). In VigiBase® , 14 824 notifications of SRI-induced hypertension (2.5%) were identified (mean age 54.3 years, mainly women 69.1%). Among them, 3 879 (26.2%) were associated to sertraline; 3 118 (21.0%) to fluoxetine; 2 725 (18.4%) to paroxetine; 2 570 (17.3%) to citalopram; 2 295 (15.5%) to escitalopram; and 237 (1.6%) to fluvoxamine. A significant ROR value was found with all six SRIs (ROR range from 1.16 to 1.92). In the FPVDB, 24 reports of hypertension were found with all six SRIs used at standard doses, mainly in women (66.7%) with a mean age of 57.8 years and a median time of onset of 6 days. In 10 cases (42%), patients had a history of hypertension. This study, performed in real conditions of life, shows a significant pharmacovigilance safety signal between the use of SRIs and the development or worsening of hypertension.

Preventable and potentially preventable serious adverse reactions induced by oral protein kinase inhibitors through a database of adverse drug reaction reports.

Antineoplastic drugs are one of the pharmacological classes more frequently involved in occurrence of "serious" adverse drug reactions. However, few epidemiological data are available regarding the preventability of adverse drug reactions with ambulatory cancer chemotherapy. We assessed the rate and characteristics of "preventable" or "potentially preventable" "serious" adverse drug reactions induced by oral protein kinase inhibitors (PKIs). We performed a retrospective study with all "serious" adverse drug reactions (ADRs) recorded from 1 January 2008 to 31 December 2009 in the French Pharmacovigilance Database with the eight oral protein kinase inhibitors marketed in France: sorafenib, imatinib, erlotinib, sunitinib, dasatinib, lapatinib, nilotinib and everolimus (Afinitor®) using the French adverse drug reactions preventability scale. This study was carried out on 265 spontaneous notifications. Most of adverse drug reactions were "unpreventable" (63.8 %). Around one third were "unevaluable" due to notifications poorly documented (medical history, dosage, use of drugs as first or second intention, concomitant drugs). One (0.4 %) adverse drug reaction was "preventable" with dasatinib (subdural hematoma) and three (1.1 %) were "potentially preventable" (hepatic adverse drug reactions): two with imatinib and one with sorafenib. For these four cases, we identified some characteristics: incorrect dosages, drug interactions and off-label uses. An appropriate prescription could avoid the occurrence of 1.5 % "serious" adverse drug reactions with oral PKIs. This rate is low and further studies are needed to compare our results by using other preventability instruments and to improve the French ADRs Preventability Scale.